WO2025106920A1 - Agents d'imagerie tep de parp et leurs procédés d'utilisation - Google Patents

Agents d'imagerie tep de parp et leurs procédés d'utilisation Download PDF

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WO2025106920A1
WO2025106920A1 PCT/US2024/056280 US2024056280W WO2025106920A1 WO 2025106920 A1 WO2025106920 A1 WO 2025106920A1 US 2024056280 W US2024056280 W US 2024056280W WO 2025106920 A1 WO2025106920 A1 WO 2025106920A1
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compound
brain
disease
pybic
imaging
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Jason Cai
Jie Tong
PengWen TAN
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Yale University
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Yale University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5217—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data extracting a diagnostic or physiological parameter from medical diagnostic data
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • a compound of Formula (I), or a salt, solvate, tautomer, or stereoisomer thereof is provided: 1 53376748.1 Attorney Docket No.047162-7482WO1(02447)
  • R 1 is H or C1-C6 alkyl comprising at least one 11 C
  • R 2 is H or 18 F
  • R 3 is 11 C or 12 C; wherein the compound comprises at least one of 11 C and 18 F.
  • a compound of Formula (II), or a salt, solvate, tautomer, or stereoisomer thereof is provided:
  • R 1 is H or C1-C6 alkyl comprising at least one 11 C
  • R 2 is 18 F or 19 F
  • R 3 is 11 C or 12 C
  • the compound comprises at least one of 11 C and 18 F.
  • Compounds of Formula (I) and Formula (II) are useful as PET imaging agents. These compounds are especially, but not exclusively, suited for imaging gliomas owing to the advantageous blood-brain barrier (BBB) permeability of the compounds of Formula (I) and Formula (II).
  • BBB blood-brain barrier
  • FIG.1A shows PARP PET tracers derived from the PARP1/2 inhibitors olaparib and rucaparib.
  • Fig.1B shows a radiochemical synthesis of [ 11 C]PyBic, according to various embodiments.
  • Figs.2A-2F show [ 11 C]PyBic PET imaging in RG2 glioblastoma-bearing rats and quantitative data analysis results. Representative horizontal summed PET standard uptake value (SUV) images from 30–60 min p.i.
  • SUV horizontal summed PET standard uptake value
  • FIG.2A Fig.2A
  • FIG.2B blocking scans
  • ROIs regions of interest
  • Fig.2E The regional distribution volume ratios (DVRs) of [ 11 C]PyBic in selected brain subregions and tumors, calculated using the simplified reference tissue method 2 (SRTM2) with the contralateral nontumor region as the pseudo reference region.
  • Fig.2F Radiometabolite analysis of [ 11 C]PyBic in rat plasma and brain homogenate at 60 min p.i.
  • Figs.3A-3D show aspects of the pharmacokinetics of compounds of Formula (I) and Formula (II).
  • Fig.3C Linear correlational analysis of the difference between the tissue-to-blood ratios at baseline and blocking studies and baseline tissue-to-blood ratios. Dots on the graph represent the mean values of each analyzed brain region or tissue, i.e., the olfactory bulb, cerebellum, tumor, contralateral nontumor cortex (nontumor), and spleen.
  • Fig.3D Linear correlational analysis of the results of baseline SRTM2 DVR and biodistribution data on tracer uptake in the cerebellum, nontumor, tumor, and brain stem, normalized by nontumor tracer uptake.
  • Figs.4A-4F show immunohistochemical (IHC) staining and western blotting of PARP1 and correlation analysis with biodistribution and PET results.
  • Fig.4A Representative IHC staining of PARP1 in RG2 tumor-bearing rats.
  • Fig.4B PARP1 IHC in tumor tissue and adjacent normal tissue.
  • FIGs.4C-4D Representative western blotting of PARP1 in selected brain subregions, including the cortex, olfactory bulb, brain stem, cerebellum, hippocampus, and tumor, using a capillary electrophoresis WES system (ProteinSimple).
  • FIG.4C Histogram graph of PARP1 expression. The116 kD band was detected by the PARP1-specific antibody.
  • FIG.4E Correlation of baseline biodistribution and WES on the olfactory bulb, stem, cerebellum, hippocampus, and tumor.
  • FIG.4F Correlation of baseline PET DVR and PARP1 WES in the tumor, cerebellum, cortex, brain stem, and hippocampus.
  • Figs.5A-5E show [ 11 C]PyBic PET imaging and metabolism study in Monkey 1.
  • Figs.6A-6B show in vivo target occupancy assays shown by Lassen plots of VT ⁇ derived from 1 tissue compartment (1TC) modeling in two different monkeys.
  • Fig.6A Lassen plot of V T (baseline) vs the difference in V T (baseline) and V T (blocking) with veliparib as a blocking drug in Monkey 1.
  • Fig.6B Lassen plot of V T (baseline) vs the difference in VT (baseline) and VT (blocking) with veliparib as a blocking drug in Monkey 2.
  • Fig.6C Lassen plot of VT (baseline) vs the difference in VT (baseline) and VT (blocking) with BGB290 as a blocking drug in Monkey 2.
  • the x-intercept is the estimated non- displaceable volume distribution (VND), and the slope is the target occupancy.
  • Fig.7A shows the synthesis of precursor and standard compounds 4 and 5.
  • Fig.7B shows a representative SemiPrep-HPLC chromatogram.
  • Fig.7C shows the HPLC trace of the co-injection of [ 11 C]PyBic and its standard compound 5.
  • Fig.8A shows the synthesis of [ 3 H]PyBic.
  • Fig.8B shows the results of a [ 3 H]PyBic saturation binding assay using rat hippocampus.
  • Figs.11A-11B show that the P-gp inhibitor verapamil did not affect [ 11 C]PyBic uptake in healthy rat brain.
  • P-gp inhibitor verapamil (1 mg/kg) was injected via i.v.10 min before radiotracer administration.
  • Fig.11A is without verapamil and Fig.11B is with verapamil.
  • Fig.12 shows the biodistribution analysis of baseline and blocking (veliparib, 5 mg/kg) at 60 min p.i.
  • Figs.13A-13C shows the results of capillary electrophoresis WES of PARP1 in tumor and normal and adjacent tissues.
  • Fig.13A is a histogram graph of five pairs of normal and tumor tissues.
  • Fig.13B is a classical view of western blotting on the same five pairs of tumor and normal tissues.
  • Figs.14A-14D shows arterial input function studies shown by SUV time activity curves in the same monkey (monkey 2).
  • Fig.14A is a test or retest study.
  • Fig.14B is baseline vs. blocking with veliparib.
  • Fig.14C is baseline vs. blocking with BGB290.
  • Fig.14D is baseline vs. P-gp with tariquidar (1 mg/kg, i.v.).
  • Fig.15 shows VT comparison among 1TCM and MA1 method in the same monkey.
  • Figs.16A and 16B show a comparison of uptake of [ 11 C]PyBic (Fig.16A) vs.
  • FIG.17A shows a representative horizontal summed PET SUV images for 10-20 min and 30–60 min p.i. baseline scans with [ 11 C](R)-FPyBic.
  • Fig.17B shows a representative horizontal summed PET SUV images for 10-20 min and 30–60 min p.i. blocking scans with [ 11 C](R)-FPyBic using veliparib 2.5 mg/kg for blocking.
  • Fig.17C shows representative time active curves (TACs) of different brain regions at baseline scan for the scan in Fig.17a.
  • Fig.17D shows representative time active curves (TACs) of different brain regions at blocking scan for the scan in Fig.17b.
  • Fig.17E shows radio-HPLC chromatograms of plasma samples taken at different time points and the blood standard for [ 11 C](R)-FPyBic.
  • Fig.18A shows a representative horizontal summed PET SUV images for 10-20 min and 30–60 min p.i. baseline scans with [ 18 F](R)-FVeliparib.
  • Fig.18B shows representative ex vivo rat brain AR imaging.
  • Fig.18C shows representative time active curves (TACs) of different brain regions at baseline scan for [ 18 F](R)-FVeliparib.
  • Fig.18D shows radio-HPLC chromatograms of plasma samples taken at different time points and the blood standard for [ 11 C](R)-FPyBic in rat.
  • Fig.18E shows radio-HPLC chromatograms of plasma samples taken at different time points and the blood standard for [ 18 F](R)-FVeliparib.
  • the present disclosure provides in one aspect veliparib-derived PARP PET imaging agents (such as but not limited to [ 11 C]PyBic) that can freely pass the blood-brain barrier and demonstrate imaging characteristics in models of gliomas and healthy primates.
  • veliparib-derived PARP PET imaging agents such as but not limited to [ 11 C]PyBic
  • the in vitro autoradiography study using the tritiated PyBic demonstrated the feasibility of quantifying PARP in human brain using [ 11 C]PyBic.
  • Based on this lead PET tracer one can develop and translate an 18 F-labeled brain penetrant PARP imaging probe to first-in-human study in healthy volunteers and glioma patients.
  • the following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter. Specific examples of components and arrangements are described below to simplify the present disclosure.
  • first and second features are formed in direct contact
  • additional features may be formed between the first and second features, such that the first and second features may not be in direct contact
  • present disclosure may repeat reference numerals and/or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed. 6 53376748.1 Attorney Docket No.047162-7482WO1(02447) Definitions As used herein, each of the following terms has the meaning associated with it in this section.
  • an element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
  • the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited.
  • specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.
  • the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise.
  • the term “or” is used to refer to a nonexclusive “or” unless otherwise indicated.
  • the statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.”
  • “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ⁇ 20% or ⁇ 10%, in certain embodiments ⁇ 5%, in certain embodiments ⁇ 1%, in certain embodiments ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • alkyl refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl 7 53376748.1 Attorney Docket No.047162-7482WO1(02447) groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups.
  • alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • solvent refers to a liquid that can dissolve a solid, liquid, or gas.
  • Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.
  • independently selected from refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise.
  • X 1 , X 2 , and X 3 are independently selected from noble gases” would include the scenario where, for example, X 1 , X 2 , and X 3 are all the same, where X 1 , X 2 , and X 3 are all different, where X 1 and X 2 are the same but X 3 is different, and other analogous permutations.
  • the term “room temperature” as used herein refers to a temperature of about 15 °C to 28 °C.
  • standard temperature and pressure as used herein refers to 20 °C and 101 kPa.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • a disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
  • the terms “co-administered” and “co-administration” as relating to a subject refer to administering to the subject a compound and/or composition of the disclosure along with a compound and/or composition that may also treat or prevent a disease or disorder contemplated herein.
  • the co-administered compounds 8 53376748.1 Attorney Docket No.047162-7482WO1(02447) and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach.
  • the co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.
  • composition refers to a mixture of at least one compound useful within the disclosure with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient.
  • Multiple techniques of administering a compound exist in the art including, but not limited to, subcutaneous, intravenous, oral, aerosol, inhalational, rectal, vaginal, transdermal, intranasal, buccal, sublingual, parenteral, intrathecal, intragastrical, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato star
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the patient.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • pharmaceutically acceptable salt refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.
  • suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic,
  • Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • a “pharmaceutically effective amount,” “therapeutically effective amount,” or “effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.
  • the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • the terms “subject” and “individual” and “patient” can be used interchangeably and may refer to a human or non-human mammal or a bird.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, 10 53376748.1 Attorney Docket No.047162-7482WO1(02447) feline and murine mammals.
  • the subject is human.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound useful within the disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder and/or a symptom of a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder and/or the symptoms of the disease or disorder.
  • a therapeutic agent i.e., a compound useful within the disclosure (alone or in combination with another pharmaceutical agent
  • a therapeutic agent i.e., a compound useful within the disclosure (alone or in combination with another pharmaceutical agent
  • an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications)
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • PARP1 poly(ADP-ribose) polymerase-1
  • BER base excision repair
  • SLB DNA single-strand break
  • DNA damage activates PARP1 towards addition with ADP- ribose, forming a polymeric, energy rich scaffold of poly(ADPribose) (PAR), which is an essential energy source in DNA SSB and BER.
  • PARP inhibitors PARPis
  • PARPis PARP inhibitors
  • olaparib i.e., olaparib (AZD2281), niraparib, rucaparib and talazoparib.
  • Malignant gliomas are highly aggressive tumors with poor prognosis, among which glioblastoma (GBM) is the most aggressive.
  • GBM glioblastoma
  • the 5-year survival rate is only 5% for GBM patients.
  • the rapid infiltration of tumor cells into surrounding tissues limits the complete surgical excision of GBM tumors.
  • BBB blood–brain barrier
  • BBB blood-tumor barrier
  • veliparib has been essentially overlooked as a leading compound for PARP PET tracer development, despite its more desirable characteristics for brain PET imaging, i.e., high brain exposure, fast brain kinetics and less P- glycoprotein (P-gp) efflux from the brain.
  • P-gp P- glycoprotein
  • the in vivo specific binding signals of [ 11 C]PyBic were tested in a rodent GBM model through baseline and blocking studies. Ex vivo metabolite analysis showed no substantive radiometabolites in healthy rat brains. PET imaging results were corroborated by ex vivo biodistribution of [ 11 C]PyBic, western blotting and immunohistochemical staining of PARP1 in selected brain regions and the implanted tumors. Furthermore, the BBB penetration of [ 11 C]PyBic was confirmed using quantitative nonhuman primate (NHP) brain PET imaging. Blocking studies with the structurally analogous veliparib and the structurally distinctive PARPi BGB-290 (Pamiparib) confirmed PARP-specific tracer uptake in NHP brains.
  • NHS quantitative nonhuman primate
  • a compound of Formula (I), or a salt, solvate, tautomer, or stereoisomer thereof is provided:
  • R 1 is H or C1-C6 alkyl containing at least one 11 C atom
  • R 2 is H or 18 F
  • R 3 is 11 C or 12 C
  • the compound contains at least one of a 11 C atom and a 18 F atom.
  • the C 1 -C 6 alkyl in the compound of Formula (I) is optionally substituted by at least one F or 18 F atom.
  • R 1 is larger than methyl, such as ethyl, propyl, butyl, pentyl, hexyl, or branched isomers thereof
  • the 11 C atom can replace any 12 C atom in the alkyl group at any location, and all such permutations of replacing a single 12 C atom by a 11 C atom are herein contemplated.
  • R 1 is C1-C6 alkyl containing at least one 11 C atom.
  • R 1 is C2-C6 alkyl containing at least two 11 C atoms, or more.
  • R 1 is 11 CH 3 .
  • R 2 is 18 F.
  • the compound of Formula (I) is selected from the group consisting of: In various embodiments, the compound of Formula (I) is selected from the group 13 53376748.1 Attorney Docket No.047162-7482WO1(02447) consisting of: In various embodiments, a compound of Formula (II), or a salt, solvate, tautomer, or stereoisomer thereof is provided: In certain embodiments, in the compound of Formula (II): R 1 is H or C 1 -C 6 alkyl containing at least one 11 C atom; R 2 is 18 F or 19 F; and R 3 is 11 C or 12 C; wherein the compound contains at least one of a 11 C atom and a 18 F atom.
  • the C 1 -C 6 alkyl in the compound of Formula (II) is optionally substituted by at least one F or 18 F atom.
  • R 1 is larger than methyl, such as ethyl, propyl, butyl, pentyl, hexyl, or branched isomers thereof
  • the 11 C atom can replace any 12 C atom in 14 53376748.1 Attorney Docket No.047162-7482WO1(02447) the alkyl group at any location, and all such permutations of replacing a single 12 C atom by a 11 C atom are herein contemplated.
  • R 1 is C 1 -C 6 alkyl containing at least one 11 C atom. In various embodiments, R 1 is C2-C6 alkyl containing at least two 11 C atoms, or more. In various embodiments, R 1 is 11 CH3. In various embodiments, R 2 is 18 F.
  • the compound of Formula (II) is selected from the group consisting of: , Compounds of Formula (II) can be synthesized by alkylation (alkylative cyclization) of the amide NH 2 and imidazole nitrogen in the compound of Formula (I) forming a ring, according to methods known in the art.
  • the compound of Formula (II) is 15 53376748.1 Attorney Docket No.047162-7482WO1(02447)
  • the compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers.
  • Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity.
  • Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs.
  • prodrug refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey & Sundberg, 17 53376748.1 Attorney Docket No.047162-7482WO1(02447) Advanced Organic Chemistry 4th Ed., Vols.
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
  • carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acidand baseprotecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction 18 53376748.1 Attorney Docket No.047162-7482WO1(02447) in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from: .
  • PET Imaging Methods In various embodiments, a method of imaging poly(ADP-ribose) polymerase-1 (PARP1) in a subject is provided. The method includes: administering the compound of Formula (I) or Formula (II) to the subject, and imaging the compound in the subject.
  • PARP1 poly(ADP-ribose) polymerase-1
  • the compound of Formula (I) or Formula (II) is administered in an amount sufficient to clinically diagnose a disease or disorder of the brain.
  • the disease or disorder of the brain is cancer.
  • the cancer in the brain expresses PARP1.
  • the imaging is or includes positron emission tomography (PET).
  • PET positron emission tomography
  • the PARP1 is imaged in the brain of the subject.
  • subject suffers from glioma.
  • the glioma can be, for example, ependymoma, anaplastic astrocytoma, 19 53376748.1 Attorney Docket No.047162-7482WO1(02447) glioblastoma, astrocytoma, brainstem glioma, diffuse midline glioma, oligodendroglioma, ganglioglioma, circumscribed astrocytic glioma, low-grade glioma, angiocentric glioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, dysembryoplastic neuroepithelial tumor, and the like.
  • the subject suffers from Alzheimer’s disease (AD), Parkinson’s disease (PD), and/or any other central nervous system (CNS) disease or neurological disease or disorder.
  • the method can be used to quantify the amount of PARP1 in the subject, for example, the brain of the subject or in other portions of the CNS where crossing the BBB (blood-brain barrier) is necessary and/or desirable for diagnostic purposes.
  • imaging is used or can be used to identify whether the subject will benefit from administration of a PARP1 inhibitor to treat, ameliorate, and/or prevent a disease or disorder.
  • the disease or disorder is cancer.
  • the disease or disorder is a central nervous system (CNS) disease or a neurological disease.
  • the cancer is glioma.
  • the glioma is a glioblastoma.
  • the CNS disease is Alzheimer’s disease (AD) or Parkinson’s disease (PD).
  • AD Alzheimer’s disease
  • PD Parkinson’s disease
  • the compounds of Formula (I) and Formula (II) described herein are useful in a variety of in vivo imaging applications (e.g., for tissue or whole body imaging). In certain embodiments, the compounds of Formula (I) and Formula (II) can be used to image tumors.
  • the compound(s) of Formula (I) and/or Formula (II) is/are administered to a subject in an amount sufficient to uptake the compound(s) of Formula (I) and/or Formula (II) into the tissue of interest, for example the brain.
  • the subject is then imaged using an imaging system such as PET for an amount of time appropriate for the compound(s) of Formula (I) and/or Formula (II).
  • the compound(s) of Formula (I) and/or Formula (II) -bound to cells or tissues expressing PARP1 are then detected by the imaging system.
  • PET imaging with compound(s) of Formula (I) and/or Formula (II) can be used to qualitatively or quantitatively detect PARP1 protein.
  • the compound(s) of Formula (I) and/or Formula (II) can be used as a biomarker, and the presence or absence of a positive signal (i.e., presence of PARP1) in a subject may be indicative that the subject would be responsive to a given therapy, e.g., a cancer therapy, or that the subject is responding or not to a therapy.
  • a positive signal i.e., presence of PARP1
  • the progression or regression of disease e.g. tumor
  • the size of the tumor can be 20 53376748.1 Attorney Docket No.047162-7482WO1(02447) monitored in a subject undergoing cancer therapy (e.g., chemotherapy, radiotherapy) and the extent of regression of the tumor can be monitored in real-time based on detection of the compound(s) of Formula (I) and/or Formula (II).
  • cancer therapy e.g., chemotherapy, radiotherapy
  • the distribution of target molecule within one or more tumors or healthy cells may also be visualized, and monitored prior and/or during a treatment and/or a disease.
  • the subject receiving the compound(s) of Formula (I) and/or Formula (II) is a mammal, for example, a human, dog, cat, ape, monkey, rat, or mouse.
  • the compound(s) of Formula (I) and/or Formula (II) described herein are useful for PET imaging of brain, lungs, heart, kidneys, liver, and skin, and other organs, or tumors associated with these organs which express PARP1.
  • the compound(s) of Formula (I) and/or Formula (II) provide a contrast of at least 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 95% or more.
  • an image using compound(s) of Formula (I) and/or Formula (II) described herein is obtained by administering the compounds to a subject and imaging in vivo the distribution of the compound(s) of Formula (I) and/or Formula (II) by positron emission tomography.
  • Non-limiting Example of a PET Procedure The following illustrative non-limiting procedure may be utilized when performing PET imaging studies on patients in the clinic. A skilled artisan can modify the procedure described herein as necessary to provide clinically useful readouts.
  • a venous catheter e.g., a 20 G two-inch venous catheter, is inserted into the contralateral ulnar vein for radiotracer administration.
  • Administration of the PET tracer is often timed to coincide with time of maximum (T max) or minimum (T min) of the imaging agent or precursor concentration in the blood, in this case compound(s) of Formula (I) and/or Formula (II).
  • T max time of maximum
  • T min minimum
  • the patient is positioned in the PET camera and a tracer dose of the PET tracer of the compound(s) of Formula (I) and/or Formula (II) is administered via i.v. catheter.
  • a subject may, prior to administration of the PET tracer, drink a liter of water to promote the renal clearance of unbound tracer from the circulation in order to enhance signal to background ratio and/or empty his bladder.
  • Either arterial or venous blood samples may be taken at 15 appropriate time intervals throughout the PET scan in order to, e.g., analyze and quantitate the fraction of unmetabolized PET tracer in plasma. Images may be acquired for up to 120 min. Within ten minutes of the injection of radiotracer and at the end of the imaging session, 1 mL blood samples may be obtained, e.g., for determining the plasma concentration of any 21 53376748.1 Attorney Docket No.047162-7482WO1(02447) labeled or unlabeled imaging agent or precursor or metabolite. Two types of PET procedures may be used. One type involves obtaining single time point estimates of tracer uptake or static imaging that provides a spatial map of regional tracer concentration.
  • Imaging agents such as compound(s) of Formula (I) and/or Formula (II), may be used in either static tracer imaging or dynamic tracer imaging.
  • the clinician may visually identify tumor lesions on a PET or CT scan and determine a region-of-interest (ROI) around these lesions.
  • ROI region-of-interest
  • Imaging agent-uptake in these ROI’s may be corrected for body weight and injected dose and quantified as standardized uptake value (SUVmax and SUVmean).
  • Tomographic images are obtained through image reconstruction.
  • ROIs may be drawn on the reconstructed image including, but not limited to, the brain, lungs, liver, heart, kidney, skin, or other organs and tissue (e.g., cancer tissue in any of the preceding list of organs).
  • Radiotracer uptakes over time in these regions are used to generate time activity curves (TAC) obtained in the absence of any intervention or in the presence of the unlabeled targeting molecule at the various dosing paradigms examined.
  • TAC time activity curves
  • a method comprises (a) administering to a subject a compound of Formula (I) or Formula (II), at a dose of about 3-14 mCi (100-518 MBq); and (b) conducting a PET scan of the subject about 1-120 minutes (such as 30-120, 30-60 or 60-120 minutes) after step (a).
  • the PET scan may be a static PET scan or a dynamic PET scan. If the PET scan is a static PET scan, the PET scan may occur 30-120, 30-60 or 60-120 minutes after administration of the imaging agent, and if the PET scan is a dynamic PET scan, it may occur 1-120, 30-120, 30-60 or 60-120 minutes after administration of the compound of Formula (I) or Formula (II), such as 1-, 35-, 70-, or 105-minutes post injection.
  • a dynamic PET scan may take a total duration of 30 to 120 minutes, such as 30 to 60 minutes, e.g., 30 minutes or 60 22 53376748.1 Attorney Docket No.047162-7482WO1(02447) minutes, with variable frame lengths.
  • the scan may be a whole-body scan or a partial body scan, e.g., a scan of a single tumor.
  • a dynamic PET scan may be a scan of a single tumor and a static PET scan may be a whole-body scan.
  • the dose administered is about 200-225 MBq (i.e., ⁇ 10%) or about 6 mCi (i.e., ⁇ 10%).
  • a subject is a subject with cancer
  • the method comprises (a) administering to the subject a compound of Formula (I) or Formula (II), at a dose of about 3-10 mCi (100-333 MBq); and (b) conducting a PET scan of the subject about 1-120 minutes (such as 30-120, 30-60 or 60-120 minutes) after step (a), wherein steps (a) and (b) are conducted prior to the initiation of a cancer treatment.
  • a subject is a subject with cancer
  • the method comprises (a) administering to the subject a compound of Formula (I) or Formula (II), at a dose of about 3-10 mCi (100-333 MBq); and (b) conducting a PET scan of the subject about 1-120 minutes (such as 30-120, 30-60 or 60-120 minutes) after step (a), wherein steps (a) and (b) are conducted at at least 2 time points, e.g., one of which is prior to the initiation of a cancer treatment, and one of which is during the cancer treatment, or wherein both time points are during the cancer treatment.
  • the two time points may be separated by, e.g., a time of 1-10 weeks, such as 2-8 weeks, such as 5-7 weeks, such as 6 weeks.
  • steps (a) and (b) are conducted at at least 3, 4, 5 or more time points, wherein the successive time points are separated by, e.g., a time of 1-10 weeks, such as 2-8 weeks, such as 5-7 weeks, such as 6 weeks.
  • Methods in which more than one iteration of steps (a) and (b) are used may comprise comparing a PET scan conducted at a first time point with a PET scan conducted at a second time point, and/or later time point.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations contemplated within the disclosure may be administered to the subject either prior to or after the onset of a disease and/or disorder contemplated herein. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations contemplated within the disclosure may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions contemplated within the disclosure to a patient may be carried out using known procedures, at dosages and for periods of time effective to image a tissue and/or treat a disease and/or disorder contemplated herein in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound contemplated within the disclosure to image a tissue and/or treat a disease and/or disorder contemplated herein in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound contemplated within the disclosure is from about 0.001 and 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions contemplated within the disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the imaging, treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being imaged, treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds contemplated within the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be imaged and/or treated; each unit containing a predetermined quantity of therapeutic 24 53376748.1 Attorney Docket No.047162-7482WO1(02447) compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms contemplated within the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the imaging of a tissue and/or treatment of a disease and/or disorder contemplated herein.
  • the compounds of the disclosure are formulated as a composition with one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable carrier.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In another embodiment, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks.
  • the frequency of administration of the various combination compositions of the disclosure varies from individual to individual depending on many factors including, but not limited to, age, tissue to be imaged, disease or disorder to be treated, gender, overall health, and other factors.
  • the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.
  • sterile injectable solutions can be prepared by incorporating the compound of Formula (I) or Formula (II) in the required amount in an appropriate solvent 25 53376748.1 Attorney Docket No.047162-7482WO1(02447) with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Compounds of the disclosure for administration may be in the range of from about 1 ⁇ g to about 10,000 mg, about 20 ⁇ g to about 9,500 mg, about 40 ⁇ g to about 9,000 mg, about 75 ⁇ g to about 8,500 mg, about 150 ⁇ g to about 7,500 mg, about 200 ⁇ g to about 7,000 mg, about 3050 ⁇ g to about 6,000 mg, about 500 ⁇ g to about 5,000 mg, about 750 ⁇ g to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.
  • the dose of a compound of the disclosure is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the disclosure used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the amount of the compound of Formula (I) or Formula (II) which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of compound of Formula (I) or Formula (II) which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a 26 53376748.1 Attorney Docket No.047162-7482WO1(02447) detectable effect. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent of active ingredient, preferably from about 0.1 percent to about 70 percent, most preferably from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • a dosage of the compound(s) of Formula (I) or Formula (II) that is in the range of from about 1 mg to 500 mg as a single intravenous infusion, although a lower or higher dosage also may be administered as circumstances dictate.
  • Examples of dosages of compound(s) of Formula (I) or Formula (II) that may be administered to a human subject for imaging purposes are about 0.1 to 500 mg, 0.1 to 200 mg, about 0.1 to 70 mg, about 0.1 to 20 mg, and about 0.1 to 10 mg, although higher or lower doses may be used.
  • Examples of dosages of compound(s) of Formula (I) or Formula (II) that can be administered to a human subject for imaging purposes are 10 ⁇ g to 1000 ⁇ g, 100 ⁇ g to 1000 ⁇ g, 100 ⁇ g to 500 ⁇ g, 200 ⁇ g to 500 ⁇ g, and 300 ⁇ g to 400 ⁇ g, although higher or lower doses may be used.
  • compound(s) of Formula (I) or Formula (II) can be administered in an amount, e.g., as a bolus injection, to a human ranging from 10 ⁇ g to 1000 ⁇ g, 100 ⁇ g to 1000 ⁇ g, 100 ⁇ g to 500 ⁇ g, 200 ⁇ g to 500 ⁇ g, and 300 ⁇ g to 400 ⁇ g.
  • administration occurs in an amount of compound(s) of Formula (I) or Formula (II), of between 0.005 ⁇ g/kg of body weight to 50 ⁇ g/kg of body weight per day, e.g., between 0.02 ⁇ g/kg of body weight to 10 ⁇ g/kg, e.g., per day, between 0.1 ⁇ g/kg of body weight to 10 ⁇ g/kg of body weight, e.g., per day, between 1 ⁇ g/kg of body weight to 10 ⁇ g/kg of body weight, e.g., per day, between 2 ⁇ g/kg of body weight to 6 ⁇ g/kg of body weight, e.g., per day or between 4 ⁇ g/kg of body weight to 5 ⁇ g/kg of body weight, e.g., per day.
  • an amount of compound(s) of Formula (I) or Formula (II) of between 0.005 ⁇ g/kg of body weight to 50 ⁇ g/kg of body weight per day, e.g.,
  • the compound(s) of Formula (I) or Formula (II) is administered to a human subject in an amount between 0.1 ⁇ g/kg of body weight to 10 ⁇ g/kg of body weight, e.g., per day, between 1 ⁇ g/kg of body weight to 10 ⁇ g/kg of body weight, e.g., per day, between 2 ⁇ g/kg of body weight to 6 ⁇ g/kg of body weight, e.g., per day or between 4 ⁇ g/kg of body weight to 5 ⁇ g/kg of body weight, e.g., per day.
  • the present disclosure is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second 27 53376748.1 Attorney Docket No.047162-7482WO1(02447) pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of the disease/disorder herein in a patient.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for intracranially, oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like.
  • other active agents e.g., other analgesic agents.
  • the compounds for use in the disclosure may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., transand perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • transdermal e.g., sublingual, lingual, (trans)buccal, (trans)urethral
  • vaginal e.g., transand perivaginally
  • intrathecal subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation,
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compounds of the disclosure may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • the tablets may be coated using suitable methods and coating materials such as OPADRYTM film coating systems available from Colorcon, West Point, Pa.
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid.
  • the present disclosure also includes a multi-layer tablet comprising a layer providing for
  • a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.
  • parenteral Administration the compounds of the disclosure may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • the compound(s) of Formula (I) and/or Formula (II) are administered intravenously, e.g., as a bolus injection.
  • Additional Administration Forms Additional dosage forms of this disclosure include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. 29 53376748.1 Attorney Docket No.047162-7482WO1(02447) Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820.
  • Additional dosage forms of this disclosure also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.
  • Controlled Release Formulations and Drug Delivery Systems may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.
  • the compounds for use the method of the disclosure may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the compounds of the disclosure are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 30 53376748.1 Attorney Docket No.047162-7482WO1(02447) hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • the therapeutically effective amount or dose of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of disease/disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors.
  • a suitable dose of a compound of the present disclosure may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different.
  • a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.
  • the administration of the modulator of the disclosure is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”).
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • 31 53376748.1 Attorney Docket No.047162-7482WO1(02447)
  • the compounds for use in the method of the disclosure may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing imaging and/or treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired imaging and/or therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED 50 .
  • Capsid assembly modulators exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such capsid assembly modulators lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • Those skilled in the art recognizes, or is able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto.
  • modifications in assay and/or reaction conditions with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure.
  • the protein binding site was prepared using the protein preparation wizard (Schrodinger, New York) in Maestro. For better accuracy, water and heteroatoms > 5 ⁇ from the active site region were removed.
  • the ligands were listed with tautomers and stereoisomers for the study; furthermore, geometry-optimized ligands were prepared using LigPrep wizard (Schrodinger, New York).
  • standard-precision SP, Schrodinger, New York
  • XP Schrodinger, New York
  • the HPLC system used for purification of crude product included a Shimadzu LC-20A pump, a Knauer K200 UV detector, and a Bioscan ⁇ -flow detector, with a Luna C18(2) semipreparative column.
  • the HPLC system used for quality control tests was composed of a Shimadzu LC-20A pump, a Shimadzu SPD-M20A PDA or SPD-20A UV detector, and a Bioscan ⁇ -flow detector, with a Gemini NX column eluting with a mobile phase of 20% CH 3 CN and 80% 0.1% triethyl amine (TEA) buffer solution (pH 11.75) at a flow rate of 2 mL/min.
  • TEA triethyl amine
  • [ 11 C]CO 2 was produced through the 14 N(p, ⁇ ) 11 C nuclear reaction by bombardment of a high-pressure target containing a mixture of nitrogen and oxygen (0.5%–1%) with a 16.8-MeV proton beam that was produced by the PET Trace cyclotron (GE Healthcare) cyclotron.
  • [ 11 C]MeI was synthesized by the gas-phase method from [ 11 C]CO2 using the FXMeI module (GE Healthcare) by initially converting [ 11 C]CO2 to [ 11 C]-methane, followed by the reaction of [ 11 C]-methane with iodine at 720 °C to produce [ 11 C]MeI.
  • the product portion was collected using a semi-PrepHPLC setup using a Phenomenex Luna C-18 HPLC column (10 ⁇ m, 10 mm ⁇ 250 mm) with a retention time of approximately 20 min.
  • the product which was collected into 50 mL of water, was then trapped on a C18 light SepPak cartridge (Waters).
  • the cartridge was washed with 10 mL of water.
  • the cartridge was eluted with 1 mL of ethanol and 3 mL of saline, and the radioactive material was finally collected in a dose vial pre-charged with 7 ml of saline and 8.4% USP sodium bicarbonate solution.
  • a different HPLC system consisting of a Shimadzu LC-20A pump, a Shimadzu SPD-M20A PDA or SPD-20A UV detector, and a Bioscan ⁇ -flow detector.
  • the production of [ 11 C]CO 2 involved the 14 N(p, ⁇ ) 11 C nuclear reaction, achieved by directing a 16.8-MeV proton beam from the PET Trace cyclotron (GE Healthcare) at a high- pressure target containing a nitrogen and oxygen mixture (0.5%–1%).
  • [ 11 C]MeI was synthesized using the gas-phase method through the FXMeI module (GE Healthcare).
  • the mixture was eluted with the HPLC mobile phase, at a flow rate of 5 mL/min.
  • the product portion was collected using a semiPrep-HPLC.
  • the product which was collected into a 50 mL of water was then trapped on a C18 light SepPak cartridge (Waters).
  • the cartridge was washed with 10 mL of water.
  • the cartridge was eluted with 1 mL of ethanol and 3 mL of saline and the radioactive material was finally collected in a dose vial pre-charged with 7 ml of saline and 8.4 % USP sodium bicarbonate solution.
  • the cyclotron produced aqueous [ 18 F]fluoride solution in H2 18 O was transferred to a V-vial in a lead-shielded hot cell, where the [ 18 F]fluoride anion was trapped on an anionic exchange resin cartridge (Chromafix-PS-HCO3) pre-activated by elution sequentially with EtOH (5 mL), an aqueous solution of potassium triflate (KOTf, 90 mg/mL, 5 mL), and deionized (DI) water (5 mL).
  • EtOH EtOH
  • KOTf potassium triflate
  • DI deionized
  • the potassium [ 18 F]fluoride was then eluted off the cartridge into a 2-mL V-vial with the mixture of aqueous solution of KOTf (10 mg/mL, 0.45 mL) and MeCN (0.5 mL).
  • the eluent was azeotropically dried at 110 °C, with two portions of anhydrous MeCN (1.0 mL ⁇ 2) added during the process.
  • a solution of the Tin precursor (5.0 mg) in anhydrous 1,3-Dimethyl-2-imidazolidinone (DMI, 0.4 mL) was then added to the reaction vial, followed by the solution of pyridine (1 M in DMI, 0.1 mL) and copper(II) triflate (0.2 M in DMI, 67 ⁇ L).
  • the reaction mixture was then heated at 180 °C for 30 min, then HCl (6 M, 0.2 mL) were added.
  • the reaction mixture was heated at 100 °C for another 10 min, then NaOH-EDTA solution was added (5M, 0.2 mL).
  • the reaction mixture was diluted with the HPLC mobile phase (1.0 mL) and purified by HPLC (column: Phenomenex Gemini C18, 10 ⁇ m, 10 ⁇ 250 mm; mobile phase: 20% MeCN and 80% 0.1% Et 3 N; flow rate: 5 mL/min).
  • HPLC HPLC mobile phase
  • the eluent was monitored by a UV detector (at 254 nm) and a radioactivity detector.
  • the fraction containing [ 18 F]-F-Veliparib was collected, diluted with DI water (50 mL), and passed through a C18 SepPak, which was then washed with 0.001 N HCl (10 mL) and dried with 10 cc air.
  • [ 11 C]CO2 involved the 14 N(p, ⁇ ) 11 C nuclear reaction, achieved by directing a 16.8-MeV proton beam from the PET Trace cyclotron (GE Healthcare) at a high- pressure target containing a nitrogen and oxygen mixture (0.5%–1%). Subsequently, [ 11 C]MeI was synthesized using the gas-phase method through the FXMeI module (GE Healthcare). This process began with the conversion of [ 11 C]CO 2 to [ 11 C]-methane, which was then reacted with iodine at 720 °C to yield [ 11 C]MeI.
  • Saturation binding assay using [ 3 H]PyBic in rat hippocampus and NHP brain tissue The saturation binding assay was performed at Gifford Bioscience (UK). The hippocampus was dissected from the rat brain.
  • the cerebellum, brain stem, frontal cortex, hippocampus, and occipital cortex were dissected from the monkey brain.
  • the dissected brain tissues were homogenized in ice-cold buffer (50 mM Tris; 5 mM MgCl2; 5 mM EDTA; protease inhibitor cocktail). After a low-speed spin (100 ⁇ g) to remove tissue pieces, the supernatant was transferred to a fresh tube and centrifuged at 17,000 ⁇ g for 10 min at 4 °C to pellet the membranes. The pellet was resuspended in fresh buffer and centrifuged a second time.
  • the pellet from the second spin was resuspended in buffer (50 mM Tris, 5 mM MgCl 2 , 0.1 mM EDTA) containing 10% sucrose as a cryoprotectant, divided into aliquots, frozen, and stored at -80 °C.
  • a sample of the washed membrane preparation was analyzed for protein content using the Pierce® BCA assay.
  • Radioligand binding assays were carried out in 96- well plates in a final volume of 250 ⁇ L per well. Then, 150 ⁇ L membrane, 50 ⁇ L cold compound in buffer (or buffer alone) and 50 ⁇ L radioligand in buffer were added to each well. The plate was incubated at 30 °C for 90 min with gentle agitation.
  • the incubation was stopped by vacuum filtration onto presoaked (incubation buffer) GF/C filters using a 96-well FilterMateTM harvester, followed by five washes with ice-cold wash buffer. Filters were then dried under a warm air stream and sealed in polyethylene, a scintillation cocktail was added, and the radioactivity was counted in a Wallac® TriLux 1450 MicroBeta counter. For each concentration of drug, nonspecific binding was subtracted from total binding to give specific binding. Data were fitted using the nonlinear curve fitting routines in Prism® (GraphPad Software Inc.) to determine K d. and B max .
  • RG2 cells ATCC, Manassas, VA
  • ATCC Manassas, VA
  • PGA Manassas
  • RG2 tumor growth was monitored by contrast-enhanced MR (CEMR) imaging at 14–18 days post implantation of tumor cells.
  • the tumor volumes are from 5.8 mm 3 to 12.3 mm 3 for the 14-day post implantation cohort, from 28.9 mm 3 to 180.6 mm 3 for the 18-day post implantation cohort.
  • Multiple cohorts of in vivo, in vitro and ex vivo studies were performed using the same (when available) or different animals.
  • MR imaging RG2-bearing rats were scanned on an 11.7 T Magnex magnet (Magnex Scientific Ltd.) interfaced to a Bruker Avance III HD spectrometer running on ParaVision 6 (Bruker Instruments).
  • Rats were anesthetized with isoflurane using a 70/30% N 2 O/ O 2 mixture as the carrier gas delivered via a nose cone. Animals were positioned prone in a heated holder to maintain body temperature at 37 °C. Before positioning in the scanner, animals were injected subcutaneously with a bolus of 200 ⁇ L T1 contrast agent gadopentetate dimeglumine (Magnevist®, Bayer). For MRI acquisition, a 20 mm 1H surface coil was used, positioned directly above the animal’s head.
  • T1-weighted MR images were acquired using a multi-slice spin-echo pulse sequence with a repetition time of 1000 ms, echo time of 6.4 ms, isotropic resolution of 250 ⁇ m and 4 averages.
  • tumor segmentation was performed using an intensity threshold and manual segmentation tools to outline the contrast- enhancing region in each slice of the MR image stack, and the segmentation results were exported.
  • the 60- and 90-min dynamic scans were reconstructed to 20 and 26 frames, respectively: 6 ⁇ 30 s, 1 ⁇ 45 s, 2 ⁇ 60 s, 1 ⁇ 90 s, 1 ⁇ 120 s, 1 ⁇ 210 s, and 10 ⁇ 300 s for 60-min scans or 15 ⁇ 300 s for 90-min scans.
  • An averaged PET image from 0 to 60 min for each measurement (mean of all frames) was co-registered to the T2 weighted image in the Waxholm Space rat brain atlas with 6- degree-of-freedom linear registration using an in-house manual registration tool.
  • TACs regional time-activity curves
  • a total of 2 baseline scans (test, retest), 2 blocking scans with veliparib (2.5 mg/ kg) and BGB290 (0.5 mg/kg), and one P-gp inhibitor tariquidar (1.4 mg/kg) were carried out on a FOCUS220 scanner.
  • PET imaging reconstruction was performed using similar procedures as described previously.
  • ROIs regions of interest
  • MR images were acquired using a Siemens 3 T Trio scanner and co-registered to an inhouse-generated monkey brain atlas and 49 53376748.1 Attorney Docket No.047162-7482WO1(02447) the PET images.
  • the PET emission data were reconstructed using a Fourier re-binning and filtered back projection algorithm with a Shepp-Logan filter.
  • SUV TACs were generated for the brain stem, cerebellum, frontal cortex, occipital cortex and globus pallidus.
  • Blood and preselected organs such as the olfactory, cerebellum, brain stem, tumor, muscle, spleen, kidney, liver, lung, and hippocampus, were collected, weighed, and counted in an automatic Wizard ⁇ counter (PerkinElmer). Radioactivity concentrations were normalized against weight, decay-corrected, and expressed as percentage of injected dose per gram tissue (%ID/g) or SUV.
  • Western blotting Western blotting was performed on normal brain and tumor tissues from RG2 rats that were lysed in protein lysis buffer (1% SDS, 10% glycerol, in 25 mM Tris–HCl, pH 6.8) supplemented with proteinase inhibitors (cOmpleteTM, Cat# 11,836,170,001, Sigma) and phosphatase inhibitors (PhosSTOPTM, Cat # 4,906,845,001, Sigma).
  • proteinase inhibitors cOmpleteTM, Cat# 11,836,170,001, Sigma
  • PhosSTOPTM phosphatase inhibitors
  • Three micrograms of protein were separated using WES capillary electrophoresis (ProteinSimple) and incubated with rabbit polyclonal anti-PARP1 antibody (Proteintech, Cat# 13,371–1-AP) in antibody dilution buffer provided with the WES machine.
  • Compass software provided by ProteinSimple was used to analyze the western blot results.
  • the absolute chemiluminescent signal values of the area under the specific peak curve generated by Compass were used to quantify the protein expression level.
  • Immunohistochemistry Sagittal-cut rat brains with RG2 tumors were paraffin-embedded and cut into 10- micron sections and deparaffinized and rehydrated for immunohistochemistry staining of PARP1 using the abovementioned antibody.
  • Metabolite analysis Two different metabolite studies, first with tumor-bearing rats and later with a nonhuman primate, were performed. The activity of the blood sample was measured. The plasma fraction was collected by centrifugation of the blood. For rats, the plasma was mixed with a urea solution and further diluted with a 0.2 mL (80:20) mixture of ammonium formate aqueous solution (0.1 M) and MeCN and run under the same solution as the mobile phase at 1 mL/min in a Gemini HPLC column (NX, 5 ⁇ m).
  • NHP plasma metabolite analysis the NHP plasma was diluted with an HPLC mobile phase comprising an 85:15 ratio of ammonium formate aqueous solution (0.1 M) and MeCN and run in a Gemini NX column at a 1.2 mL/min flow rate.
  • Kinetic modeling Volume of distribution (V T , mL ⁇ cm ⁇ 3 ) values were derived through 1-tissue (1 T) compartment, 2TCM, and MA1 kinetic modeling as described before.
  • Target occupancy and V ND were calculated using the Lassen plot.
  • the physicochemical and pharmacological parameters were calculated, i.e., LogP, MDCK permeability, PSA, LogS, and XP scores, to predict the brain permeability and binding 51 53376748.1 Attorney Docket No.047162-7482WO1(02447) affinity of PyBic (Table 1).
  • the calculated XP score (-7.866) was slightly higher than that of veliparib (-7.976), which was consistent with their reported IC50 values (6 nM and 5.2 nM for PyBic and veliparib, respectively.
  • [ 11 C]PyBic can be obtained via a chemoselective N-methylation reaction using [ 11 C]MeI and veliparib as the labeling precursor.
  • Veliparib (4) and the PyBic standard (5) were synthesized following the reported procedure with slight modifications (Fig.7a).
  • the reference standard (5) was synthesized from precursor 4 using either methyl iodide (MeI) under basic conditions in 56% yield or paraformaldehyde in 77% yield.
  • [ 11 C]PyBic PET imaging in RG2 ⁇ bearing rat brains To explore the feasibility of using [ 11 C]PyBic in rat brain PET imaging, tritium- labeled PyBic, [ 3 H] PyBic (Fig.8A) was obtained for saturation binding assays using rat hippocampal homogenates.
  • the K D and B max values in the rat hippocampus were 0.46 nM and 50 fmol/mg (protein), respectively.
  • the RG2 tumor size ranged from 6.5 to 180.6 mm 3 at 14–18 days post-implantation of tumor cells, and the average size was 54.6 ⁇ 56.0 mm 3 (mean ⁇ SD).
  • [ 11 C]PyBic PET imaging in 9 rats was carried out for either a 0– 90 min or a 0–60 min scan.
  • the administered dose of [ 11 C]PyBic was equivalent to 0.4 ⁇ 0.12 ⁇ g/kg of cold mass of PyBic.
  • the contralateral nontumor brain region showed much lower tracer uptake, with an average SUV of 0.39 ⁇ 0.04 (mean ⁇ SD, Fig. 2C). All the selected normal brain regions showed significantly lower tracer uptake than the tumors (p ⁇ 0.05, Fig.2C).
  • the tumor SUV exceeded 1 within 10 min p.i. and then decreased to 0.39 ⁇ 0.10 (mean ⁇ SD) after 40 min p.i. (Fig.2D).
  • the contralateral nontumor ROI was chosen as the reference region because it was the brain region with the lowest tracer uptake and was the least influenced by preinjected veliparib as the blocking drug (Figs.10A-10B).
  • a strong linear correlation was observed between DVR (0–60 min) and DVR (0–90 min).
  • [ 11 C]PyBic exhibits a lower nonspecific signal in muscle and relatively higher nonspecific signals in the brain than [ 3 H] veliparib (Table 3).
  • the mean tissue-to-plasma ratios for [ 11 C]PyBic in selected rat tissues were as follows: brain (0.9), kidney (5.3), liver (4.7), lungs (2.4), spleen (4.0), muscle (2.2) at 60 min p.i.
  • Table 2 Volume of distribution (VT) values (mL/cm 3 ) of [ 11 C] primates of PyBic in two non- human primates (NHPs) under baseline conditions or with preinjected Veliparib, BGB290, or tariquidar.
  • VT Volume of distribution
  • V eliparib Test Retest Veliparib BGB290 Tariquidar brainstem 11.0 2.1 8.4 9.1 1.6 1.5 8.0 caudate 10.8 2.4 14.7 9.4 2.2 2.4 8.4 cerebellum 17.6 2.3 14.9 14.0 2.0 1.8 12.4 cingulate 11.9 2.6 14.6 14.0 2.9 3.2 12.4 frontal cortex 12.9 2.4 19.7 18.2 2.8 3.0 14.6 insula 12.3 2.6 11.2 12.7 2.4 2.9 10.9 occipital cortex 15.5 2.2 16.3 15.8 2.0 2.2 13.5 pons 11.6 2.2 8.0 9.9 1.6 1.6 8.9 putamen 13.8 2.5 9.5 11.9 2.1 2.4 10.4 temporal cortex 12.9 2.3 14.7 13.8 2.3 2.6 12.0 thalamus 11.2 2.4 6.9 7.7 1.8 2.2 7.8 Table 3.
  • BGB290 a structurally different PARP1/2 inhibitor
  • FIG.14C Injection of the P-gp inhibitor tariquidar did not change the AIF compared to the baseline study (Fig.14D).
  • the late-time SUV (60–90 min) images of the blocking scans showed consistently low and nearly homogeneous tracer distribution in all brain regions, indicating effective blockade by veliparib and BGB290 at the injected doses.
  • the cerebellum had the highest 57 53376748.1 Attorney Docket No.047162-7482WO1(02447) uptake, followed by the occipital cortex, frontal cortex and globus pallidus, showing the lowest tracer uptake, while in the blocking scans, the tracer washed out of the brain quickly, with reduced contrast among brain regions at later imaging windows due to the effective blockade of PARP binding sites in all brain regions (Figs.5B-5C).
  • [ 11 C]PyBic metabolism study in NHP Similar to the rat metabolism study, the same two major radiometabolite peaks from the radio-HPLC chromatograms were observed, indicating cross-species conservation in the metabolism profiles of [ 11 C]PyBic.
  • the metabolism rate of this tracer was moderate in NHPs, with plasma parent fractions of 73% and 52% at 15 min and 90 min p.i., respectively (Fig. 5D).
  • the radiometabolites were not expected to be brain penetrant, at least not to an extent enough to interfere with the quantification of PARP1 in the brain, based on the rat brain homogenate radio-HPLC data (Fig.2F).
  • V T Brain PET kinetic modeling in NHPs
  • 1TCM 1-tissue compartment model
  • 2TCM 2-tissue compartment model
  • MA1 multilinear analysis
  • V T values from 1TCM in the monkey baseline scan ranged from 7.3 mL/cm 3 for the amygdala to 15.5 mL/cm 3 for the occipital cortex (Table 2), while the VT values for the monkey blocking scan ranged from 2.1 mL/cm 3 to 2.7 mL/cm 3 .
  • Both K 1 and V T calculated using 1 T models were similar between the test and retest baseline as well as with the P-gp inhibition scan using tariquidar as the P- gp inhibitor.
  • the non-displaceable binding potential (BP ND ) for the brain regions of the two monkeys was obtained.
  • PET imaging results showed higher tracer uptake in the orthotopic RG2 glioblastoma relative to the rest of the rat brain.
  • the quantification of PARP1 using molecular biological methods and biodistribution analysis confirmed the PET imaging results.
  • the uptake of [ 11 C] PyBic is significantly reduced by the PARP1/2 inhibitor veliparib in both PET imaging and biodistribution analysis, indicating the in vivo binding specificity of the radiotracer.
  • the high brain-to-plasma ratio in healthy NHPs demonstrated the high brain permeability and specific binding of [ 11 C]PyBic in NHPs, supporting its use as a brain PARP PET imaging probe.
  • Several PARPi-derived PET radiotracers have been developed for PARP imaging.
  • PET tracer [ 11 C]PJ34 was intended for imaging PARP in a streptozotocin-induced type I diabetes-related necrosis model, where a higher uptake of [ 11 C]PJ34 in both the pancreas and liver was observed.
  • Two 18 F-labeled analogs of 59laparib, [ 18 F] FBO and [ 18 F]PARP-Fl have been used to image rodent models of ovarian cancer, pancreatic cancer, and glioma.
  • veliparib (ABT-888) has a relatively lower PARP trapping capability and is reported to be a weak P-gp substrate, which makes it appealing as a lead compound for developing brain PET imaging agents with fast and reversible brain kinetics.
  • ABT-888 N- methylated derivative of veliparib, PyBic, was synthesized on the premise that the removal of the N–H hydrogen-bond donor would further decrease its susceptibility to active efflux at the BBB and that the slightly increased hydrophobicity would improve its cell membrane permeability and BBB penetration.
  • SRTM2 simplified reference tissue method 2
  • the PARP-specific uptake of [ 11 C]PyBic in the RG2 rat brains does not exclude the possibility that the tracer is entering the brain through the damaged BBB and/or the BTB around the tumors. Caution should be taken when interpretating the kinetics modeling results.
  • two healthy NHPs were imaged after intravenous bolus injections of [ 11 C]PyBic.
  • veliparib Based on the metabolism profile of veliparib, it was hypothesized that the oxidization product (compound 6) of methylpyrrolidine is the major radiometabolite. Based on the effective blocking by veliparib in the rodent and NHP PET imaging and the fact that a minimum amount of radiometabolites were detected in the rat brain homogenates (Fig. 2F), the radiometabolites are not expected to interfere with the interpretation of the brain PET imaging results. Compared to other PARP1/2 inhibitors, such as olaparib, talazoparib, and rucaparib, veliparib has a lower PARP trapping capability, implicating a faster K off rate than other PARP1/2 inhibitors, a desirable feature for quantitative brain PET imaging.
  • PARP1/2 inhibitors such as olaparib, talazoparib, and rucaparib
  • the veliparib can block the brain uptake of PyBic effectively at the doses of 5 mg/kg in rats and 2.5 mg/kg in monkeys, because sufficient amount of veliparib can reach its target in the brain, even though it is a weak substrate of p-gp. This is consistent with previous results using veliparib at 3.1 mg/kg/d to 25 mg/kg/d, which increased the efficacy of temozolomide in rat glioma model.
  • the efflux ratio of veliparib in MDR1-MDCK cells was 1.8, indicating veliparib as a weak P-gp substrate.
  • the efflux ratio of PyBic was measured to be 0.52, indicating PyBic is not a P-gp substrate.
  • Embodiment 1 A compound of Formula (I), or a salt, solvate, tautomer, or stereoisomer thereof: wherein: R 1 is H or C 1 -C 6 alkyl comprising at least one 11 C; R 2 is H wherein the compound comprises at least one of 11 C and 18 F.
  • Embodiment 2 The compound of Embodiment 1, wherein R 1 is C 1 -C 6 alkyl comprising at least one 11 C.
  • Embodiment 3 The compound of any one of Embodiments 1-2, wherein R 1 is 11 CH3.
  • Embodiment 4 The compound of any one of Embodiments 1-3, wherein R 2 is 18 F. 62 53376748.1 Attorney Docket No.047162-7482WO1(02447)
  • Embodiment 5 The compound of any one of Embodiments 1-4, which is selected from the group consisting of: Embodiment 6: The compound of any one of Embodiments 1-5, which is selected from the group consisting of: Embodiment 7: A compound of Formula (II), or a salt, solvate, tautomer, or stereoisomer thereof: least one 11 C; R 2 is 18 F or 19 F; and R 3 is 11 C or 12 C; wherein the compound comprises at least one of 11 C and 18 F.
  • Embodiment 6 The compound of any one of Embodiments 1-5, which is selected from the group consisting of: Embodiment 7: A compound of Formula (II), or a salt, solvate, tautomer, or stereoisomer thereof: least one 11 C;
  • Embodiment 8 The compound of Embodiment 7, wherein R 1 is C1-C6 alkyl comprising at least one 11 C. 63 53376748.1 Attorney Docket No.047162-7482WO1(02447)
  • Embodiment 9 The compound of any one of Embodiments 7-8, wherein R 1 is 11 CH3.
  • Embodiment 10 The compound of any one of Embodiments 7-9, wherein R 2 is 18 F.
  • Embodiment 11 The compound of any one of Embodiments 7-10, which is selected from the group consisting of: ,
  • Embodiment 12 A method of imaging poly(ADP-ribose) polymerase-1 (PARP1) in a subject, the method comprising: administering the compound of claim 1 or claim 7 to the subject, and imaging the compound in the subject.
  • Embodiment 13 The method of Embodiment 12, wherein the imaging comprises positron emission tomography (PET).
  • Embodiment 14 The method of any one of Embodiments 12-13, wherein the PARP1 is imaged in the brain of the subject.
  • Embodiment 15 The method of any one of Embodiments 12-14, wherein the subject suffers from glioma, optionally wherein the glioma is glioblastoma.
  • Embodiment 16 The method of any one of Embodiments 12-14, wherein the subject suffers from Alzheimer’s disease (AD), Parkinson’s disease (PD), and/or any other central 64 53376748.1 Attorney Docket No.047162-7482WO1(02447) nervous system (CNS) disease.
  • Embodiment 17 The method of any one of Embodiments 12-16, wherein the imaging is used to quantitate PARP1 in the subject.
  • Embodiment 18 The method of any one of Embodiments 12-17, wherein the imaging is used to identify whether the subject will benefit from administration of a PARP1 inhibitor to treat, ameliorate, and/or prevent a disease or disorder.
  • Embodiment 19 The method of Embodiment 18, wherein the disease or disorder is cancer or a central nervous system (CNS) disease.
  • Embodiment 20 The method of Embodiment 19, wherein the cancer is glioma.
  • Embodiment 21 The method of Embodiment 20, wherein the glioma is selected from the group consisting of ependymoma, anaplastic astrocytoma, glioblastoma, astrocytoma, brainstem glioma, diffuse midline glioma, oligodendroglioma, ganglioglioma, circumscribed astrocytic glioma, low-grade glioma, angiocentric glioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, and dysembryoplastic neuroepithelial tumor.
  • the glioma is selected from the group consisting of ependymoma, anaplastic astrocytoma, glioblastoma, astrocytoma, brainstem glioma, diffuse midline glioma
  • Embodiment 22 The method of any one of Embodiments 20-21, wherein the glioma is glioblastoma.
  • Embodiment 23 The method of Embodiment 19, wherein the CNS disease is Alzheimer’s disease (AD) or Parkinson’s disease (PD).
  • Embodiment 24 The method of any one of Embodiments 12-23, wherein the compound is administered in an amount sufficient to clinically diagnose a disease or disorder of the brain.

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Abstract

L'invention concerne des agents d'imagerie par tomographie par émission de positrons (TEP) pour la quantification de poly(ADP-ribose)polymérase-1 (PARP1) dans le cerveau humain.
PCT/US2024/056280 2023-11-15 2024-11-15 Agents d'imagerie tep de parp et leurs procédés d'utilisation Pending WO2025106920A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6548494B1 (en) * 1999-08-31 2003-04-15 Agouron Pharmaceuticals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US7732491B2 (en) * 2007-11-12 2010-06-08 Bipar Sciences, Inc. Treatment of breast cancer with a PARP inhibitor alone or in combination with anti-tumor agents
US20120035244A1 (en) * 2010-07-29 2012-02-09 The Regents Of The University Of Michigan Parp1 targeted therapy
US20170283436A1 (en) * 2014-08-29 2017-10-05 Celia Dominguez Probes for imaging huntingtin protein

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6548494B1 (en) * 1999-08-31 2003-04-15 Agouron Pharmaceuticals, Inc. Tricyclic inhibitors of poly(ADP-ribose) polymerases
US7732491B2 (en) * 2007-11-12 2010-06-08 Bipar Sciences, Inc. Treatment of breast cancer with a PARP inhibitor alone or in combination with anti-tumor agents
US20120035244A1 (en) * 2010-07-29 2012-02-09 The Regents Of The University Of Michigan Parp1 targeted therapy
US20170283436A1 (en) * 2014-08-29 2017-10-05 Celia Dominguez Probes for imaging huntingtin protein

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Title
DATABASE PubChem 11 December 2006 (2006-12-11), ANONYMOUS: "2-(2-methyl-2-pyrrolidinyl)-1H-benzimidazole-4-carboxamide | C13H16N4O ", XP093316728, Database accession no. CID 11960528 *
PHILIP W. MILLER; NICHOLAS J. LONG; RAMON VILAR; ANTONY D. GEE: "Synthesis of 11C, 18F, 15O, and 13N Radiolabels for Positron Emission Tomography", ANGEWANDTE CHEMIE, VERLAG CHEMIE, HOBOKEN, USA, vol. 47, no. 47, 5 November 2008 (2008-11-05), Hoboken, USA, pages 8998 - 9033, XP072081504, ISSN: 1433-7851, DOI: 10.1002/anie.200800222 *

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