EP4583928A2 - Composition radionucléidique et procédé d'utilisation associée pour la détection de cellules tumorales - Google Patents

Composition radionucléidique et procédé d'utilisation associée pour la détection de cellules tumorales

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Publication number
EP4583928A2
EP4583928A2 EP23864036.1A EP23864036A EP4583928A2 EP 4583928 A2 EP4583928 A2 EP 4583928A2 EP 23864036 A EP23864036 A EP 23864036A EP 4583928 A2 EP4583928 A2 EP 4583928A2
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EP
European Patent Office
Prior art keywords
alkyl
independently
alkylaryl
co2h
aryl
Prior art date
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Application number
EP23864036.1A
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German (de)
English (en)
Inventor
Jacob HOUGHTON
Vilma JALLINOJA
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Research Foundation of the State University of New York
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Research Foundation of the State University of New York
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Publication of EP4583928A2 publication Critical patent/EP4583928A2/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
    • C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • 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
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
    • 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
    • A61K51/0495—Pretargeting
    • 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
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1268—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules host-guest, closed hollow molecules, inclusion complexes, e.g. with cyclodextrins, clathrates, cavitates, fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells

Definitions

  • Pretargeted positron emission tomography provides quantitative, non-invasive whole- body in vivo profile of macromolecules with an overall lower total body radiation dose compared to directly radiolabeled macromolecules (Altai, 2017 and Jallinoja, 2021).
  • Pretargeting is a two-step strategy that involves the administration of a target binding macromolecule which accumulates at the target site over several days while the unbound macromolecule excretes from non-target tissue.
  • a bioorthogonal small molecule radioligand is administered.
  • Figure 1 The low molecular weight of the radioligand allows its target accumulation and excretion to occur faster than that of the initial macromolecule.
  • the present invention harnesses a host-guest complex formation as the specific pretargeting interaction between the macromolecule and the radioligand. It was hypothesized that due to the high in vivo stability, modularity and low immunogenicity, the chosen host-guest pair, cucurbit[7]uril- adamantane (CB7-Adma, Ka ⁇ 10 14 M -1 ) makes an ideal interaction pair for pretargeted PET (Assaf KI, 2015, Shetty D, 2015 and Wanka L, 2013).
  • the strong complex between the two molecules forms when the Adma guest with an adjacent positively charged moiety binds to the carbonyl framed cavity of the macrocyclic CB7 host molecule via multiple van der Waals and ion-dipole interactions. So far, the medical imaging applications utilizing host-guest chemistry have been limited to pre-formed host-guest complexes to increase stability and/or sensitivity of imaging agents (Zhao, 2022, Sembo-Backonly, 2021 and Wu 2021). In nuclear medicine, the high affinity non-covalent binding between CB7 and Adma molecules has remained minimally explored (Strebl MG, 2018).
  • the present invention provides a compound having the structure: wherein Y 1 , Y 2 , Y 3 are each, independently, -H, alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylheteroaryl, alkyl-CO 2 H, alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl) 2 , alkyl- N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H)
  • the present invention provides a compound having the structure: wherein Y1, Y2, Y3 , Y4 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl- N(alkylaryl)2, alkyl-N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkylaryl-CO2R4)2, alkyl-N(alkylheteroaryl-CO2 , al
  • the present invention provides a compound having the structure: wherein Y1, Y2, Y3 , Y4 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl- N(alkylaryl)2, alkyl-N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkylaryl-CO2R4)2, alkyl-N(alkylheteroaryl-CO2 , al
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 .
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently , , , . [0180] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 are each , . [0181] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 are each , . [0182] In some embodiments, Y 1 andY 3 is , Y 2 and/or Y 4 is .
  • the L is an alkyl, alkenyl, alkynyl, alkylether, alkylthioether, alkylamino, alkylamido, alkylester, alkylaryl, alklyheteroaryl, polyethylene glycol (PEG), aryl, heteroaryl, a natural amino acid, an unnatural amino acid, a disulfide or thioether containing linker or combinations thereof.
  • the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or a polyethylene glycol (PEG) or combinations thereof.
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, -NH- alkyl, amide. [0195] In some embodiments, each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, -NH- alkyl. [0196] In some embodiments, R 4 is -OH. [0197] In some embodiments, R 4 is -NH 2 .
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, 4,9- diamino diamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane. [0203] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane, diamantane , 4,9-diamino diamantane or ferrocene.
  • the guest molecule A is substituted or unsubstituted adamantane or diamantane.
  • the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
  • the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), -N- (alkyl).
  • the guest molecule A is substituted or unsubstituted adamantane.
  • the guest molecule A is substituted or unsubstituted diamantane. [0209] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene. [0210] In some embodiments, the guest molecule A is unsubstituted adamantane. [0211] In some embodiments, the guest molecule A is substituted adamantane. [0212] In some embodiments, the guest molecule A is 4,9-diamino diamantane. [0213] In some embodiments, the guest molecule A is unsubstituted ferrocene. [0214] In some embodiments, the guest molecule A is unsubstituted diamantane.
  • the guest molecule A is substituted diamantane.
  • the substituted diamantane having the following structure: .
  • the guest molecule A is substituted ferrocene.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the a compound having the structure wherein n and m are each n and m are each independently 1, 2, or 3; more preferably, n and m are wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein Y 1 , Y 2 , Y 3 , Y 4 are each, independently, -H, alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylheteroaryl, alkyl-CO 2 H, alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-OH, alkylaryl-OH, alkylheteroary
  • n and m are each independently 0, 1, 2, 3, 4, 5, or 6. [0225] In some embodiments, n and m are each independently 1, 2, or 3. [0226] In some embodiments, n and m are 1. [0227] In some embodiments, n is 1, 2, or 3. [0228] In some embodiments, m is 1, 2, or 3. [0229] In some embodiments, n is 1 or 2. [0230] In some embodiments, m is 1 or 2. [0231] In some embodiments, n is 1. [0232] In some embodiments, m is 1. [0233] In some embodiments, n and m are the same. [0234] In some embodiments, n and m are different.
  • o is 0, 1, 2, 3, 4, 5, or 6.
  • o is 0, 1, 2, or 3.
  • o is 1 or 2.
  • o is 1.
  • R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, - OH, -O-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
  • R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl.
  • each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, - O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or - Si(alkyl)3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, - NH-alkyl, amide, aryl, heteroaryl, or alkyl-CF3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, - NH-alkyl, or amide.
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, - or NH-alkyl.
  • R 4 is -OH.
  • R 4 is -NH 2 .
  • Y 1 , Y 2 , Y 3, Y 4 are each independently alkyl-CO 2 H, , alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkylaryl-CO 2 R 4 ) 2 , alkyl-N(alkylheteroaryl-CO 2 R 4 ) 2 , alkyl-N(alkylheteroaryl-CO 2 R 4 ) 2 , alkyl-N(alkylhetero
  • Y1, Y2, Y3, Y4 are each independently alkyl-CO2H, , alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-N(alkylaryl-CO2H)2, alkyl- N(alkylheteroaryl-CO2H)2, alkyl-N(alkyl-CO2H)2, alkyl-N(alkylaryl-OH)(alkyl-CO2H), alkyl- N(alkylheteroaryl-OH)(alkyl-CO2H), or alkylheteroaryl- P(O)(OH)2.
  • Y1, Y2, Y3, Y4 are each independently alkyl-CO2H, or alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2. [0256] In some embodiments, at least one of Y1, Y2, Y3, Y4 is alkyl-CO2H. [0257] In some embodiments, at least one of Y1, Y2, Y3, Y4 is alkyl-CO2NH2. [0258] In some embodiments, at least one of Y1, Y2, Y3, Y4 is alkyl-N(alkyl-CO2H)2.
  • At least one of Y1, Y2, Y3 and Y4 is H. [0265] In some embodiments, none of Y1, Y2, Y3 and Y4 are H. [0266] In some embodiments, Y1, Y2 Y3, and Y4 are the same. [0267] In some embodiments, at least one of Y1, Y2, Y3 and Y4 is H. [0268] In some embodiments, none of Y 1 , Y 2 , Y 3 and Y 4 are H.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently - , , , , or [0272] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 are each , . [0273] In some embodiments, Y1, Y2, Y3, Y4 are each or . [0274] In some embodiments, Y 1 andY 3 is , Y 2 and/or Y 4 is .
  • alkylether alkylthioether, alkylamino, glycol (PEG), aryl, heteroaryl, a natural amino acid, an unnatural amino acid, a disulfide or thioether containing linker or combinations thereof.
  • the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or a polyethylene glycol (PEG) or combinations thereof.
  • the chemical linker L is an alkyl or a PEG or combinations thereof.
  • the chemical linker L is a PEG.
  • the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, or m or 7; more preferably, m is 1, 3, or 7. [0280] In some embodiments, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0281] In some embodiments of chemical linker L, m is 1, 3 or 7. [0282] In some embodiments of chemical linker L, m is 3.
  • A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2, - NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3.
  • A is substituted with -NH 2 , -alkyl-NH 2 , -NH-alkyl, or alkyl.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF 2 , -CF 3 , -OCHF 2 or -OCF 3 .
  • the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), -N- (alkyl).
  • the guest molecule A is substituted or unsubstituted adamantane.
  • the guest molecule A is substituted or unsubstituted diamantane.
  • the guest molecule A is substituted or unsubstituted ferrocene. [0295] In some embodiments, the guest molecule A is unsubstituted adamantane. [0296] In some embodiments, the guest molecule A is substituted adamantane. [0297] In some embodiments, the guest molecule A is 4,9-diamino diamantane . [0298] In some embodiments, the guest molecule A is unsubstituted ferrocene. [0299] In some embodiments, the guest molecule A is unsubstituted diamantane. [0300] In some embodiments, the guest molecule A is substituted diamantane.
  • the substituted diamantane having the following structure: .
  • the guest substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl).
  • the substituted ferrocene is substituted with C 1 -C 6 alkyl, -alkyl-N-(C 1 -C 6 alkyl).
  • the substituted ferrocene is substituted with -alkyl-N-(C 1 -C 6 alkyl).
  • the substituted ferrocene having the following structure: .
  • the present invention provides a compound having the structure: wherein L is a chemical linker; wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; wherein A is a guest molecule which is substituted or unsubstituted adamantane, ferrocene, diamantane , 4,9-diamino diamantane , bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, pentamantane cyclohexamantane, super-adamantane, 1,3,5,7-tetramethyl-1,3,5,7-tetrasilaadamantane, adamanzane, antimony trioxide, arsenic trioxide, 2,4,6-trioxa-1,3,5,7-tetraarsaadamantane, diamondoi
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or - Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, -NH- alkyl, amide, aryl, heteroaryl, or alkyl-CF 3 .
  • n and m are each n and m are each independently 1, 2, or 3; more preferably, n and wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH- alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 ; wherein X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl-thiourea, alkenyl-
  • each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, - O-alkyl, -NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
  • each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, - O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or - Si(alkyl)3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, amide, aryl, heteroaryl, or alkyl-CF3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, or amide. [0323] In some embodiments, each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, or - NH-alkyl. [0324] In some embodiments, R 4 is -OH. [0325] In some embodiments, R 4 is -NH 2 .
  • the present invention provides a compound having the structure: wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; preferably, n and m are each independently 1, 2, or 3; more preferably, n and m are 1; wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH- alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 ; wherein X is alkyl-aryl-thiourea, alkyl-hetero
  • each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or - Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, - NH-alkyl, amide, aryl, heteroaryl, or alkyl-CF 3 .
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, - NH-alkyl, or amide. [0331] In some embodiments, each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, or - NH-alkyl. [0332] In some embodiments, R4 is -OH. [0333] In some embodiments, R4 is -NH2.
  • the present invention provides a compound having the structure: wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; wherein A is a guest molecule which is substituted or unsubstituted adamantane, ferrocene, diamantane , 4,9-diamino diamantane , bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, pentamantane cyclohexamantane, super-adamantane, 1,3,5,7-tetramethyl-1,3,5,7-tetrasilaadamantane, adamanzane, antimony trioxide, arsenic trioxide, 2,4,6-trioxa-1,3,5,7-tetraarsaadamantane, diamondoid, hexamethylenetetramine, phosphorus pentasulfide, phosphorus pentoxide, phosphorus pentoxid
  • the present invention provides a compound having the structure: wherein n m are or n m are independently 1, 2, or 3; more preferably, n and m are 1; wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH- alkyl, -CHF2, -CF3, -OCHF2, -OCF3, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3; wherein X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl-thiourea, alkenyl-ary
  • the present invention provides a compound having the structure: wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; preferably, n and m are each independently 1, 2, or 3; more preferably, n and m are 1; wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH- alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 ; wherein X is alkyl-aryl-thiourea, alkyl-hetero
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or - Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, -NH- alkyl, amide, aryl, heteroaryl, or alkyl-CF 3 .
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, or amide. [0341] In some embodiments, each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, or - NH-alkyl. [0342] In some embodiments, R4 is -OH. [0343] In some embodiments, R4 is -NH2.
  • the compound is other than .
  • the present invention provides a compound having the structure: alklyheteroaryl,or polyethylene glycol (PEG); wherein n and m are each independently 0, 1, 2, or 3; wherein A is a guest molecule which is substituted or unsubstituted adamantane, ferrocene, diamantane , 4,9-diamino diamantane , bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, pentamantane cyclohexamantane, super-adamantane, 1,3,5,7-tetramethyl-1,3,5,7-tetrasilaadamantane; and wherein each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH-alkyl, - CHF
  • n is 1, 2, or 3.
  • n is 1 or 2.
  • m is 1 or 2.
  • n is 1.
  • m is 1.
  • R 1 and R 2 are each independently H, halogen, alkyl, alkenyl, alkynyl, - OH, -O-(alkyl), -CHF 2 , -CF 3 , -OCHF 2 or -OCF 3 .
  • R 1 and R 2 are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl. [0368] In some embodiments, R 1 and R 2 are each independently, C 1 -C 6 alkyl or C 1 -C 6 alkenyl. [0369] In some embodiments, R1 and R2 are each independently C1-C6 alkyl. [0370] In some embodiments, R1 and R2 are C1-5 alkyl. [0371] In some embodiments, R1 and R2 are C1-3 alkyl. [0372] In some embodiments, R1 and R2 are methyl.
  • alkyl is C1-6 alkyl. [0374] In some embodiments, alkyl is C1-3 alkyl. [0375] In some embodiments, alkyl is methyl. [0376] In some embodiments, aryl is phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydronaphthyl; indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. [0377] In some embodiments, aryl is phenyl, p-toluenyl (4-methylphenyl), or naphthyl.
  • aryl is phenyl.
  • the chemical linker L is an alkyl, alkenyl, alkynyl, alkylether, alkylthioether, alkylamino, alkylamido, alkylester, alkylaryl, alklyheteroaryl, polyethylene glycol (PEG), aryl, heteroaryl, a natural amino acid, an unnatural amino acid, a disulfide or thioether containing linker or combinations thereof.
  • the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or a polyethylene glycol (PEG) or combinations thereof.
  • the chemical linker L is an alkyl or a PEG or combinations thereof. [0382] In some embodiments, the chemical linker L is a PEG. [0383] In some embodiments, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably m is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0384] In some embodiments, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or m 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0385] In some embodiments of chemical linker L, m is 1, 3 or 7.
  • m is 3.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, 4,9- diamino diamantane , ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF 2 , -CF 3 , -OCHF 2 or -OCF 3 .
  • A is substituted with -OH, -NH 2 , halogen, alkyl, -O-alkyl, -alkyl-NH 2 , - NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 .
  • A is substituted with -NH 2 , -alkyl-NH 2 , -NH-alkyl, or alkyl.
  • the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), or -N- (alkyl).
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane , 4,9-diamino diamantane or ferrocene. [0395] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane or diamantane. [0396] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane. [0397] In some embodiments, the guest molecule A is substituted or unsubstituted diamantane. [0398] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene.
  • the guest molecule A is unsubstituted adamantane.
  • the guest molecule A is substituted adamantane.
  • the guest molecule A is 4,9-diamino diamantane .
  • the guest molecule A is unsubstituted ferrocene.
  • the guest molecule A is unsubstituted diamantane.
  • the guest molecule A is substituted diamantane.
  • the substituted diamantane having the following structure: .
  • the guest substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), or -NH-(C1-C6 alkyl).
  • the substituted ferrocene is substituted with C1-C6 alkyl, or -alkyl-N-(C1- C6 alkyl).
  • the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl).
  • the substituted ferrocene having the following structure: .
  • the present invention provides a compound having the structure: wherein L is alkyl, alkenyl, ; wherein n and m are each independently 1, 2, or 3; wherein A is a guest molecule which is adamantane, ferrocene, or diamantane ; and wherein R4 is -OH, -O-(C1-C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH.
  • the compound is other than .
  • L is alkyl, alkenyl, alkynyl, alkylether, or polyethylene glycol (PEG); wherein n and m are each independently 1, 2, or 3; wherein A is a guest molecule which is adamantane, ferrocene, or diamantane; and wherein R 4 is -OH, -O-(C 1 -C 6 alkyl), or NH-(C 1 -C 6 alkyl), more preferably R 4 is -OH.
  • n and m are each independently 1, 2, or 3.
  • n and m are 1.
  • n is 1, 2, or 3.
  • n is 1, 2, or 3.
  • n is 1 or 2.
  • m is 1 or 2.
  • n is 1.
  • m is 1.
  • R 1 and R 2 are each independently H, halogen, alkyl, alkenyl, alkynyl, - OH, -O-(alkyl), -CHF 2 , -CF 3 , -OCHF 2 or -OCF 3 .
  • R 1 and R 2 are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl.
  • R1 and R2 are each independently, C1-C6 alkyl or C1-C6 alkenyl.
  • R1 and R2 are each independently C1-C6 alkyl.
  • R1 and R2 are C1-5 alkyl.
  • R 1 and R 2 are C 1-3 alkyl.
  • R 1 and R 2 are methyl.
  • R 1 and R 2 are ethyl.
  • the present invention provides compound having the structure: , , or .
  • the present invention provides a metal complex comprising the compound described in the invention, wherein the compound coordinates to a metal.
  • the present invention provides a metal complex having the structure: , wherein M is the metal; wherein Y1, Y2, Y3 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl)2, alkyl- N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkylaryl-CO2R4)2, alkyl- N(alkylheteroaryl-
  • the present invention provides a metal complex having the structure: wherein M is the metal; wherein Y 1 , Y 2 , Y 3 , Y 4 are each, independently, -H, alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylheteroaryl, alkyl-CO 2 H, alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl- N(alkylaryl) 2 , alkyl-N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(
  • the metal complex is other than . 0, 1, 2, 3, 4, 5, or 6.
  • n and m are each independently 1, 2, or 3.
  • n and m are 1.
  • n is 1, 2, or 3.
  • m is 1, 2, or 3.
  • n is 1 or 2.
  • n is 1.
  • m is 1.
  • n and m are the same.
  • n and m are different.
  • R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, - OH, -O-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
  • R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl.
  • R 1 and R 2 are each independently, C 1 -C 6 alkyl or C 1 -C 6 alkenyl.
  • R 1 and R 2 are each independently C 1 -C 6 alkyl.
  • R 1 and R 2 are C 1-5 alkyl. [0455] In some embodiments, R 1 and R 2 are C 1-3 alkyl. [0456] In some embodiments, R 1 and R 2 are methyl. [0457] In some embodiments, R 1 and R 2 are ethyl.
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
  • each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, - O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or - Si(alkyl)3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, amide, aryl, heteroaryl, or alkyl-CF3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, amide.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl.
  • R4 is -OH.
  • R4 is -NH2.
  • X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl- thiourea, alkenyl-aryl-thiourea, or alkenyl -heteroaryl-thiourea.
  • X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, or alkyl-cycloalkyl- thiourea.
  • X is alkyl-aryl-thiourea, or alkyl-heteroaryl-thiourea.
  • X is alkyl-aryl-thiourea.
  • Y1, Y2, Y3, Y4 are each independently alkyl-CO2H, , alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkylaryl-CO 2 R 4 ) 2 , alkyl-N(alkylaryl-CO 2 R 4 ) 2 , alkyl-N(alkylaryl-CO 2 R 4 ) 2 , alkyl-N(alkylheter
  • Y 1 , Y 2 , Y 3, Y 4 are each independently alkyl-CO 2 H, or alkyl-CO 2 NH 2 , or alkyl-N(alkyl-CO 2 H) 2 .
  • at least one of Y1, Y2, Y3, Y4 is alkyl-CO2H.
  • at least one of Y1, Y2, Y3, Y4 is alkyl-CO2NH2.
  • at least one of Y1, Y2, Y3, Y4 is alkyl-N(alkyl-CO2H)2.
  • At least one of Y1, Y2, Y3, Y4 is -CH2-CO2H.
  • at least one of Y1, Y2, Y3, Y4 is -CH2-CO2NH2.
  • at least one of Y1, Y2, Y3 , Y4 is -CH2-N(alkyl-CO2H)2
  • at least two of Y1, Y2 and Y3, Y4 are the same.
  • at least three of Y1, Y2, Y3 and Y4 are the same.
  • Y1, Y2 Y3, and Y4 are the same. [0481] In some embodiments, at least one of Y1, Y2, Y3 and Y4 is H. [0482] In some embodiments, none of Y1, Y2, Y3 and Y4 are H. In Y4 - , , . [0484] In some embodiments, Y1, Y2, Y3, Y4 are each , , [0485] In some embodiments, Y1, Y2, Y3, Y4 are each , or [0486] In some embodiments, Y 1 , Y 2 , Y 3 , Y 4 are each independentl , .
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently . some an alkynyl, alkylether, alkylthioether, alkylamino, alkylamido, alkylester, alkylaryl, alklyheteroaryl, polyethylene glycol (PEG), aryl, heteroaryl, a natural amino acid, an unnatural amino acid, a disulfide or thioether containing linker or combinations thereof.
  • the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or a polyethylene glycol (PEG) or combinations thereof.
  • the chemical linker L is an alkyl or a PEG or combinations thereof. [0492] In some embodiments, the chemical linker L is a PEG. [0493] In some embodiments, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0494] In some embodiments, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably m is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0495] In some embodiments of chemical linker L, m is 1, 3 or 7.
  • m is 3.
  • the guest molecule A is adamantane, diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene- modified peracetic acid, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, 4,9-diamino diamantane or ferrocene.
  • the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
  • the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), -N- (alkyl).
  • the guest molecule A is substituted or unsubstituted adamantane or diamantane. [0504] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane. [0505] In some embodiments, the guest molecule A is substituted or unsubstituted diamantane. [0506] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene. [0507] In some embodiments, the guest molecule A is unsubstituted adamantane. [0508] In some embodiments, the guest molecule A is substituted adamantane.
  • the guest molecule A is 4,9-diamino diamantane. [0510] In some embodiments, the guest molecule A is unsubstituted ferrocene. [0511] In some embodiments, the guest molecule A is unsubstituted diamantane. [0512] In some embodiments, the guest molecule A is substituted diamantane. [0513] In some embodiments, the substituted diamantane having the following structure: . [0514] In some embodiments, the guest molecule A is substituted ferrocene.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl).
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl). [0518] In some embodiments, the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl). [0519] In some embodiments, the substituted ferrocene having the following structure: .
  • the a metal complex having the structure: wherein M is the metal; wherein Y1, Y2, Y3 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl)2, alkyl- N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkylaryl-CO2R4)2, alkyl- N(alkylheteroaryl, alkyl-N
  • the present invention provides a metal complex having the structure: wherein M is the metal; wherein Y1, Y2, Y3 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl)2, alkyl- N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkylaryl-CO2R4)2, alkyl- N(alkyl-N(alkylaryl-
  • R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, - OH, -O-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
  • R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl.
  • R1 and R2 are each independently, C1-C6 alkyl or C1-C6 alkenyl.
  • R1 and R2 are each independently C1-C6 alkyl.
  • Y1, Y2, Y3 are each independently alkyl-CO2H, , alkyl-N-(CO2R4)2, alkyl- N-(alkyl-CO 2 R 4 ) 2 , alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-N(alkylaryl-CO 2 H) 2 , alkyl- N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkyl-CO 2 H) 2 , alkyl-N(alkylaryl-OH)(alkyl-CO 2 H), alkyl- N(alkylheteroaryl-OH)(alkyl-CO 2 H), or alkylheteroaryl- P(O)(OH) 2 .
  • the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0578] In some embodiments of chemical linker L, m is 1, 3 or 7. [0579] In some embodiments, of chemical linker L, m is 3. [0580] In some embodiments, A is substituted with -OH, -NH 2 , halogen, alkyl, -O-alkyl, -alkyl-NH 2 , - NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 .
  • the guest molecule A is adamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, 4,9- diamino diamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, 4,9-diamino diamantane or ferrocene.
  • the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
  • the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), -N- (alkyl).
  • the guest molecule A is 4,9-diamino diamantane. [0595] In some embodiments, the guest molecule A is unsubstituted ferrocene. [0596] In some embodiments, the guest molecule A is unsubstituted diamantane. [0597] In some embodiments, the guest molecule A is substituted diamantane. [0598] In some embodiments, the substituted diamantane having the following structure: . [0599] In some embodiments, the guest molecule A is substituted ferrocene.
  • the substituted ferrocene is substituted with C 1 -C 6 alkyl, -alkyl-N-(C 1 -C 6 alkyl), -OH, -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl), -CHF 2 , -CF 3 , -OCHF 2 , or -OCF 3 .
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl).
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl). [0603] In some embodiments, the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl). [0604] In some embodiments, the substituted ferrocene having the following structure: . [0605] In some embodiments, the a metal complex having the structure:
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, amide.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl.
  • R4 is -OH.
  • R4 is -NH2.
  • n and m are each independently 0, 1, 2, 3, 4, 5, or 6.
  • n and m are each independently 1, 2, or 3.
  • n and m are 1.
  • the guest molecule A is substituted or unsubstituted adamantane, 4,9- diamino diamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, 4,9-diamino diamantane or ferrocene.
  • the guest molecule A is 4,9-diamino diamantane. [0741] In some embodiments, the guest molecule A is unsubstituted ferrocene. [0742] In some embodiments, the guest molecule A is unsubstituted diamantane. [0743] In some embodiments, the guest molecule A is substituted diamantane. [0744] In some embodiments, the substituted diamantane having the following structure: . [0745] In some embodiments, the guest substituted ferrocene.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl).
  • the present invention provides a metal complex having the structure: wherein M is the metal; wherein L is a chemical linker; wherein n and m are each independently 1, 2, or 3; wherein A is a guest molecule which is adamantane, ferrocene, or diamantane; and wherein R4 is -OH, -NH2, -O-(C1-C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2.
  • the present invention provides a metal complex having the structure: wherein is the metal; wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; preferably, n and m are each independently 1, 2, or 3; more preferably, n and m are 1; wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH- alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 ; wherein X is alkyl-aryl-thiourea,
  • the present invention provides a metal complex having the structure: wherein L is a chemical linker; wherein n and m are each independently 1, 2, or 3; wherein A is a guest molecule which is adamantane, ferrocene, or diamantane; and wherein each occurrence of R 4 is independently -OH, -NH 2, -O-(C 1 -C 6 alkyl), or NH-(C 1 -C 6 alkyl), more preferably R 4 is -OH or -NH 2 .
  • the present invention provides metal complex having the structure: wherein n independently 1, 2, or 3; more preferably, n and m are 1; wherein o is 0, 1, 2, 3, 4, 5, or 6; preferably o is 1, 2, or 3; more preferably, o is 1; wherein each occurrence of R4 is independently -OH, -NH2, -O-(C1-C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2 ; wherein X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl-thiourea, alkenyl-aryl- thiourea, alkenyl -heteroaryl-thiourea, alkenyl -cycloalkyl-thiourea, alkynyl-aryl-thiourea, alkynyl- heteroaryl-thiourea,
  • A is substituted with -OH, -NH 2 , halogen, alkyl, -O-alkyl, -alkyl-NH 2 , - NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 .
  • A is substituted with -NH 2 , -alkyl-NH 2 , -NH-alkyl, or alkyl.
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, - O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or - Si(alkyl)3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, amide, aryl, heteroaryl, or alkyl-CF3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH- alkyl, or amide.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, or - NH-alkyl.
  • the present invention provides a metal complex having the structure: or , wherein the metal.
  • the metal is Copper-62 ( 62 Cu), Copper-64 ( 64 Cu), Copper-67 ( 67 Cu), Gallium-68 ( 68 Ga) Scandium-44 ( 44 Sc), Scandium-47 ( 47 Sc), Scandium-43 ( 43 Sc), Lead-203 ( 203 Pb), Lead- 212 ( 212 Pb), Lanthanum-132 ( 132 La), Lanthanum-135 ( 135 La), Yttrium-86 ( 86 Y), Yttrium-90 ( 90 Y), Lutetium 177 ( 177 Lu), Terbium -149 ( 149 Tb), Terbium-152 ( 152 Tb), Terbium-155 ( 155 Tb) or Terbium-161 ( 161 Tb).
  • the metal is Copper-62 ( 62 Cu), Copper-64 ( 64 Cu), Copper-67 ( 67 Cu), Scandium-44 ( 44 Sc), Scandium-47 ( 47 Sc), or Scandium-43 ( 43 Sc). [0767] In some embodiments, the metal is Copper-64 ( 64 Cu).
  • the present invention provides a pharmaceutical composition comprising the metal complex described in the invention and a marker attached to a host molecule. [0769] In some embodiments, the marker is a biological marker. [0770] In some embodiments, the marker is modified. [0771] In some embodiments, the marker is un-modified. [0772] In some embodiments, the marker is a tumor marker or a cancer marker.
  • the tumor marker is a prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), cancer antigen 19-9 (CA 19-9), cancer antigen 15-3 (CA 15- 3), cancer antigen 27-29 (CA 27-29), lactate dehydrogenase (LDH), or neuron-specific enolase (NSE).
  • PSA prostate-specific antigen
  • PAP prostatic acid phosphatase
  • CA 125 cancer antigen 125
  • CEA carcinoembryonic antigen
  • AFP alpha-fetoprotein
  • HCG human chorionic gonadotropin
  • HCG human chorionic gonadotropin
  • CA 19-9 cancer antigen 19-9
  • cancer antigen 15-3 CA 15- 3
  • cancer antigen 27-29 CA 27-29
  • LDH lactate dehydrogenas
  • the tumor marker is prostate-specific antigen (PSA), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA 19-9), cancer antigen 15-3 (CA 15- 3), or cancer antigen 27-29 (CA 27-29).
  • PSA prostate-specific antigen
  • CEA carcinoembryonic antigen
  • the tumor marker is a carcinoembryonic antigen (CEA).
  • the host molecule comprises cucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, cucurbit[8]uril, cucurbit[10]uril, cucurbit[14]uril, cyclodextrin, or calix-[5]-arenes. [0778] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, cucurbit[8]uril, or cucurbit[10]uril.
  • the host molecule comprises cucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, or cucurbit[8]uril. [0780] In some embodiments, the host molecule comprises cucurbit[7]uril, or cucurbit[8]uril. [0781] In some embodiments, the host molecule is cucurbit[7]uril. [0782] In some embodiments, the interaction between the host and the guest molecule is a non-covalent interaction.
  • the present invention provides a method of detecting cells in a subject comprises administering an effective amount of metal complex having the structure: , wherein M is the metal; wherein Y1, Y2, Y3 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl)2, alkyl- N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkyl-CO
  • the present invention provides a method of detecting cells in a subject comprises administering an effective amount of metal complex having the structure: wherein M is the metal; wherein Y 1 , Y 2 , Y 3 , Y 4 are each, independently, -H, alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylheteroaryl, alkyl-CO 2 H, alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl- N(alkylaryl) 2 , alkyl-N(alkylaryl-CO 2 H) 2 , alkyl-N(alkyl) 2
  • the present invention provides a method of detecting cells in a subject comprises administering an effective amount of metal complex having the structure: , wherein M is the metal; wherein Y1, Y2, Y3 are each, independently, -H, alkyl-N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2 , alkylheteroaryl, alkyl-CO2H, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH-CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl)2, alkyl- N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkylaryl-CO2H)
  • the metal complex is other than . some with -OH, -NH 2 , halogen, alkyl, -O-alkyl, -alkyl-NH 2 , -NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 .
  • A is substituted with -NH 2 , -alkyl-NH 2 , -NH-alkyl, or alkyl.
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH-alkyl, -CHF 2 , -CF 3 , -OCHF 2 , -OCF 3 , amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -H, -OH, -NH 2 , halogen, alkyl, -O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
  • each occurrence of R4 is independently, -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, amide, aryl, heteroaryl, or alkyl-CF3.
  • Y1, Y2, Y3 are each independently alkyl-CO2H, , alkyl-N- (CO2R4)2, alkyl-N-(alkyl-CO2R4)2, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH- CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl- CO 2 H) 2 , alkyl-N(alkylaryl-CO 2 R 4 ) 2 , alkyl-N(alkylheteroaryl-CO 2 R 4 ) 2 , alkyl-N(alkyl-CO 2 H) 2 , alkyl- N(alkylaryl-OH)(alkyl-CO 2 H), alkyl-Nalkylhe
  • Y 1 , Y 2 , Y 3 are each independently alkyl-CO 2 H, , alkyl-N- (CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkyl-CO 2 H) 2 , alkyl-N(alkylaryl-OH)(alkyl-CO 2 H), alkyl- N(alkylheteroaryl-OH)(alkyl-CO 2 H), or alkylheteroaryl- P(O)(OH) 2 .
  • Y 1 , Y 2 , Y 3 are each independently alkyl-CO 2 H, or alkyl- CO 2 NH 2 , or alkyl-N(alkyl-CO 2 H) 2 .
  • at least one of Y1, Y2, Y3 is alkyl-CO2H.
  • at least one of Y1, Y2, Y3 is alkyl-CO2NH2.
  • at least one of Y1, Y2, Y3 is alkyl-N(alkyl-CO2H)2.
  • Y1, Y2, Y3 and Y4 are H. [0809] In some embodiments of the method, none of Y1, Y2, Y3 and Y4 are H. [0810] In some embodiments of the method, Y1, Y2, Y3, Y4 are each independently alkyl-CO2H, , alkyl- N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-CO2R4, alkylaryl-NH- CO2R4, alkylaryl-CO2R4, alkylheteroaryl-CO2R4, alkyl-N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl- CO2H)2, alkyl-N(alkylaryl-CO2R4)2, alkyl-N(alkylheteroaryl-CO2R4)2, alkyl-N(alky
  • Y1, Y2, Y3, Y4 are each independently alkyl-CO2H, , alkyl- N-(CO2R4)2, alkyl-N-(alkyl-CO2R4)2, alkylaryl-CO2H, alkylheteroaryl-CO2H, alkyl-N(alkylaryl-CO2H)2, alkyl-N(alkylheteroaryl-CO2H)2, alkyl-N(alkyl-CO2H)2, alkyl-N(alkylaryl-OH)(alkyl-CO2H), alkyl- N(alkylheteroaryl-OH)(alkyl-CO2H), or alkylheteroaryl- P(O)(OH)2.
  • At least one of Y 1 , Y 2 , Y 3 , Y 4 is -CH 2 -N(alkyl-CO 2 H) 2 [0819] In some embodiments of the method, at least two of Y 1 , Y 2 , Y 3 , Y 4 are the same. [0820] In some embodiments of the method, at least three of Y 1 , Y 2 , Y 3 , Y 4 are the same. [0821] In some embodiments of the method, Y1, Y2, Y3, Y4 are the same. [0822] In some embodiments of the method, at least one of Y1, Y2, Y3 and Y4 is H.
  • R 1 and R 2 are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl. [0843] In some embodiments of the method, R 1 and R 2 are each independently, C 1 -C 6 alkyl or C 1 -C 6 alkenyl. [0844] In some embodiments of the method, R 1 and R 2 are each independently C 1 -C 6 alkyl. [0845] In some embodiments of the method, R1 and R2 are C1-5 alkyl. [0846] In some embodiments of the method, R1 and R2 are C1-3 alkyl.
  • R1 and R2 are methyl.
  • R 1 and R 2 are ethyl.
  • X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl- cycloalkyl-thiourea, alkenyl-aryl-thiourea, or alkenyl -heteroaryl-thiourea.
  • alkyl is methyl.
  • alkyl is ethyl.
  • aryl is phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydronaphthyl; indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • aryl is phenyl, p-toluenyl (4-methylphenyl), or naphthyl.
  • aryl is phenyl.
  • the chemical linker L is an alkyl or a PEG or combinations thereof. [0863] In some embodiments of the method, the chemical linker L is a PEG. [0864] In some embodiments of the method, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably m is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0865] In some embodiments of the method, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; preferably m is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7.
  • m is 1, 3 or 7. [0867] In some embodiments of the method of the chemical linker L, m is 3. [0868] In some embodiments of the method, A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2, -NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3. [0869] In some embodiments the method, A is substituted with -NH2, -alkyl-NH2, -NH-alkyl, or alkyl.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, 4,9-diamino diamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, 4,9-diamino diamantane or ferrocene.
  • the guest molecule A is substituted or unsubstituted adamantane or diamantane. [0875] In some embodiments of the method, the guest molecule A is substituted or unsubstituted adamantane. [0876] In some embodiments of the method, the guest molecule A is substituted or unsubstituted diamantane. [0877] In some embodiments of the method, the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF 2 , -CF 3 , -OCHF 2 or -OCF 3 .
  • the guest molecule A is unsubstituted ferrocene.
  • the guest molecule A is unsubstituted diamantane.
  • the guest molecule A is substituted diamantane.
  • the substituted diamantane having the following structure: .
  • the substituted ferrocene In some embodiments of the method, the molecule A is substituted ferrocene.
  • the substituted ferrocene is substituted with C1-C6 alkyl, - alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the substituted ferrocene is substituted with C1-C6 alkyl, - alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl).
  • the metal complex is other than .
  • n and m are each independently 1, 2, or 3.
  • n and m are 1.
  • n is 1, 2, or 3.
  • m is 1, 2, or 3.
  • 0900 In some embodiments of the method, n is 1 or 2.
  • n is 1.
  • m is 1.
  • Y 1 , Y 2 , Y 3 are each independently alkyl-CO 2 H, or alkyl- CO 2 NH 2 , or alkyl-N(alkyl-CO 2 H) 2 .
  • at least one of Y 1 , Y 2 , Y 3 is alkyl-CO 2 H.
  • at least one of Y 1 , Y 2 , Y 3 is alkyl-CO 2 NH 2 .
  • at least one of Y 1 , Y 2 , Y 3 is alkyl-N(alkyl-CO 2 H) 2 .
  • At least three of Y1, Y2, Y3 and Y4 are the same.
  • Y1, Y2 and Y3 are the same.
  • at least one of Y1, Y2, Y3 and Y4 is H.
  • none of Y1, Y2, Y3 and Y4 are H.
  • Y 1 , Y 2 , Y 3 , Y 4 are each independently -H, , , or , , [0934] In some embodiments of the method, Y 1 , Y 2 , Y 3 , Y 4 are each , , , . [0936] In some embodiments of the method, Y1, Y2, Y3, Y4 are each independentl , . [0937] In some embodiments of the method, Y1 andY3 .
  • X is alkyl-aryl-thiourea.
  • alkyl is C 1-6 alkyl.
  • alkyl is C 1-3 alkyl.
  • alkyl is methyl.
  • alkyl is ethyl.
  • aryl is phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydronaphthyl; indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • aryl is phenyl, p-toluenyl (4-methylphenyl), or naphthyl.
  • aryl is phenyl.
  • the chemical linker L is an alkyl, alkenyl, alkynyl, alkylether, alkylthioether, alkylamino, alkylamido, alkylester, alkylaryl, alklyheteroaryl, polyethylene glycol (PEG), aryl, heteroaryl, a natural amino acid, an unnatural amino acid, a disulfide or thioether containing linker or combinations thereof.
  • the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or a polyethylene glycol (PEG) or combinations thereof.
  • the chemical linker L is an alkyl or a PEG or combinations thereof. [0952] In some embodiments of the method, the chemical linker L is a PEG. [0953] In some embodiments of the method, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, or m or 7; more preferably, m is 1, 3, or 7. [0954] In some embodiments of the method, the chemical linker L has the following structure: , wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7. [0955] In some embodiments of the method of chemical linker L, m is 1, 3 or 7.
  • m is 3.
  • A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2, -NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3.
  • A is substituted with -NH 2 , -alkyl-NH 2 , -NH-alkyl, or alkyl.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, 4,9-diamino diamantane, ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
  • the guest molecule A is substituted or unsubstituted adamantane, diamantane, 4,9-diamino diamantane or ferrocene.
  • the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -N-(alkyl), -CHF 2 , -CF 3 , -OCHF 2 or -OCF 3 .
  • the guest molecule A is substituted with halogen, alkyl, -O- (alkyl), -N-(alkyl).
  • the guest molecule A is substituted or unsubstituted adamantane or diamantane.
  • the guest molecule A is unsubstituted ferrocene.
  • the guest molecule A is unsubstituted diamantane.
  • the guest molecule A is substituted diamantane.
  • the substituted diamantane having the following structure: .
  • the substituted ferrocene In some embodiments of the method, the molecule A is substituted ferrocene.
  • the substituted ferrocene is substituted with C1-C6 alkyl, - alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
  • the substituted ferrocene is substituted with C 1 -C 6 alkyl, - alkyl-N-(C 1 -C 6 alkyl), -OH, -O-(C 1 -C 6 alkyl), -NH-(C 1 -C 6 alkyl).
  • the substituted ferrocene is substituted with C 1 -C 6 alkyl, - alkyl-N-(C 1 -C 6 alkyl). [0980] In some embodiments of the method, the substituted ferrocene is substituted with -alkyl-N-(C 1 - C 6 alkyl). [0981] In some embodiments of the method, the substituted ferrocene having the following structure: .
  • M is the metal; wherein Y 1 , Y 2 , Y 3 , Y 4 are each, independently, -H, alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylheteroaryl, alkyl-CO 2 H, alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl- N(alkylaryl) 2 , alkyl-N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2
  • the metal complex having the structure: wherein M is the metal; wherein Y 1 , Y 2 , Y 3 are each, independently, -H, alkyl-N-(CO 2 R 4 ) 2 , alkyl-N-(alkyl-CO 2 R 4 ) 2 , alkylheteroaryl, alkyl-CO 2 H, alkylaryl-CO 2 H, alkylheteroaryl-CO 2 H, alkyl-CO 2 R 4 , alkylaryl-NH-CO 2 R 4, alkylaryl-CO 2 R 4 , alkylheteroaryl-CO 2 R 4 , alkyl-OH, alkylaryl-OH, alkylheteroaryl-OH, alkyl-N(alkylaryl) 2 , alkyl- N(alkylaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO 2 H) 2 , alkyl-N(alkylheteroaryl-CO
  • each occurrence of R4 is independently, -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF 3 , or -Si(alkyl) 3 .
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, -NH-alkyl, amide.
  • each occurrence of R 4 is independently, -OH, -NH 2 , alkyl, -O-alkyl, -NH-alkyl.
  • R 4 is -OH.
  • R 4 is -NH 2 .
  • n and m are each independently 0, 1, 2, 3, 4, 5, or 6.
  • the non-covalent interaction is ion-ion interaction, ion- dipole interaction, dipole-dipole interaction, hydrogen bonding, cation- ⁇ interaction, ⁇ - ⁇ interaction, van der Waals interaction or hydrophobic interaction.
  • the non-covalent interaction is ion-ion interaction, or van der Waals interaction.
  • the metal complex described in the invention and the host molecule described in the invention form a high affinity host-guest complex.
  • the compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • the compounds described in the present invention are in racemic form or as individual enantiomers.
  • a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • substituents i.e. R1, R2, etc. are to be chosen in conformity with well- known principles of chemical structure connectivity.
  • biological marker refers to a broad subcategory of medical signs – that is, objective indications of medical state observed from outside the patient – which can be measured accurately and reproducibly. Medical signs stand in contrast to medical symptoms, which are limited to those indications of health or illness perceived by patients themselves.
  • biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”
  • WHO World Health Organization
  • a biomarker as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease”.
  • An even broader definition takes into account not just incidence and outcome of disease, but also the effects of treatments, interventions, and even unintended environmental exposure, such as to chemicals or nutrients.
  • biomarkers In their report on the validity of biomarkers in environment risk assessment, the WHO has stated that a true definition of biomarkers includes “almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological. The measured response may be functional and physiological, biochemical at the cellular level, or a molecular interaction.” Examples of biomarkers include everything from pulse and blood pressure through basic chemistries to more complex laboratory tests of blood and other tissues. [1195] As used herein, the term “Guest-Host” refers to host guest interactions involving two molecules or materials that can form complexes through unique structural relationships and noncovalent binding.
  • PSA Prostate-specific antigen
  • BPH benign prostatic hyperplasia
  • PAP Prostatic acid phosphatase
  • ovarian cancer is the most common cause of elevated CA 125, but cancers of the uterus, cervix, pancreas, liver, colon, breast, lung, and digestive tract can also raise CA 125 levels. Several noncancerous conditions can also elevate CA 125. CA 125 is mainly used to monitor the treatment of ovarian cancer.
  • Carcinoembryonic antigen (CEA) is normally found in small amounts in the blood. Colorectal cancer is the most common cancer that raises this tumor marker.
  • AFP Alpha-fetoprotein
  • HCG Human chorionic gondadotropin
  • HCG may indicate cancer in the testis, ovary, liver, stomach, pancreas, and lung. Marijuana use can also raise HCG levels.
  • CA 19-9 marker is associated with cancers in the colon, stomach, and bile duct. Elevated levels of CA 19-9 may indicate advanced cancer in the pancreas, but it is also associated with noncancerous conditions, including gallstones, pancreatitis, cirrhosis of the liver, and cholecystitis.
  • CA 15-3 is most useful in evaluating the effect of treatment for women with advanced breast cancer.
  • Elevated levels of CA 15-3 are also associated with cancers of the ovary, lung, and prostate, as well as noncancerous conditions such as benign breast or ovarian disease, endometriosis, pelvic inflammatory disease, and hepatitis. Pregnancy and lactation also can raise CA 15-3 levels.
  • CA 27-29 marker, like CA 15-3, is used to follow the course of treatment in women with advanced breast cancer. Cancers of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver may also raise CA 27-29 levels. Noncancerous conditions associated with this substance are first trimester pregnancy, endometriosis, ovarian cysts, benign breast disease, kidney disease, and liver disease.
  • LDH lactate dyhydrogenase
  • NSE Neuron-specific enolase
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon- carbon double bonds may be present.
  • C 2 -C n alkenyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C 2 -C 6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C 6 alkenyl, respectively.
  • C 2 -C n alkynyl is defined to include groups having 1, 2...., n-1 or n carbons.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • An embodiment can be a C2- Cn alkynyl.
  • An embodiment can be C2-C12 alkynyl, C3-C12 alkynyl, C4-C12 alkynyl and so on.
  • Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.
  • heteroalkyl includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10- membered nonaromatic ring containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
  • “monocycle” includes any stable polyatomic carbon ring of up to 10 atoms and may be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aromatic monocycle elements examples include but are not limited to: phenyl.
  • “bicycle” includes any stable polyatomic carbon ring of up to 10 atoms that is fused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted.
  • non-aromatic bicycle elements examples include but are not limited to: decahydronaphthalene.
  • aromatic bicycle elements examples include but are not limited to: naphthalene.
  • aryl is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted.
  • aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • polycyclic refers to unsaturated or partially unsaturated multiple fused ring structures, which may be unsubstituted or substituted.
  • arylalkyl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group as described above. It is understood that an “arylalkyl” group is connected to a core molecule through a bond from the alkyl group and that the aryl group acts as a substituent on the alkyl group.
  • arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or polycyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic aromatic heteroaryl groups include phenyl, pyridine, pyrimidine or pyridizine rings that are (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5- membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyr
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • alkylheteroaryl refers to alkyl groups as described above wherein one or more bonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above.
  • alkylheteroaryl is connected to a core molecule through a bond from the alkyl group and that the heteroaryl group acts as a substituent on the alkyl group.
  • alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like.
  • heterocycle or “heterocyclyl” refers to a mono- or poly-cyclic ring system which can be saturated or contains one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to ten-membered and is either saturated or has one or more degrees of unsaturation.
  • the heterocycle may be unsubstituted or substituted, with multiple degrees of substitution being allowed.
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), heteroaryl ring(s), aryl ring(s), or cycloalkyl ring(s).
  • heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.
  • the alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • halogen refers to F, Cl, Br, and I.
  • substitution refers to a functional group as described above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms, provided that normal valencies are maintained and that the substitution results in a stable compound.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituent groups include the functional groups described above, and halogens (i.e., F, Cl, Br, and I); alkyl groups, such as methyl, ethyl, n-propyl, isopropryl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups, such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups, such as phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p- trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or pluraly.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the compounds used in the method of the present invention may be prepared by techniques described in Vogel’s Textbook of Practical Organic Chemistry, A.I. Vogel, A.R. Tatchell, B.S. Furnis, A.J. Hannaford, P.W.G. Smith, (Prentice Hall) 5 th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5 th Edition (2007), and references therein, which are incorporated by reference herein. However, these may not be the only means by which to synthesize or obtain the desired compounds.
  • a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically active agent means any substance or compound suitable for administration to a subject and furnishes biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or affects the structure or any function of the subject.
  • Pharmaceutically active agents include, but are not limited to, substances and compounds described in the Physicians’ Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and “Approved Drug Products with Therapeutic Equivalence Evaluations” (U.S.
  • compositions which have pendant carboxylic acid groups may be modified in accordance with the present invention using standard esterification reactions and methods readily available and known to those having ordinary skill in the art of chemical synthesis. Where a pharmaceutically active agent does not possess a carboxylic acid group, the ordinarily skilled artisan will be able to design and incorporate a carboxylic acid group into the pharmaceutically active agent where esterification may subsequently be carried out so long as the modification does not interfere with the pharmaceutically active agent’s biological activity or effect.
  • the compounds used in the method of the present invention may be in a salt form.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • the compounds of the present invention may also form salts with basic amino acids such a lysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.
  • “administering” an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
  • the compounds used in the method of the present invention may be administered in various forms, including those detailed herein.
  • the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • Liposomes are also a pharmaceutically acceptable carrier as are slow-release vehicles.
  • a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional antitumor agents.
  • the compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or topically onto a site of disease or lesion, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the compounds used in the method of the present invention can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or in carriers such as the novel programmable sustained-release multi-compartmental nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the unit will be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection or parenteral administration.
  • the compounds can be administered alone or mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used.
  • the active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form.
  • suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders.
  • Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. [1246] For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • the compounds and compositions of the present invention can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by topical administration, injection or other methods, to the afflicted area, such as a wound, including ulcers of the skin, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No.
  • reagents for the SDS PAGE and Western Blotting were purchased from ThermoFisher Scientific.
  • PBS7.4 solution was prepared from phosphate buffered saline powder pH 7.4.
  • INSTRUMENTS [1263] 4-9 were purified with a reverse phase (RP) HPLC set up including an Agilent HPLC 1260 Infinity II LC System comprised of a 1260 Quat Pump VL, 1260 DAD WR and LabLogic Flow-RAM radio-HPLC Detector equipped with a LabLogic Systems Limited NaI Detector with a Luna 5 ⁇ m C18(2) 100 ⁇ LC column 250 ⁇ 10 mm (Phenomenex) column.
  • RP reverse phase
  • the chemical purity of 5, 7, 9 and the radiochemical purity of 1-3 were measured with the same HPLC instrument using a Kinetex 5 ⁇ m EVO C18100 ⁇ column, 150 ⁇ 4.6 mm (Phenomenex) analytical column.
  • the radiochemical purity of [ 89 Zr]Zr-DFO-M5A was analyzed with BioScan AR-2000 radio-TLC scanner.
  • the quality control of CB7-M5A and DFO-M5A was performed with BioRad NGC-Chormatography System including SystemPump10 and Multi UV/Vis- Conductivity detector using a Superdex 200 Increase 10/300GL Cytiva size exclusion column (SEC).
  • the radioactivity of log D, blood half-life, cell internalization and in vivo biodistribution samples were measured with Hidex Automatic Gamma Counter.
  • the radioactivity of the radiotracer doses was measured with a CRC-55tR Capintec Inc dose calibrator.4-9 were characterized with a 500 MHz Bruker Avance III proton nuclear magnetic resonance spectroscopy and Q-Exactive HF (Thermo-Fisher) Orbi-trap mass spectrometer high-resolution mass spectrometry instrument.
  • the % solvent B remained at 5 the first minute of the run followed by gradient from 5 to 95 over 17 minutes using a 1 mL/min flow rate.
  • the final RP HPLC method was used to analyze the in vitro plasma stability samples of 1-3.
  • the solvent A and B were H 2 O and acetonitrile.
  • the % of solvent B remained at 0 for the first 5 minutes of the run.
  • the solvent B% was increased to 95 over a 15-minute gradient.
  • the FPLC – size exclusion method used to analyze the purity of the CB7-M5A and DFO-M5A involved the use of PBS7.4 as the only solvent over a 70-minute period with a flow rate of 0.7 mL/min.
  • the water phase was extracted with diethyl ether (3 ⁇ 40 mL) followed by combining and evaporating the diethyl ether phases to yield oily material.
  • Iodomethane (30 mL) and sodium hydroxide (119 mg; 2.98 mmol; 1.6 eq.) were added to the reaction vial.
  • the methylation reaction was stirred for 2 hours, which was followed by evaporating the iodomethane and adding fresh iodomethane which was repeated once more.
  • the solvent was evaporated and replaced with dichloromethane. Undissolved sodium hydroxide was filtered out and the dichloromethane evaporated.
  • the crude product NBOC-Adma material was dissolved in acetonitrile (7 mL).
  • MIAPaCa-2 human pancreatic carcinoma cells were grown in DMEM/High glucose medium containing 4mM L-glutamine, 4.5 g/L glucose, and sodium pyruvate, 1% (vol/vol) Penicillin-Streptomycin,10% (vol/vol) fetal bovine serum and 2.5% (vol/vol) Horse Serum (donor herd) (Sigma-Aldrich). Both cells were kept in a 37 °C environment containing 5% CO 2 and extracted using 0.25% Trypsin-EDTA. [1295] ANIMALS [1296] All animals were female nude mice (NU/NU Charles River). The mice were housed in static microisolator caging with corn cob bedding (The Anderson Bed-o’Cobs 1/8”).
  • the protein lysates were prepared in NuPAGE LDS Sample buffer. Each protein sample (20 ⁇ g) was separated by SDS-PAGE using a NuPAGETM 4 to 12%, Bis-Tris, 1.0–1.5 mm, Mini Protein Gels at 100V for 15 minutes followed by an increase to 150V for an additional 60 minutes. Proteins were transferred electrophoretically onto Invitrolon TM PVDF/Filter Paper Sandwiches at 100 V for 60 minutes. Membranes were blocked in 5% Non- Fat Dry Milk prepared in TBS Tween TM 20 Buffer for 1 hour and incubated with the primary antibodies overnight at 4°C.
  • the mixture was stirred on a thermomixer for 10 minutes (900 rpm) at room temperature followed by centrifuging the sample for 5 minutes (1000 rcf).200 ⁇ L of each phase was transferred, and the samples were weighed and counted on a gamma counter to determine the relative amount of radioactivity in each phase.
  • the cohorts were euthanized for in vivo biodistribution 4, 8 or 24 h post radioligand injection and the 24h cohort was also imaged with a small animal PET/computer tomography (PET/CT) scanner (Siemens Inveon) at 4, 8 and 24 h post radioligand injection prior to euthanasia.
  • PET/CT PET/computer tomography
  • An additional cohort/timepoint for pretargeted 2 was assigned, which was euthanized 2 h post radioligand injection for dosimetry calculations.
  • a cohort of BxPC3 and MIAPaCa-2 tumor bearing female nude mice (n 4/cohort) were injected intravenously with [ 89 Zr]Zr-DFO-M5A (0.7 nmol; 100 ⁇ g; 2.3-3.4 MBq in 200 ⁇ L in PBS). The mice were imaged with a small animal PET/CT scanner 72 h post injection followed by in vivo biodistribution.
  • mice Pretargeting with 2 in MIAPaCa-2 xenografts
  • the mice were imaged with a small animal PET/CT scanner 24 h post radioligand injection, followed by in vivo biodistribution.
  • the dosimetry of pretargeted 2 [1340] The estimated dosimetry of the pretargeted 2 in an adult human male (70 kg) was calculated based on the in vivo biodistribution of the pretargeted 2 in BxPC3 tumor bearing mice. The biodistribution data was fitted using a linear interpolation between time points. The linear function of each organ was used to interpolate the concentration at intervals of 1 h to give a better estimate of the kinetics. The integration time was extended 48 h with the assumption that the %ID/organ was constant after the first 24 h and the only change in concentration between 24 and 48 h was due to radioactive decay. A trapezoidal approximation was then used to obtain the integral over the time intervals.
  • the present invention describes the development and characterization of three Adma- radioligands for CB7-Adma host-guest pretargeted PET.
  • the use of copper-64-labeled Adma radioligand along with a CB7-modified anti-CEA full-length antibody as the pretargeting agent pair for pretargeted PET in BxPC3 tumor bearing nude mice resulted in high, long remaining target uptake of the radioligand.
  • the total body radiation dose of the pretargeting strategy was only 3.3% of that of the directly zirconium- 89-labeled hT84.66-M5A.
  • the cucurbit[7]uril-adamantane strategy is highly suitable for pretargeted positron emission tomography.
  • the exceptional stability of the pretargeting agents and the specific and high tumor uptake of the pretargeted adamantane radioligands provides great potential for the platform.

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Abstract

La présente invention concerne un composé ayant la structure : ou un sel ou un ester de ce dernier.
EP23864036.1A 2022-09-09 2023-09-08 Composition radionucléidique et procédé d'utilisation associée pour la détection de cellules tumorales Pending EP4583928A2 (fr)

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