TW201210621A - Fluorodeuteriomethyl tyrosine derivatives - Google Patents

Abstract

This invention relates to deuterated tyrosine derivatives labeled with 18F or 19F, methods of preparing such compounds, compositions comprising such compounds, kits thereof and uses of such compounds, compositions or kits for imaging proliferative diseases.

Description

201210621 VI. Description of the Invention: [Technical Field] The present invention relates to an 18F or labeled deuterated tyrosine derivative, a method for preparing a S-specific compound, a composition comprising the same, and a kit thereof And the use of such compounds, compositions or kits for imaging proliferative diseases. [Prior Art] The present invention relates to the subject matter mentioned in the scope of the patent application, that is, the deuterated tyrosine derivative of the formula (1), its use and its preparation method. In the fields of oncology, neurology and cardiology, molecular imaging has the potential to detect disease progression or therapeutic effects earlier than the most regular methods. In several promising molecular imaging technologies that have been developed for optical imaging and MRI, PET has received special attention due to its high sensitivity and ability to provide quantitative and kinetic data. Positron emitting isotopes include carbon, nitrogen, and oxygen. These isotopes can be substituted for their non-radioactive counterparts in the target compound to produce a display that is biologically functional and chemically aligned with the original S molecule for ρΕτ imaging. On the other hand, 8p is the most convenient labeled isotope due to its relatively long half-life (109.6 min), which allows for the preparation of the biosynthesis and subsequent studies of biochemical processes. In addition, its high β+ yield and low β+ energy (635 keV) are also advantageous. The 20% of the mouth is known to have a short half-life, and the radioactive tracer containing 11 需 requires an accelerator, while the 18F PET tracer allows for off-site production and regional distribution in terms of a half-life of 109 minutes. 158268.doc 201210621 Tumor diagnosis using positron emission tomography (pET) exploits the fact that tumor tissue proliferates more rapidly than positive* healthy tissue. The best known example for imaging disease is 2_[18f]fluorodeoxyglucose ([isF]FDG), the most widely used PET radiopharmaceutical (J Nucl Med (1978), 19, 1154-1161 ). However, many misjudgments and artifacts have been attributed to fdg imaging and are increasing as the world's use of FDG increases. The most common regional line of interpretative misjudgments using FDG is associated with absorption in active skeletal muscle (Seminars in Nuclear Medicine, (2004), XXXIV, 2, pp. 122-133). Many benign conditions can cause a large accumulation of FDG, which may lead to false positive interpretations. Most of these artifacts are associated with inflammation, infection, or granulomatous processes (Seminars in Nuclear Medicine, (2004), XXXIV, 2, pp. 122-133; Seminars in Nuclear Medicine, (2004), XXXIV, 1, pp. 56 to 69; (2004), J Nucl Med (2004), 45, pp. 695-700). Other tumors (including mucosa-associated lymphoma, small lymphocytic lymphoma, certain neuroendocrine tumors, sclerosing bone metastases, and renal cell carcinoma) may be virtually inconspicuous due to low absorption or high adjacent background radiation. The specific correlation with PET-CT is related to the misjudgment of respiratory differences between modes' and is independent of the dedicated combination scanner (Seminars in Nuclear Medicine, (2004), XXXIV, 2, pp. 122-133). Radiolabeling has been studied. Amino acids for tumor imaging (jager et al., j

Nucl Med" 2001, 42(3), 432-45) to overcome the limitations encountered with [18F]FDG. Initially 'natural amino acids are labeled with carbon-11, such as [11C] valine, L-^ C] leucine, L-[UC]methionine, and structurally similar analogs. The main neutral amino acids are mainly via non-sodium-dependent L-form 158268.doc 201210621 Amino acid transporter After absorption into tumor cells, these tracers remain in the tumor cells primarily due to protein synthesis. The limitation of radiolabeled natural amino acids involves the production of a variety of radiolabeled S metabolites via metabolic degradation of several pathways, It is difficult to analyze the absorption of the parent compound by tumors. Kinetic studies have shown that amino acid transport better reflects tumor proliferation than protein synthesis. In the past decade, tyrosine derivatives have received special attention and have been shown to be introduced. <9-([i8F]fluoroethyl)-tyrosine ([18F]FET) is effective in brain tumor imaging' but not suitable for peripheral tumors (Wester et al, j Nucl Med. 1999, 40, 663, J Nucl. Med. 1999, 40, 205AJ. Nucl. Med. 1999, 40, 1367: ^ Others may be concerned Tyrosic acid derivatives include 3-[18F]fluoro-α-methyl-tyrosine (In〇ue et al.,; Nud. Med 1998, 39, 205), 〇-([18f]fluoroantimony) cheese Amino acid (Ishiwata et al.,

Nucl· Med. Biol., 2004, 31, 191), ~([丨8f]fluoropropyl)tyrosine (Tang et al., Nucl. Med. Biol., 2003, 30, 733), 〇-([ 18F]fluoropropenyl)-tyrosine (Arstad et al., w〇2〇〇7〇732〇〇) and 〇([181?]fluoroethyl)·α_mercapto-tyrosine (Wang et al. , Bioorg. Med. chem. Lett·' 2010, 20, 3482). These radiolabeled tyrosine derivatives all have disadvantages, i.e., low yield and high quality doses in the electrophilic radiofluorination process for the preparation of 3_[丨8f]fluoro-α-methyl-tyrosine. Other guanamines and organisms show poor absorption in cell culture, low accumulation or poor pharmacokinetics in tumor-bearing mice, resulting in images with high f-fields. Acid derivative (Tanaka et al., us '824'76G B2) ', however, the example shown in this patent is 0-(3_-propylpropyl) alpha-methyl-luthenic acid at 13 762 metastatic mammary gland The mouse tumor did not show 158268.doc 201210621 High absorption (0.454% ID at 30 min pi) also did not show rapid washout (0,454°/〇ID at 30 min p_i., relative to 4 h pi) 0.069% ID) (US 6,824,760 B2). Another derivative ([18F]fluoroethyl)-α-methyl-tyramine disclosed in this patent has recently been published (Wang et al.

Bioorg. Med. Chem. Lett., 2010, 20, 3482), which shows that its absorption in U-13 8 M G human glioblastoma cells is 10 times lower than that of "gold standard" FETs. (9-([18F] gas methylglutamic acid (DFMT, Tsukada et al, J. Nucl. Med., 2006, 47 079; Tsukada et al, Eur. J. Nucl. Med. Mol. Imaging, 2006 33 1017 and Urakami et al., Nucl. Med. Biol., 2009, 36, 295) have recently been shown to provide better images in tumor-bearing mice. The reason may be that D is compared to its L-isomer. - The isomer is recognized by the tumor, but is not recognized by other organs in the body' and it is rapidly excreted via the kidney, thereby improving image quality (Tsukada et al. 'J. Nucl. Med., 2006 679). Yes, the absorption of DFMT in tumor-bearing mice is quite low (in HeLa xenografts, 2.57 ± 0.547% ID/g at ih pi) 〇 aliphatic 18F-fluorination reaction for 18F-labeled radiopharmaceuticals It is very important that the radiopharmaceutical is used as an in vivo imaging agent to visualize and visualize diseases such as solid tumors or brain diseases. Since the 1 isotope has a short half-life of only about 110 minutes, Therefore, the most important technical goal in the use of I sF_ standard radioactive drugs is rapid preparation. And the administration of the radioactive compound. A variety of 18F radiolabeled pet tracers are currently being investigated for use in many of the same diseases, with the following highlighting a few of these tracers:

H〇/YrVNH

[18F]FLT a

[18F]FCH [18F]DFMT

03⁄4 [«FJFMeNER

[18F]FET (glioma): Floeth et al., 乂#mc/· Med., 2008, 49(5), 730-737>5. Vees# A > Eur. J. Nucl. Med. Mol. /maging,2009, 36(2),182-193; [18F]FLT (cell proliferation): Buck et al, 2009, 48(2), 205-215 and van Waarde et al, Cwrr. P/rnrm· Ζ ) α., 2008, 14(31), 3326-3339 ; [18F]FCH (prostate cancer): Beheshti et al. 'Mo/· /magz'wg. 5io/·, 2009, 11(6), 446-454 And Husarik et al, J. Nucl. Med. Mol. Imaging, 2008, 35(2): 253-263; [18F] DFMT (tumor imaging): Urakami et al. A > Nucl. Med. Biol., 2009, 36 (3), 295-303>5.Murayama^ 158268.doc 201210621 person, XA^/· Md., 2009, 50(2), 290-295; [uF]FMeNER (norepinephrine transporter): Schou Et al' 2004, 53, 5 7-67 ; [18F]SPA-RQ (Cath Neurokinin Type 1 (ΝΚι) Receptor Imaging):

Hargreaves et al, J. 2002, 63 (Suppl 11), 18-24; [18F]NR2B (NMDA receptor imaging): Hamill et al, X Label. Compd. Radiopharm., 2005, 48, 1-10; , 8F] FMDAA1106 (neuroinflammation): Zhang et al, do not oorg. Med. C/zew., 2005, 13, 1811-1818; [18F] FMPEP (cannabinoid subtype-1 receptor): Donohue et al, ·/. Med C/zew., 2008, 51, 5833-5842. Most of these tracers have a radioactive label attached as a [18F]fluoroalkyl group (i.e., fluoromethyl, fluoroethyl, fluoromethoxy, fluoroethoxy). Shorter [18F] fluoroalkyl chains (eg, fluoromethoxy) are generally associated with a significant decrease in metabolic stability; this is often highlighted by high bone resorption during in vivo experiments because the free fluoride released is preferentially in the bone Accumulated in. In order to improve the metabolic safety of these groups, the method uses hydrazine to replace the hydrogen atom in the fluoroalkyl bond. The reason for using this method is proposed by rF]FMDAAU()6 (Zhang et al., Yang-fine U〇5'13, 1811_1818); it is proposed that the hydrocarbon (C_H) bond of the [F] fluoromethyl group can be affected by the enzyme. Attack and cleave, then hydrogen will be removed from the same carbon atom to produce (Figure 2). This carbon woman will be stabilized by resonance with adjacent oxygen atoms, which promotes decomposition of the starting compound. 158268.doc 201210621 OMe

Flowchart 1 In the design of [i8f]FMDaa11〇6, substituted by the 在 in the study of Zhang et al. (Zhang et al. 'c/zem., 2005, 13, 1811-1818). The reason for this practice is: 1 The ruthenium atom has a bioelectron isosteric property similar to that of a hydrogen atom. The 氘 substitution can have only minimal effect on the binding affinity; 2) the 氘 substitution can be expected to reduce the defluorination rate of the [18F] fluoromethyl group because of carbon-氘 (CD) The keys are generally stronger and harder to break than the CH bond. This method has been used in other cases to increase metabolic stability, and some examples are as follows: 158268.doc 201210621

D4-[18F]FCH (prostate cancer): Leyton et al, Ca/icer Tie·?,, 2009, 69(19), 7721-7728; [18F]FMeNER-D2 (norepinephrine transporter): Schou Et al., 2004, 53, 57-67 and k, Eur. J. Nucl. Med. Mol. Imaging., 2QQ, 35, 153-157; [18F]NR2B-D2 (NMDA receptor imaging): Hamill et al. Person, J. Label. Compd. radiopharm., 2005, 48, 1-10; [18F]FDDAA1106 (neurological inflammation): Zhang et al, Mec/· C/zem., 2005, 13, 181, 1818; [18F ] FMPEP-D2 (Cannabinoid subtype-1 receptor): Donohue, //· Mec?· C/zew·, 2008, 51, 5833-5842. In all of this filial piety, it was found that the compounds of the analogs substituted with deuterium were more metabolically stable. However, it has not been reported whether the stability of the radiolabeled tracer substituted by deuterium increases hydrolytical stability. Hydrolysis studies on groups that have not been substituted by hydrazine (i.e., [18f] fluorodecyloxy) have only been reported. For example, [18F]FMeMcN (Zessin et al., #Me/· Med. 5/〇/., 2001, 28, 158268.doc •10- 201210621

857-863) found that the change in H, P and mixture, the use of PH8 and 50% propionate can significantly increase the stability of hydrolysis.疋Γ 疋Γ • • • However, these conditions do not apply to all PET tracers, especially those who are sensitive to alkali. There is a continuing need for new agents and methods for increasing the hydrolytic stability of radiolabeled compounds. The present invention discloses compounds and methods of synthesizing and using such compounds to enhance the hydrolysis stability of radiolabeled compounds. Problems to be Solved by the Present Invention and Their Solutions Although the above advances have been made in determining that DFMT is a tyrosine derivative suitable for tumor imaging and especially cancer imaging, there is still a need for an improved signal, improved hydrolysis stability and/or Or a novel derivative or agent that the imaging agent absorbs in the tumor for higher tumors. In contrast, the compounds of the invention are characterized by an extremely rapid accumulation in tumors and much higher than their hydrogen analogs, and are more stable in aqueous solution over the same time period than DFMT. SUMMARY OF THE INVENTION The present invention relates to the subject matter mentioned in the scope of the patent application, that is, the tyrosine amino acid derivative of the formula (1), (DI), (D-Ia) ' (LI) or (L-Ia) , its use and its preparation method. [Embodiment] In a first aspect, the invention relates to a compound of formula (I),

158268.doc (I) 201210621 where χ is an atom (F); Y is CHD or CD2; and D is 氘. The formula includes its individual isomers, diastereomers and enantiomers or mixtures thereof and pharmaceutically acceptable salts thereof. Preferably, the fluorine atom (F) is an 18F or 19F isotope. Preferably, Y is a CD2. In the first embodiment, the present invention relates to a compound of the formula (1) wherein the gas atom (F) is an 18F isotope. Preferably, the fluorine atom (F) is an 18f isotope and the γ-based CD2» is in the second embodiment. The present invention relates to a compound of the formula (1) which is a 19F isotope. Preferably, the fluorine atom (F) is a 19f isotope and the γ is CD2. In a third embodiment, the invention relates to a compound of formula (H)'

Wherein X is a II atom (F); Y is a CHD, or CD2; and D is 氘. 158268.doc 12 201210621 Preferably, the fluorine atom (F) is an 18F or 19F isotope. More preferably, the fluorine atom (F) is an 18F isotope. Preferably, Y is a CD2 (D-Ia).

18

F. Preferably, the compound of the formula (D-Ι) or (D-Ia) is one in which the fluorine atom (F) isotope and the Y-based CD2.

In a fourth embodiment, the invention relates to a compound of the formula (Lq), (L-I) X-based fluorine atom (F); Y-based CHD, or CD2; and D represents deuterium. Preferably, the fluorine atom (F) is 18F or 19F. The auditor α Jing is better, the fluorine atom (F) is an 18F isotope. Preferably, Y is a CD2 (L-Ia).

X (L-Ia) 158268.doc 201210621 Preferably, the compound of the formula (L-J) or (L-Ia) is one in which the fluorine atom (F) is an isotope and the Y is a CD2. The invention further relates to suitable inorganic or organic acid salts, hydrates and solvates of the formula (1), (ethylidene, (L7)' (1) or (d7) compounds. Embodiments and preferred features may be combined And is within the scope of the invention. The compound of the invention is · · Fluor [2H2] fluorenyl) DL- uric acid

〇-([18F][2H2] fluorenyl)_l-glycine

Fluorine [2H2]methyl)_D_luic acid

158268.doc 0 201210621 〇-(Fluoro[2H2]methyl)-DL-tyrosine

(rac), 〇-(fluoro[2H2]fluorenyl)-L-tyrosine

◦-(fluoro[2H2]fluorenyl)-D-tyrosine

Preferably, the compound of the invention is: 〇-([18F]fluoro[2H2]decyl)-D-tyrosine

158 158268.doc •15- 201210621 〇-(Fluoro[2H2]methyl)-D-tyrosine

In a second aspect, the invention relates to a process for obtaining a compound of formula (I). The process of the invention is an indirect fluorine labeling process, see Scheme 2.

Formula IV for indirect labeling of former Formula I, (new F-18 labeled Pet imaging agent) Formula III (F-18 labeled prosthetic group) Formula II - (for synthesis of known F-18 labeled prosthetic precursors) = Novel Compounds Flowchart 2: Indirect Fluoride Labeling Methods Under the present invention, these methods are used to obtain a method of intermolecular labeling of a compound of formula (I) as described above. The embodiments and preferred features described in the first aspect will be incorporated herein. The indirect fluorine labeling method comprises the steps of: - coupling a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (I),

X

H2n

〇(1) 158268.doc •16· 201210621 wherein X is a fluorine atom (F); Y is CHD or CD2; and D is not shown in Figure 1, and wherein the compound of formula (III) is suitably F-1 8 or F-19 The excipients labeled and the compound of formula (IV) are D- or L-tyrosine or mixtures and/or salts thereof. The indirect fluorine labeling method comprises the steps of: - coupling a compound of the formula (II) with a fluorine atom (F) moiety to obtain a compound of the formula (III), - a compound of the formula (III) and a compound of the formula (IV) To obtain a compound of formula (I),

Wherein X is a fluorine atom (F); Y is CHD or CD2; D is deuterium, and - the desired compound is converted into a pharmaceutically acceptable inorganic or organic acid salt, a hydrate thereof, a complex, Vinegar, decylamine, and solvate, wherein the compound of formula (II) is used to synthesize a suitable precursor of the known prosthetic group, 158268.doc • 17- 201210621 labeled with F-1 8 or F-19, formula (in) The compound is a suitable F-18 or F-19-labeled prosthetic group, and the compound of formula (IV) is hydrazine- or L-tyrosine acid or a mixture and/or salt thereof. Preferably, the method is a method for obtaining an indirect labeling of a compound of formula (I), which comprises the steps of: - coupling a compound of formula (II) with a fluorine atom (F) moiety (wherein the fluorine atom) Part (F) comprises an 18F isotope) to obtain a compound of formula (111), - a compound of formula (III) is coupled with a compound of formula (IV) to obtain a compound of formula (I), and - if desired Conversion of the compound to its pharmaceutically acceptable inorganic or organic acid salt, hydrate, complex, ester, guanamine, and solvate thereof, wherein the compound of formula (II) is used to synthesize a known prosthetic group labeled with F_18 Suitable precursors of the formula 'III() are suitable excipients labeled with 1?18, and the compounds of formula (IV) are D- or L-tyrosine or mixtures and/or salts thereof. More preferably, the method is a method for obtaining an indole labeling of 〇_([i8F]fluoro[2H2]methyl)_D-tyrosine ([18F]D-DFMT), which comprises the following steps: CD2Br2 is coupled with K[18F]F to obtain "pcDsBr, - coupling FCDaBr to D-glycolic acid to obtain [丨dfmt, and - converting the obtained compound into its pharmaceutically acceptable amount as needed 158268.doc -18-201210621 Inorganic or organic acid salts, hydrates, complexes, esters, decylamines, and solvates thereof. Preferably, the method is used to obtain an indirect labeling method for a compound of formula (1) And comprising the steps of: - coupling a compound of formula (II) with a fluorine-containing atom moiety (wherein the gas-containing atom (F) moiety comprises a % isotope) to obtain a compound of formula (10), - a compound of formula (ΠΙ) Coupling with a compound of formula (IV) to obtain a compound of formula (I), and - if desired, converting the compound obtained into a pharmaceutically acceptable inorganic or organic acid salt, hydrate, complex, ester thereof, a guanamine, and a solvate thereof, wherein the compound of the formula (II) is used for the synthesis of a known prosthetic group labeled with f-19 Should precursor "compound of formula (III) by suitable F_ 19 lines labeled prosthetic group of 'formula and (IV) compound is D- or L- tyrosine, or mixtures thereof and / or salts. A method in which a cold F19 compound is synthesized via the same synthetic route used to prepare a hot F18 compound has been shown (Iwata et al., j Label. Compds.

Radiopharm., 2003, 46, 555-566 and Donohue et al, J. Med. Chem., 2008, 51, 5833-5842) 〇 For all of the above methods, the compound of formula (I) is preferably a formula (Ld) , (L-Ia), (D-Ι) or (D-Ia) compound, and more preferably a compound of the formula (D-Ι) or (D-Ia). The reagents, solvents and conditions which can be used for this fluorination are well known and well known to those skilled in the art. See, for example, /· C/zem., 27 158268.doc -19- 201210621 (1985): 177-191. Preferably, the solvent used in the process of the present invention is DMF, DMSO, acetonitrile, DMA, or a mixture thereof, and the solvent is preferably acetonitrile. The reagents, solvents and conditions which can be used for the alkylation are familiar and well known to those skilled in the art. See, for example, Wester et al., >1.>111 (:1.1»46 (1·1999, 40,663. Preferably, the solvent system used in the method of the invention, DMSO, acetonitrile, DMA, or a mixture, preferably DMSO. A method for obtaining a compound of the formula (LI), (L-Ia), (D-Ι) or (D-Ia), wherein the formula (LI), (L-Ia) , (D-Ι) or (D-Ia) compounds are as disclosed above and wherein the above examples and preferred features are incorporated herein. The compounds of formula (II) are well known synthetics via F-1 8 or F- Suitable precursors for the 19-labeled known prosthetic group (Zhang et al., Bioog. Med. Chem., 2005, 13, 1811-1818;) Preferably, the compound of formula (II) is R1, /R2 γ (Π Wherein R1 is selected from the group consisting of halogens and sulfonates, wherein the gas is bromine or iodine, and the sulfonate is a sulphuric acid, tosylate, trifluorosulfonate or Nitrobenzenesulfonate; R2 is a leaving group selected from the group consisting of dentate and a phthalate, wherein the halogen is chlorine, bromine or iodine, and the sulfonate is sulfonic acid 158268.doc -20· 201210621 ester, Tosylate, triflate or nitrobenzene acid Ester; Y-based CHD or CDJ D represents gas. Non-limiting examples of compounds of formula (11) known to those skilled in the art are: (Eaborn and Stanczyk, J. Chem. Soc. Perkin Trans 2, 1991 471-473; B 〇thner-By et al., J. Am. Chem. Soc., 1987, 1〇9, 4180-4184; Takaya et al., J. 〇rg. Chem·, 1981, 46, 2846-2854): 氘化二Methyl bromide (CDsBi·2), monobromodibromomethane (CHDBr2), deuterated diiodomethane (CD2I2), mono-deuterated diiodomethyl (CHDI2). Preferably, the compound of formula (II) is deuterated dibromomethane. (CD2Br2) The compound of formula (III) is a well-known F-18 or F-19-labeled prosthetic group (Zhang et al., Bioog. Med. Chem., 2005, 13, 1811-1818; Donohue et al., J. Med. Chem., 2008, 51, 5833-5842). Preferably, the compound of the formula (ΙΠ)

R1, /XY (III) wherein R1 is selected from the group consisting of halogen and a reductive acid group, wherein ii is a gas, bromine or iodine' and a sulfonate mesylate, a tosylate, Trifluorosulfonate or nitrobenzenesulfonate; 158268.doc •21 - 201210621 X-type gas atom (F), I atom (F) is preferably 18F or 19F isotope, better 18F isotope; Y system CHD or CD2, and D indicates 氘. More preferably, the compound of formula (III) is

R1, /X Y (HI) wherein X is a 19F isotope; and Y is a CD2. More preferably, the compound of formula (III) is R1\ /X γ (in) wherein X is an 18f isotope; and Y is a CD2. Those familiar with UCI) compounds known to the skilled artisan: Sugao II simmering (FCDAr), sulphide bromine [Up] fluoromethicone ([18F]FCD2Br), mono-deuterated bromofluoromethane (FCHDBr), military Sputum bromine is widely. Fluorodecane ([F]FCHDBr), deuterated fluoroiododecane (FCD hawthornization [%] fluoroiododecane ([fjfcdj), mono-deuterated fluoroiodomethane (FCHDI), mono-deuterated [18f] defeat峨甲炫([18f]FCHDI), toluenesulfonic acid oxime i-acetic acid (FCD2OTos). Preferably, when the fluorine atom (F) is 4 isotope, the compound of formula (111) is deuterated bromine [F] Fluorofluorene ([F]FCD2Br), mono-deuterated bromine [isF] fluoroindole 158268.doc -22- 201210621 ' ([F]FCHDBr), saponification [18F] fluoroanthridine ([18f]fcd2I) Monosinating [18f]fluoroiododecane ([18F]FCHDI) » More preferably, the compound of formula (III) is deuterated bromine [ISF] fluoromethyl. ([18F]FCD2Br). Preferably, when When the fluorine atom (F) is a 19F isotope, the compound of formula (III) is deuterated bromofluoromethane (FCDzBr), monofluorinated bromofluoromethane (FCHDBr), deuterated fluoroiodomethane (FCDJ), monofluorene fluoroiodomethane. (FCHDI), fluorobenzene methyl sulfonate (FCD2OTos). The compound of formula (IV) is suitable for use as an indirect labeled precursor of the well-known d_4L_tyrosine or a mixture thereof and/or a salt thereof. Non-limiting examples of compounds of formula (IV) are known to be: L-tyrosine, D-tyrosine And mixtures thereof, L-tyrosine, salts of D-tyrosine, and mixtures thereof. Preferably, the compound of formula (IV) is D-alkylic acid. The fluorine atom (F) moiety preferably comprises 1$. Or 191?. More preferably, the fluorine atom (F) moiety comprising 18F may be a chelate complex known to those skilled in the art (for example, 4, 7, 13, 16, 21, 24_6) Oxa-1,10-azabicyclo[8.8.8]·hexadecane κ18ρ (crown ether salt. Kl8F), 18_crown-6 ether salt K18F, K18F, H18F, KH18F2, Rb18F,

Cs F Na F), or a tetraalkylammonium salt known to the skilled artisan (e.g., [18F] tetrabutylammonium fluoride), or a sulfonium quaternary salt known to those skilled in the art ( For example, [4] gasified tetrabutyl scales). Most preferably, the gas-containing atom (F) moiety is CV4, KuF, h18f, or #%. More preferably, the fluorine-containing atom (F) moiety contains 19f. Even more preferably, the fluorogen (F) moiety of the 158268.doc •23-201210621 is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8. 8]-hexadecane 1^(crown ether salt 1<:1^扒〇行乂〖??), 1,4,7,10,13,16-hexaoxacyclooctadecane KF, KF, fluorine Tetrabutylammonium, tetrabutylammonium dihydrogen trifluoride. In a third aspect, the invention relates to a composition comprising a compound of formula (I), (LI), (L-Ia), (D-Ι) or (D-Ia) or a mixture thereof and a pharmaceutical composition Acceptable carrier or diluent. Those skilled in the art are familiar with the auxiliaries, vehicles, excipients, diluents, carriers or adjuvants which are suitable for the desired pharmaceutical formulation, formulation or composition, as is known in the art. Administration of a compound, pharmaceutical composition or combination of the invention is carried out in any generally acceptable mode of administration. It is preferred to deliver intravenously. In general, the dosage of the active compound can be administered to a pharmaceutical composition according to the present invention in the range of 37 MBq (1 mCi) to 740 MBq (20 mCi). In particular, doses in the range of 15 〇 MBq to 370 MBq will be used. In the fourth aspect, the present invention relates to a compound of the formula (I) which is a radiopharmaceutical of a mammal. The compound of the formula (1) is a radiopharmaceutical for imaging a proliferative disease. In other words, the invention relates to the use of a compound of the formula for the manufacture of a radiopharmaceutical for imaging a proliferative disease of a mammal. Preferably, the compound of formula (1) is a compound of formula (L Ia), (D I) or (d-la) wherein F is an 18f isotope. 158268.doc •24· 201210621 Preferably, the proliferative disease is a cancer characterized by the presence of tumors and/or metastases. Preferably, the tumor is selected from the group consisting of gastrointestinal or colorectal malignant cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, prostate tumor, endometrial cancer, ovarian cancer, Testicular cancer, melanoma, small cell and non-small cell bronchial carcinoma, lung tumor, dysplastic oral mucosal cancer, invasive oral cancer, breast cancer (including hormone-dependent and hormone-independent breast cancer), squamous cell carcinoma, Neurocancerous diseases (including cancer neuroblastoma, glioma, astrocytoma, osteosarcoma, meningioma, soft tissue sarcoma); hemangioma and endocrine tumors (including pituitary adenoma, pheochromocytoma, paraganglioma) ), hematological tumor diseases (including lymphoma and leukemia). Preferably, the tumor is a prostate cancer, a prostate tumor or a lung tumor. Preferably, the metastasis is a metastasis of the above tumor. More preferably, the metastasis is a metastasis of prostate cancer, prostate tumor or lung tumor. Preferably, the compounds and uses of the invention are used in the manufacture of PET imaging tracers for imaging tumors in mammals, wherein the tumor is preferably a prostate cancer/prostate tumor or a lung tumor. The radiopharmaceutical of the present invention is a suitable imaging tracer or MicroPET for positron emission tomography (pET). Imaging includes a PET imaging step and computerized tomography (CT) imaging or nuclear magnetic resonance computed tomography (mRT) costing before or after this. The invention additionally provides a method for imaging a proliferative disease, the method comprising A detectable amount of a labeled compound of the formula (I), (LI), (L-Ia), (D-Ι) or (D-158268.doc -25·201210621 la), or a pharmaceutically acceptable hydrate thereof, Solvates, esters, amines or prodrugs are introduced into the patient. Preferably, F is an i8F isotope. The invention also relates to a method for imaging or diagnosing a proliferative disease comprising the steps of: - administering to a mammal an effective amount comprising, (Lq), (L_la), (D-Ι) or (D-Ia) a compound of the compound, - obtaining an image of the mammal, and - evaluating the image. The compounds of the equations (1), (L-I), (L-Ia), (εμμφα) are as defined herein above and include all embodiments and preferred features contained herein. In a fifth sample, the invention relates to the use of a compound of formula (1) for the determination of a substance and/or for the identification of a chromatogram. More preferably, the use is a compound of formula (1) wherein the fluorine isotope is % or % (more preferably 19) ρ). The compound of the formula (1) wherein the fluorine isotope is I9F is suitable as a reference and/or far-measuring agent. The compounds of the formula (I) are as defined above and include the households contained herein, with examples and preferred features.

In the sixth aspect, the too clear trousers Js A 曰 梃 曰 梃 梃 梃 梃 梃 梃 梃 梃 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰a sealed vial of the compound, the complex, and the —* ^ ^, decylamine, and solvate: a hydrazine compound; and a compound of the formula IV. The kit includes, depending on the situation, the carrier, diluent, and adjuvant used in the first fruit of the medicine. 158268.doc •26·201210621 Agent or adjuvant. The compounds of formula II and IV are as described in the second aspect. In a seventh aspect, the present invention relates to a method of monitoring tumor and/or metastatic size by imaging a patient PET using a compound of formula (1). It has been surprisingly found that the F-18_compound of the invention is a potential pET radiant display for imaging tumors and/or metastases in a mammal. The compound of the present invention rapidly accumulates and preserves tumors and/or metastases in tumors and 7 or transfusions, and measures tumor and/or metastasis from the obtained pET image. I measured tumor and or transferred size. 'In the appropriate time interval, the spear J was used to image the patient at least twice with the compound. Tumors are monitored by imaging the patient with the compounds of the invention, or the size is transferred and the tumor and/or metastatic size obtained is compared. Definitions used in the present invention are defined as follows, but are not intended to limit the invention. If a compound according to the invention is present in a palm center or other form of isomeric ~' then this document is intended to cover all such forms. A construct comprising an enantiomer and a diastereomer. The compound containing the palm of the hand may be used as a racemic mixture or an enantiomerically enriched mixture or a mixture of diastereomers or as a mixture of diastereomers, or may be isolated from such isomers using well-known techniques. Mixtures, and individual stereoisomers may be used alone. In the case where the compounds can exist in tautomeric forms (such as hydrazine-dilute tautomers), it is expected that each tautomeric form will be encompassed by the present invention. , whether in a balanced form or mainly in one form. 158268.doc -27· 201210621 In the context of the present invention, preferred salts are pharmaceutically acceptable salts of the compounds of the invention. The invention also encompasses salts which are not themselves suitable for pharmaceutical use, but which can be used, for example, to isolate or purify a compound according to the invention. The pharmaceutically acceptable salts of the compounds of the present invention include inorganic acid, acid retardant and acid addition salts of sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfonate. Acid, naphthalene disulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, frequency fruit acid, bar acid, fumaric acid, maleic acid and benzoate. The pharmaceutically acceptable salts of the compounds of the present invention include salts of conventional bases such as, for example, and preferably, alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium salts). And an ammonium salt derived from ammonia or an organic amine having from 1 to 16 slave atoms, such as, for example, and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, Monoethanolamine, diethanolamine, diethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylene Amines and N, thiol. set. Stereochemistry can be represented in several ways. For amino acids, D/L derived from a Fischer projection of an amino acid is often used. For all compounds of the invention, 'D is stereochemically corresponding to the stereoscopic descriptor "R" in the cahn, Ingold, Prelog system, and L corresponds to the stereoscopic description symbol "S". Without further elaboration, it will be apparent to those skilled in the art that Therefore, the following preferred embodiments are to be considered as merely illustrative and are not intended to limit the remainder of the invention in any way. 158268.doc -28-201210621 parts [18F]DFMT represents 〇-([18F]fluoromethyl )-D-tyrosine.

H々. H

[18F] DDFMT stands for <9-([18F]fluoro[2H2]fluorenyl)-D-Lialin

All of the applications, patents, and publications cited herein are hereby incorporated by reference. The following examples 0 can be similarly successfully repeated by substituting the reagents and/or operating conditions of the present invention in general or specific descriptions, and the following examples are successfully repeated. From the above description, those skilled in the art can readily determine the present invention. The basic characteristics 'and the ; ^ from its spirit and the scope of the τ, can make a variety of changes and improvements to the 'money' to adapt to a variety of materials and conditions. Unless otherwise stated, what constitutes a pharmaceutical composition. Otherwise, when referring to the compound of the formula of the present invention, the present invention includes all hydrates, salts, and the general synthetic radiofluorination reaction of the compound 158268.doc -29 201210621 F-18 can be, for example, familiar in the art. A typical reaction vessel (such as a Wheaton vial) is known to be carried out in a microreactor. The s-reaction can be heated by typical methods such as oil baths, heaters or microwaves. The radioactive fluorination reaction is carried out in dimethyl decylamine using potassium carbonate as a base and "kryptofix" as a crown ether. However, other solvents known to the expert can also be used. Such possible conditions include (but are not limited to): acetonitrile, dimercaptoarrene, cyclobutane, dioxins, tetrahydro sulphur, tertiary alcohols and o-dichlorobenzene as solvents' and with and without It is suitable for the alkali metal of the alkali metal chelate crown ether, the slave S long-term four-burning base: and the four-burning town of niacin as the test. Water and/or alcohol may be included as a cosolvent in this reaction. The radiofluorination reaction is carried out for 1 to 6 minutes. The preferred reaction time is from 5 to 50 minutes. A more preferred reaction time is from 1 至 to 40 minutes. These and other conditions for this radiofluorination are known to experts (Coenen, Fluorine-18 Labeling Methods: Features and Possibilities of Basic Reactions, (2006), Schubiger P.A_, Friebe M., Lehmann L. ( Edit), PET-Chemistry - The Driving Force in Molecular Imaging. Springer, Berlin Heidelberg, pages 15 to 50). The radiofluorination can be carried out in "hot chambers" and/or using modules that allow automatic or semi-automatic synthesis (Review: Krasikowa, Synthesis Modules and Automation in F-18 labeling (2006), Schubiger PA, Friebe M., Lehmann L. (ed.), PET-Chemistry - The Driving Force in Molecular Imaging. I58268.doc -30- 201210621

Springer, Berlin Heidelberg, pp. 289-316). Synthesis of F-19 Compounds Scheme 3a shows a method for synthesizing racemic 〇_[i9F]fluoromethyltyrosine 4 from a method known to those skilled in the art. It is known from the 1 synthesis 2 series literature (Liu et al., j. Med. Chem., 2004, 47, 1223-123 3). A method of alkylating 2 to 3 is known for (9-(fluoroindolyl)-tyrosine acid (J Labelled Compds. Radiopharm. 2003, 46, 555_566) 'a similar method can be used for this. Alkane (Raymond, /. CAern, 1971, 75, 3235) and fluorenyl sulfonate toluene sulfonate (Donohue et al, 乂 2008, 51, 5833-5842) are known. There are precedents for the hydrolysis of amine protecting groups such as the third butoxyol (Boc) (Greene and Wuts, "protecting Groups in 〇rganic Syntheses", third edition, pages 369 to 453 and 94 to 653 The R and s isomers can be separated by methods known to those skilled in the art (ie, for palm chromatography). 158268.doc •31· 201210621

4(S) 4(R) Scheme 3a: Synthesis of 0-(fluoro[2H2]decyl)-DL-tyrosine 4,4(S) and 4(R). This synthesis can be carried out using the method described in Scheme 3b, and a similar process has been disclosed whereby alkylation by 3- gas-L-tyrosine or 3-gas-D-tyrosine can be achieved, Synthesis of 3-gas-0-mercapto-L-tyrosine and 3-gas-0-mercapto-D-luic acid (Trimurtulu et al., J. dm. C/zem. Soc., 1994, 1 16 , 4729-4737): 158268.doc -32- 201210621

4(R) Scheme 3b: Synthesis of 0-(fluoro[2H2]methyl)-D-tyrosine 4(R). F-18 Synthesis of a Compound of the Invention As shown in Scheme 4, a Type II precursor is reacted with [18F] fluoride to obtain a 1SF-labeled Type III intermediate, which is then combined with a Type IV precursor. The reaction is carried out to obtain the desired type I product, and the 18F compounds are synthesized. CD2Br2 deuterated dibromomethane

Formula II K[18F]F, K2C03 K222

0 D-tyrosine formula IV

18FCD2Br type III

NaOH, DMSO Η2Ν^γ ( 〇

D-DFMT

Scheme I Scheme 4: Radioactive synthesis of 0-([18F]fluoro[2H2]decyl)-D-tyrosine ([18F]D-DFMT). 158268.doc -33- 201210621 Experimental part abbreviation AcOH Acetic acid nBuOH n-butan-1-ol DMA N,N-dimercaptoacetamide DMF Ν, Ν-dimethylformamide DMSO Dimercapto sulfoxide EtOH Ethanol FCS fetal bovine serum GBq GigaBequerel H hour HPLC high pressure liquid chromatography K222 Kryptoflx 2.2.2 Min min MBq MegaBequerel MeOH methanol PBS phosphate buffered saline PET/CT positron emission tomography / computed tomography rt room temperature SPE solid Phase Extraction TFA Trifluoroacetic Acid General: All solvents and chemicals were obtained from commercial sources and used without further purification. Unless otherwise stated, an anhydrous solvent and an inert atmosphere (nitrogen or argon) are used. For the abbreviations not explained in the text, the above table lists the abbreviations used in this paragraph and the examples section. I58268.doc -34· 201210621 Compounds and intermediates prepared according to the methods of the invention may require purification', preparative HPLC according to the preparative HPLC method described below. 〇-([i8F]fluoroindolyl)_D_tyrosine (DFMT) was synthesized according to the procedure of known literature (Tsukada et al, j Nucl Med, 2006, 47, 679). 1 · Chemical experiment Example 1 0-([18F]fluoro[2H2]fluorenyl)-D-sialamic acid ([18F]D-DFMT)

[18F]fluoride (2879 MBq) was fixed in a pretreated QMA (Waters) canister (pretreated by washing the sleeve with 5 mL of 0.5 M K2C03 and 10 mL of water). The [18F] fluoride was eluted using a solution of K2C03 (2.7 mg) in 50 pL of water and Kadis mg) in 950 pL of acetonitrile. The solution was dried at 120 ° C by stirring under vacuum and using a nitrogen flow of 15 〇 mL/min. Further, acetonitrile (丨mL) was added, and the drying step was repeated. A solution of deuterated dibromomethane (CD2Br2; 100 pL) in acetonitrile (900 μM) was added and heated at 13 ° C for 5 min. The reaction was cooled to 50 C ' and the [18F] fluoroantimony ruthenium bromide was distilled into the dmSO (1 mL) via 4 meteorite sleeves under a nitrogen flow of 50 ° C and 50 mL/min. In a solution of 10% NaOH (13.5 μM D-tyrosine (3 mg). Heat the solution for 5 min at ll ° ° C and then cool to 40 ° C. by HPLC (ACE 5 μ C1 8 25〇xl〇mm ; EtOH:AcOH:H20 158268.doc -35- 201210621 (100:1:900); flow rate 5 mL/min), the reaction mixture was purified. The peak of the product was collected and concentrated to Dry. The dried product was redissolved in pBS. 177 MBq (13% dc) of []8F]D-DFMT (not optimized) was obtained from 2879 MBq [18F] fluoride in 121 min.

〇 Figure 1 shows the chromatogram of the final product D-DFMT, la): radioactive spectrum, lb): UV spectrum. HPLC system: Agilent 11 00 HPLC column: Synergi Hydro 4 μ 250 x 4.6 mm Eluent: A water + 0.1% TFA (Agilent 7) B Acetonitrile + 0.1% TFA Gradient: 00 00 min 15% B 15 〇〇15 % B Flow rate: 1 mL/min Example 2. Radioactive synthesis of 〇-([18F]fluoroindolyl)_D• tyrosine ([i8F]DFMT) Fix [8F]fluoride (3 73 6 MBq) in the pre- The QMA (Waters) set was treated (pretreated by washing the sleeve with 5 mL of 0.5 M K2C 3 and 10 mL of water). The [丨8F] fluoride was eluted using a solution of K2C〇3 (27 mg) in 50 water and k: 222 (15 mg) in 95 μg of acetonitrile. The solution was dried at 120 C by stirring under vacuum and using a flow of 15 〇 mL/min of nitrogen 158268.doc -36 - 201210621. Further acetonitrile (1 mL) was added and the drying step was repeated. Add a solution of dibromodecane (CH2Br2) (100 μί) in acetonitrile (900 μΙ〇) and heat at 130 ° C for 5 min. Cool the reaction to 50 ° C and at 50 ° C and [l8F]Fluorodecyl bromide was distilled into a D-case containing 10% NaOH (13·5 μιη) in DMSO (1 mL) via 4 Shishishi sleeves under a nitrogen flow of 50 mL/min. In a solution of aminic acid (3 mg), the solution was heated at 11 ° ° (: 5 min, and then cooled to 40 ° C. by HPLC (ACE 5 μ C18 250 x 10 mm ; Et0H: AcOH: H20 (100: 1:900); flow rate 5 mL/min), the reaction mixture was purified. The peak of the product was collected and concentrated to dryness. The dried product was redissolved in PBS. Within 60 min, from 3736 MBq [18F] Fluoride obtained 285 MBq (12% d_c.) of [丨8F]DFMT (not optimized). Example 3. Hydrolysis stability of [18F]DFMT at room temperature [18F] in PBS with 0.1 M HC1 The solution of DFMT was adjusted to pH 7 and pH 5. The solution was kept at room temperature and TLC (TLC Silicone 60 F254 plate Merck; nBuOH: AcOH: PBS (4:1:2)) was used at different time points. The results are shown in Table 1. Example 4. [18F]DFMT at 37 ° C The hydrolytic stability

The solution of [18F]DFMT in PBS was adjusted to pH 7 and pH 5 with 0.1 M HCl. This solution was heated at 37 ° C and analyzed by TLC (TLC Silicone 60 F254 plate Merck; nBuOH: AcOH: PBS (4:1:2)) at different time points. The results are shown in Table 1. Example 5. Hydrolysis stability of [l8F]D-DFMT at room temperature The solution of [18F]D-DFMT contained in PBS was adjusted to I58268.doc -37 - 201210621 pH 7 and pH 5 with 0.1 M HCl. The solution was kept at room temperature and analyzed by TLC (TLC Silicone 60 F254 plate Merck; nBuOH: AcOH.PBS (4:1:2)) at different time points. The results are shown in Table 1. Example 6. Hydrolysis stability of [18F]D-DFMT at 37 ° C

The solution of [I8F]D-DFMT in PBS was adjusted to pH 7 and pH 5 with 0.1 M HCl. The solution was heated at 37 ° C and TLC was used at different time points (TLC Shiyue 60 F254 plate) Merck; nBuOH: AcOH: PBS (4:1:2)) for analysis. The results are shown in Table 1. RTpH5 37°C pH 5 RTpH7 37°C pH 7 Time (9) DFMT D-DFMT DFMT D-DFMT DFMT D-DFMT DFMT D-DFMT 0 97.39 100.00 97.39 100.00 94.29 100.00 94.29 100.00 1 93.35 97.65 91.06 95.19 93.00 98.00 91.57 97.65 2 91.31 96.81 85.69 92.61 91.16 97.43 87.67 93.25 3 90.67 95.44 83.00 92.73 91.32 95.08 86.07 90.71 Table 1. Hydrolysis stability of [18F]DFMT and [18F]D-DFMT in aqueous solutions at different pH and temperature. These results clearly show that the guanidine-substituted analog D-DFMT is more stable than DFMT. 2. Biological experiments Example 1: Cell Absorption Assay To evaluate the difference between [18f]d-dfmt and [18F]D-FMT, we investigated the uptake of radiolabeled compounds into A549 and NCI-H460 human lung cancer cells. Inoculate 80,000 A549 cells or NCI-H460 cells in each chamber of a 48-well culture plate (Becton Dickinson; Cat. No. 3 53078) in an incubator (37. (:, 5% C02), at 10%) FCS Supplement 158268.doc •38· 201210621 Cultured in RPMI 1640 medium with GlutaMAX (Invitrogen; Cat # 31331) for 1 day. Wash cells once with PB S, and then with 1 μ (: ί radiotracer ([ 18F] D-DFMT, [18F]D-FMT) in PBS for 10 to 30 minutes at 37 ° C. After incubation, the cells were washed once with cold PBS, lysed with 1 M NaOH, and finally gamma The horse counter measures the lysate. Surprisingly, the absorption of [18F]D-DFMT is higher than C8F]D-FMT» after 30 minutes '[18 corpse] 0-0卩; \41' is the highest in 549 cells , which was 6.8% applied dose per 106 cells, while [18F]D-FMT showed 5.3% applied dose/106 cells in A549 cells (see Figure 2). After 30 minutes, these NCI-H460 cells showed 4.1. % applied dose / [18F] D-DFMT uptake of 1 〇 6 cells, while [18F] D-FMT showed 2.1% applied dose / 1 〇 6 cells in NCI-H460 cells (see Figure 2). : [18 F] D-DFMT biodistribution in female NMRI (nu/nu) mice in NCI-H460 tumor-bearing mice for biodistribution and excretion studies. To induce tumors, according to standard methods, 5 Χ 〇 6 NCI-H460 lung tumor cells were inoculated subcutaneously to the right shoulder. After inoculation of the tumor cells for weeks, tracer injection and biodistribution studies were performed. 6 [i8f]d_DFmt was injected via the tail vein (3 animals per time point) ) to conscious animals. Quantitative collection of urine and feces at 15 ' 30, 60, 120 and 240 min time points. At the same time point, by decapitation and bloodletting under isoflurane anesthesia, kill Animals, and then remove the following organs and tissues for weighing and measuring Up radioactivity using gamma counters: spleen, liver, kidney, lung, fetus 158268.doc •39- 201210621 month, heart, brain, fat, Thyroid, muscle, skin, blood 'tail, stomach (no content), intestine (including contents), pancreas, adrenal gland and uterus. In order to obtain the total amount of radioactivity (=100%) administered in each animal, directly Measuring 3 aliquots of the injection solution The results of biodistribution and excretion were recorded as the percentage of injected dose per gram of tissue (%ID/g) and the tumor to organ ratio (T/T-ratio) was calculated (Table 2). [18F]D-DFMT showed good absorption into NCI-H460 tumors, which remained stable for a few hours before washout occurred. The pancreas showed the only other organ absorbed by [18F]D-DFMT. The elimination from the body is very fast. Table 2: Time P: 0ί5 h 0,5 h 1,0 h 2,0 h 4.0 h %dose/g SDSDSDSDSD Spleen 273 0.34 1.66 0.43 1.19 — 0.21 0.81 0.16 0·39 0.07 Liver 129 0.53 1.5$ 0^6 1.00 064 0 12 〇J1 0.05 __ 5.35 0.71 2.66 OJ22 1.75 0.3? 彳0 76 0.44 0.05 Lung Z89 0.52 1.W 0.65 1,10 --- 0.11 104 056 0.99 1.18 Bone 1.73 0.43 1.74 0.2B 1.67 0.54 15? 0 19 157 0. Ϊ8 heart 3.02 0.29 105 0.39 1*36 0 9Π d09 0·36 0.01 aim 0.7β 0.09 0.85 0.216 0^4 n ii 059 0.12 0*26 0.05 T25 fat 0.40 0.11 0.28 0.16 — olo 〇· 23 135 ---. ·Μ ___0.23 0.20 0.10 0·24 ?&Gland _ 2Λ1 0.48 148 0.76 0.1Ϊ 0.42 0.01 胆食 1.19 0.66 1.46 0.46 198 1.25 0.18 \22 0.12 Machine meat Ζ0$ 0.48 1.73 0.440 1M — 0·” OiU 0.38 0.03 4.29 0.14 3.57 0.52 3.68 0.50 197 0.72 OM 0.14 2.34 i56 0.42 0^8 1.89 ~~162 0.69 '"〇S 1.33 ΪΛ5 ~--112 Π ις 0.92 ' αΐβ 0.16 οΤόέ 0.34 0.35 0.12 0.03 Liquid tail 3.52 0.51 4.63 2.70 1.98 -----上丄? 0 33⁄4 037 Z93 2.99 宵274 0.16 1· shot 0.85 1.3β ^ 0.06 0.83 012 0 .47 0.09 uterus 4.11 0.50 2.49 0.63 2.19 -- ... 0.31 1.01 0.13 028 0.49 0.12 Ovum 4.00 0.81 138 0.47 U2 097 0.51 0.05 151 0.19 1.11 022 (U8 0.18 063 0.15 031 0.01 Pancreas 20.92 1.96 11.30 1.74 8.35 & 24 2^6 3.10 0.16 Adrenal gland ___ 3.03 0.49 1.17 0.31 0.69 A—0,25 0,80 0.04 0.402 Total SDSDSDSDSD Urine 31.55 7.79 38.35I Ϊ8Ό4 51.79 25 17 576 80.36 1.97 Μ---- 0.011 0.003 0^2 0.55 αΐ8 0.29 0.51 0.45 τ/τ·ratio SDSD_ SDSDSD 聛1.59 0.19 122 0.44 3^3 0.82 246 0.90 227 0.47 Liver m 0.42 i31 0.32 3.79 Λ02 057 2.82 0.81 F 0.81 0.11 0.93 0.52 2.14 — __.0.5 03⁄4 1.58 0.39 1.99 0.53 Lung 1.52 0.25 2·03 0.30 3.37 Ζ02 0.41 Z03 1.56 ft Z58 0.63 Z06 0.27 2.31 127 032 0.55 0.04 Road 0.86 4.35 1.16 443 〇70 131 1.02 3.37 0.40 Muscle Z12 0.47 114 0.50 22f η 2L33 0.B4 2.3 0.40 Blood 1.70 0.23 2.22 0 · 25 3J24 — ---ζ:ζί — 156 0.69 2.54 0.64 zzi 0.43 123 0.2B 4.36 1.26 107 0.5Ϊ 3.1fl 0.61 •40- 158268. Doc 201210621 Example 3: [18f] D-DFMT biodistribution in mice with NCI-H292 tumors as described in Example 2, in female NMRI (nu/nu) mice with NCI-H292 lung tumors, Biodistribution and excretion studies were performed using [18F]D-DFMT. The results of biodistribution and excretion were recorded as the percentage of injected dose per gram of tissue (%ID/g) and the tumor to organ ratio (T/T-ratio) was calculated (Table 3). [18F]D-DFMT showed very high absorption into the NCI-H292 tumor' which remained stable 1 hour before the washout occurred. The pancreatic line shows the only other organ that [18f]d-dfmt absorbs. The elimination from the body is very rapid. Table 3: Time point: Oish-0,5 h 1,0 h 2,0 h 4.0h_ an SDSDSDSDSD" * 287 〇 171 1.53 1.72 0.74 0.62 0.14 0.54 ^ 115 1-02 1.16 0.25 0.57 0.08 0.58 024 Liver Z52 0 -40 Kidney 5.95 5.00 2.12 2,38 057 1.99 0.21 U7 0.20 0·82 0.10 0.58 0 13 075 0.60 031 Bone 279 (M5 17a 0.15 1,85 0.M ΐ!5 ο3δ 1.11 0.14 1.75 〇J3 Heart 3.02 '188 0.79 1.56 0.34 0.64 0.12 - Block Si 1,22 0.476 1.01 5.41 0.61 0.08 IU9 0-21 Aim 0Μ 0.^ ----0.31 0.05 6.88 2.62 0.31 0.13 0.14 Fat 〇.«S _: '196 0.76 1.61 0.42 α70 0.19 0.65 Ww Gallbladder 0.47 O-ϋ? 0.67 0.06 4.83 0.70 1.3S 0.48 6.78 0.10 1-2« . —_ 252 0.439 1.50 0.23 0.5S 0 23 Muscle 18fi 0.1ϋ 觼瘸U.77 1.72 15.16 4.59 12.34 4.61 4.31 1.05 4.14 1.57 2.60 1.29 1.65 0.40 0.71 0.06 0.68 0-30 Bim Ζ9β Z38 1.01 1.32 0.26 0.60 0.08 0.62 0-27 Blood fl 30 4.13 2.34 2.15 6.15 220 0.69 ΣΪ4 1-9i Tail 4.46 卩M 256 1.68 1.39 0.19 0.78 0.11 0.61 U 厶3 100 〇."_ a 4.64 2.11 1.57 0.07 0.81 0.18 0.68 jyi uterus 3- W 111 —'3.49 1.04 1.51 0.09 1.03 0.22 0.66 038 4β1 0.12 Meal. 204 〇.«>_ 1.85 0.86 0.91 0.27 0.55 0.09 oeo 16.21 5.77 8,06 3.22 5,34 1.48 5^5 ZW 22.55 3.« 1.15 3.39 1.55 0.49 0.90 0.15 —Ϊ61 0-20 Glycarine I 1 Total SDSDSDSDSD 杲26.31 9-16 34.87 13.44 54,18 7.07 73.26 3.06 69.50 0.72 a 0.01 0.01 1.77 2.77 1.58 1.05 1.13 Λ便 - ··Τ/Τ-proportion s·卩· SDSDSDSD Brand 5.20 0.46 6.22 2.15 7.44 1.74 B.93 0.56 7.53' 0.98 7.6 ^〇9 Tfi 2J0 * 7.39 1.23 10.38 1.58 Liver 5.91 〇-6? ----Ϊ17 0.76 6.09 Ϊ.60 5.23 0.69 5.75 Kidney · 2,55 0-55 Lung 5.33 0.48 6.36 1.03 9.47 1.94 7.46 1.01 7.92 3.06 Bone 8.55 1.11 17.38 4.34 8.19 0.Ϊ5 1Z74 1.08 9.7β 1.55 12.35 0.43 193 1.13 7.01 1.06 2.33 0.33 8.59 0.56 Aim 'β.06 1.79 6.58 1.08 162 1.34 8.14 2.16 9.14 1.56 13.37 1.53 5.46 0.66 7.17 1.37 7.96 1.98 7.S5 1 7.08 2.14 7.23 2.11 Muscle 7.62 0-4« 5*26 0-25 7.41 1.38 Blood sowing • 41 - 158268.doc 201210621 Example 4 : [18F 】D-DFMT is in the Biodistribution in the mice of A549 tumors

Biodistribution and excretion studies were performed using [18F]D-DFMT in female NMRI (nu/nu) mice with A549 lung tumors as described in Example 2. The results of biodistribution and excretion were recorded as the percentage of injected dose per gram of tissue (%ID/g) and the tumor to organ ratio (T/T_ratio) was calculated (Table 4). [18F]D-DFMT showed very high absorption into the Α549 tumor, which remained stable 1 hour before the start of washing. The pancreatic line showed the only other organ absorbed by [18F]D-DFMT. The elimination from the body is very rapid. Table 4 :

158268.doc 42· 201210621 Example 5: Direct comparison of [18F]D_DFMT and [18F]D-FMT in biodistribution experiments using mice with NCI-H292 tumors as described in Example 2, with NCI-H292 Biodistribution and excretion studies using [18F]D-DFMT or [18F]D-FMT in female NMRI (nu/nu) mice with lung tumors. The time points used were 15, 30, 60, 120 and 240 min ([i8F] D-FMT replaced 240 min with 180 min). The results of biodistribution and excretion were recorded as the percentage of injected dose per gram of tissue (%ID/g) (Table 5), and the tumor to organ ratio (T/T-ratio) was calculated (Table 6). [18F]D-DFMT showed twice the absorption line in NCI-H292 tumors, while other organs showed only a slight increase in [18F]D-DFMT relative to [!8f]d_FMt. This produces a higher and better tumor to organ ratio, especially at an earlier time point. Table 5: Time point: ofk5 η 0.5 hi,un 2,0 h 3,W4,01i-- %剤董/g 1 sa I SD ί S.0, 丨SDSO spleen DD-FMT itr Λ OA U.^9 ΛΛ«^* 2.71 1.53 1.72 0.74 0.62 0.14 0.54 0.17 Fat D»FMT 1.11 0.07 0.77 0.04 6.5ό 0.06 0.42 0.13 Liver DD-FMT 1S2 0.40 2.15 1.02 1.16 0.25 0.57 0.06 0.58 0.24 Liver D-FMT 204 0.09 1-14 0.21 0.71 0.10 0.46 0.09 0.40 0.19 Kidney DP-FMT & 95 1.18 5.00 2.12 1.99 0.21 0·82 〇.1〇〇75 0.29 Kidney D-FMT 4.39 Ό.5Τ' ...'·Γ45" ~~α52~ '1.24' ——δΤΓ ' —ϋ 0.09~ "0Λ2' Lung DD-FMT 2.79 0.44 2.38 0.57 127 0.20 0.58 0.13 0.60 0.31 Lung D-FMT Z64 0.35 1.20 0.17 0.77 0.03 0.50 6.09 0.33 0.11 Heart DD-FMT 3.02 0.24 2.88 0.79 1.56 0.34 0.64 0.12 0.62 0.27 Heart D-FMT Z51 0,1 Plant 1.50 0.36 0.93 0.04 0.55 ~δΜ~ 0.37 0.14 Tumor DD-FMT 14.77 15.16 4.t>y 12^4 4.ti1 4-Ή 1ΛΚ) 4.14 1〇Ι Tumor D-FMT Λ 04 7.73 1.67 4.75 6.46 3.11 D.7i 1 246 1-ϋ5> Blood DD-FMT Ζ81 0.30 2.38 1.01 1.32 0.26 0.60 0.08 0.62 027 Blood D-FMT 2.14 0. 08 1.22 0.20 0.77 0.05 0.53 0.07 0.35 0.13 Pancreas DD-FMT " 22*55 3.43 16l21 5.77 8.06 3.22 5.34 1.48 2.62 thief gland D-FMT 12.72 2.06 7.68 1.13 4.25 1.08 4.42 0.54 3.75 142 ! I Total bU i bubU i SU: Urine DD-FMT 26.31 9.16 34.87 13.44 54.18 7.07 73.26 3.06 6a50 0.72 Exhibition D-FMT 33.7〇□.〇7 48.01 5.36 W_17 Γ53- 75Μ 0.66 80.62 4.40 Feces DD-FMT * 0.01 0.01 1.77 277 1.58 1.05 1.13 157 Real D- FMT 0.01 0.01 0.04 ―uw~ 0.21 0.35 1.26 1.6δ 158268.doc -43- 201210621 Table 6: _ time point: 0,25 h 0.5 h 1,0 h 2,0 h 3,0/4,0 h T/ SO· SOSD spleen DD-FMT 5l20 0.46 6.22 2.15 7.44 1.74 6.93 .0.56 7.60 1.09 Spleen D-FMT 3.95 1.06 6,94 1.28 6.20 0.33 6.27 1.11 5.76 0.79 Liver DD-FMT 191 0.60 7.39 1.23 10.38 1.58 7.53 0.98 7.59 2.10 Liver D-FMT 176 1.01 674 0.41 6.77 1.47 6.74 0.55 6.31 0.49 Kidney I>D-FMT 255 0.55 3.17 0.76 6.09 1.60 5.23 0.69 5.75 1.50 w D-FMT 174 0.38 3.18 0.34 3.85 0.68 4.12 0, 69 5.04 1.26 Lung D*D-FMT 5l33 0.48 6.3 6 1.03 9.47 1,94 7.46 1.01 7.92 3.06 Lungs D-FMT 288 0.54 6.39 0.55 6.16 0.76 6.24 1.30 7.3$ 0.75 Heart DD-FMT 4.89 0.34 5.26 077 7.79 1.31 6.69 0.83 7.12 2.10 Heart D-FMT a〇7 0.93 5.Ϊ9 0.49 5.13 0.64 5.69 V01 6.50 0.34 Brain DD-FMT 17^8 4.34 12.74 1.08 12.35 0.43 7.01 1.06 8.59 0.56 皤D*FMT 11.93 287 11.85 1.96 7.13 1.05 6.81 0.93 7.71 0.85 Muscle D~I>FMT 7.82 0.49 6.0$ 1.79 ai4 2.18 5.46 0.66 7.85 178 Muscle D-FMT & 40 230 6.84 0.56 5.21 0.87 4.82 0.95 5.55 1.09 Blood DD-FMT 5.26 0.25 6.58 1.08 9.14 1.56 7.17 1.37 7.08 2.14 Blood D-FMT 3160 1.03 e.33 0.30 6.19 0.74 5.93 1.06 6.81 0.54 Example 6: Direct comparison of [18F]D-DFMT with [18f]D-FMT in biodistribution experiments using mice with NCI-H460 tumors as described in Example 2, in females with NCI-H460 lung tumors Biodistribution and excretion studies were performed using [i8f]D-DFMT or [18F]D-FMT in NMRI (nu/nu) mice. The time points used were 1 5, 30, 60, 120 and 240 min ([18F] D-FMT replaced 240 min with 180 min). The results of biodistribution and excretion were recorded as the percentage of injected dose per gram of tissue (%ID/g) (Table 7), and the tumor to organ ratio (T/T-ratio) was calculated (Table 8). [8F] D-DFMT showed almost twice the absorption line [18F]D-FMT in NCI-H460 tumors, while other organs showed only a slight increase in [18F]D-DFMT relative to [18F]D-FMT. This produces a higher and better tumor to organ ratio, especially at earlier time points. • 44· 158268.doc 201210621 Table 7: Timeline: 0,25 h 0,5 h I n I 2,un 0tD/4t0 h %剤/g 1 SD | SD SD SD S,D. Spleen DD-FMT 273 0.34 1.66 0.43 119 0.28 0.81 0.16 0.39 0.07 Spleen D-FMT 1.81 0.21 1.36 0.05 0.69 0.10 0.43 0.03 0.30 0.02 Liver DD-FMT Z29 0.53 1.56 0.26 1.00 0.21 0.64 0.12 0.31 0.05 Liver D-FMT 1.92 0.05 0.96 0.10 0.65 0.04 0.41 0.01 0.30 0.02 Kidney DD-FMT 5.35 0.71 Z66 0.22 1.75 0.32 1.34 076 0.44 0.05 Kidney D-FMT 5.78 271 Z18 0.40 1.03 0.16 0.67 0.05 0.49 0.13 Lung DD-FMT Z89 0.52 181 0.55 1.10 0.11 1.04 0.56 0.98 1.18 Lungs D-FMT 215 0.18 1.22 0.02 0.69 0.07 0.41 0.02 0.23 0.02 Heart DD-FMT 3.02 0.29 2.05 0.39 1.36 0.20 0.80 0.09 0.36 0.01 Heart D-FMT Z32 0.14 1.75 0.13 0.94 0.21 0.46 0.02 0.29 ο.οέ Tumor DD-FMT 4.29 U.14 3.57 aw 3.60 ϋ .ί>ϋ 1.97 ϋ./Ζ 0.66 ϋ.14 雎 tumor D-FMT Z12 0.96 Z37 0.21 2· 14 0.34 1.28 0.35 0.94 0.15 Blood DD-FMT Z56 0.38 1.62 0.28 1.15 0.15 0.76 0.08 0.35 0.03 Blood D-FMT 1.95 0.19 1.28 0.08 0.77 0.20 0.44 0.01 0.29 0.02 Pancreas DD-FMT 20.92 1.96 11.30 1.74 8.35 3.40 6.24 2.26 116 0.16 Pancreas D-FMT 13.23 0.38 8.45 078 4.83 1.36 3.63 0.82 . 2.68 0.66 I i ! I Total I bU ! bU i~5ΠΙ S bUbU Urinary DD-FMT 31.55 7.79 3 ^35 18.04 51.79 25.17 71.19 5.76 80.36 1.9^ Urine D-FMT 38.71 5.96 —53_f2 12.06 64.01 6.61 ~7SM~ 2.22 84T4'9 5T3 Wing DD-FMT • 0.01 0.00 0.32 0.55 0.18 0.3⁄4 0.51 0.45 Feces D-FMT - 0.05 0.08 0.01 0.01 0.19 0.28 0.22 0.17 Table 8: Time point: 0,25 h 0,5 h 1,0 h 2,0 h 3,0/4,0 h T/T-ratio | SD i SD l, so SD | SO. Spleen DD-FMT 1.59 0.19 122 0.44 3.23 0.98 2.46 0.90 227 0.47 Spleen D-FMT 1.21 0,63 174 0.10 3.12 0.49 3.05 1.03 3.15 0.26 SfD-D-FMT 194 0.42 2.31 0.32 3.79 0.82 3.02 0.57 282 0.81 liver. PJMT 1.11 0.52 2.47 0.20 3.26 0.34 3.12 0,83 3.18 0.66 Kidney DD-FMT 0.61 0.11 0.93 0.52 2.14 0.43 1.58 0.39 1.99 0.53 Kidney D-FMT 0.41 0.28 1.12 0.29 2·0.28 1.93 0.65 104 0.74 Lung DD-FMT 1.52 0.25 2.03 0.30 3.37 0.50 2.02 0.41 203 1.56 Lungs D-FMT 1.01 0.51 1.95 0.20 3 .12 0,48 3.08 079 4.05 0.78 Heart DD-FMT 1.43 0.15 1.75 0.15 274 0.47 2.42 0.63 Z42 0.39 Heart D-FMT 0.93 0.45 1.36 0.11 232 0.42 2.77 0.75 3.29 0.67 Brain DD-FMT 5.56 0.86 4.35 1.16 4.43 0.79 3.31 1.02 3.37 0.40 Brain D-FMT 4.02 1.39 2.70 0.37 3.57 0.68 3.76 1.77 3.93 0.55 Muscle DD-FMT 212 0.47 Z14 0.50 Z27 0.40 2.33 0.84 230 0.40 Muscle D-FMT 1.49 0.68 1.68 0.35 128 0.29 2.11 0.59 263 0.43 Blood DD-FMT 1.70 0.23 111 0.26 3.24 0.53 2.56 0.69 Z54 0.64 Blood D-FMT 1.12 0.57 1.85 0.15 2.85 0.56 2.90 0.82 3.25 0,61 Example 7: PET/CT imaging of [18F]D-DFMT in mice with NCI-H292 tumors 39 MBq ( Inveon,

In mice with NCI-H292 tumors, intravenous injection of 6 [18F]D-DFMT 55 to 65 minutes later, in microPET/CT -45-158268.doc 201210621

[18F]D-DFMT was imaged on Siemens. In NCI-H460 xenografts, high tumor contrast was observed. Due to the rapid renal clearance of this ligand, very low background radioactivity was observed in addition to pancreatic absorption and urine in the bladder (Figure 3). Example 8: [18F] PET/CT imaging of D-DFMT in mice with A549 tumors in mice with H460 tumors was injected intravenously with 8.43 MBq [18F]D-DFMT for 55 to 65 minutes after microPET/CT ( Inveon, Siemens) imaged [18F]D-DFMT. In H460 xenografts, high tumor contrast was observed. Due to the rapid renal clearance of this ligand, very low background radioactivity was observed in addition to pancreatic absorption and urine in the bladder (Fig. 4). BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an HPLC chromatogram of <9-([18F]fluoro[2H2]methyl)-D-tyrosine (D-DFMT). La) Radioactive map, lb): UV map. Figure 2 shows the cell uptake analysis of DFMT and DDFMT in A549 and H460 cells. Figure 3 is a PET/CT image of [18F]D-DFMT in mice with NCI-H292 tumors. Figure 4 is a PET/CT image of [18F]D-DFMT in mice bearing A549 tumors. 158268.doc • 46·

Claims (1)

201210621 VII. Patent application scope: 1. A compound of formula (1) Wherein X is a fluorine atom (F); Y is CHD or CD2; D is hydrazine, and its single isomer, diastereomer and enantiomer or mixture, and a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein the formula (I) is a formula (D-Ι) or (L-I), (D-I) (L-I) wherein X is a fluorine atom (F); Y is CHD or CD2; and D is 氘. 3. The compound of claim 2, wherein the formula (D-Ι) is a formula (D-Ia), 158268.doc 201210621 (D-Ia) wherein X is a fluorine atom (F); and D is 氘. 4. The compound of any one of claims 1 to 3, wherein the atom (F) is an isotope or a 19F isotope. 5. A compound according to claim 1 or 2 which is: 〇-([18F]fluoro[2H2]methyl)-DL-tyrosine 〇 (rac) 〇-([18F]fluoro[2H2]fluorenyl)-L-carbamic acid 158268.doc 201210621 〇-([UF]fluoro[2H2]fluorenyl)-D-tyrosine 〇-(fluoro[2H2]methyl)-DL-tyrosine 〇-(fluoro[2H2]fluorenyl)-L-tyrosine 〇-(fluoro[2H2]methyl)-D-tyrosine Obtaining Formula (1) 6. An indirect fluorine labeling method comprising the steps of: coupling a compound of formula (III) with a compound of formula (IV): 158268.doc 201210621, Wherein X is a fluorine atom (F); Y is CHD or CD2; D is 氘, and the compound of the formula (III) is a suitable F_18 or F-19-labeled prosthetic group, and the compound of the formula (IV) is D- or L- Tyrosic acid or a mixture and/or salt thereof. 7. 8. 9. 10 A pharmaceutical composition comprising a compound of formula (I), (D_j), (D-Ia) or (LI) as claimed in claims 1 to 5 or a mixture thereof and a pharmaceutically acceptable carrier Agent or diluent. Use of a compound of formula (I) according to claims 1 to 5 for the manufacture of a radiopharmaceutical for imaging a proliferative disease in a mammal. The use of claim 8, wherein the proliferative disease is characterized by the presence of a prostate cancer, a prostate tumor, or a lung tumor. A kit comprising a sealed vial containing a predetermined amount or less: a compound of the formula; and a compound of formula IV, wherein the compound of formula II is suitable for use in the synthesis of known compounds! The precursor of the prosthetic group labeled with ?_18 or F_i9, and the compound of the formula: D or L-tyrosine or a mixture and/or salt thereof. 158268.doc