Radionuclide composition and method of using same for detection of tumor cells
The CB7-mAb pretargeting technology addresses radiation-induced toxicity in alpha-particle therapy by using a bifunctional radioligand with CB7 and 203Pb, enabling precise tumor targeting and reduced side effects.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-09-04
- Publication Date
- 2026-03-12
AI Technical Summary
Radiation-induced hematopoietic toxicity limits the efficacy of directly radiolabeled macromolecules used in image-guided targeted alpha-particle therapy for cancer treatment.
A pretargeting technology using a CB7-modified monoclonal antibody (CB7-mAb) conjugated with a bifunctional small-molecule radioligand, leveraging the stability and adaptable nature of CB7 and the extended half-life of 203Pb for therapeutic applications.
Enhances the tracking and delivery of therapeutic radiation to tumors while minimizing toxicity, allowing for effective cancer treatment with reduced side effects.
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Figure US2025044918_12032026_PF_FP_ABST
Abstract
Description
RADIONUCLIDE COMPOSITION AND METHOD OF USING SAME FOR DETECTION OF TUMOR CELLS
[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 807,275, filed May16, 2025, and U.S. Provisional Application No.63 / 690,365, filed September 4, 2024, the contents of which are hereby incorporated by reference.
[0002] Throughout this application, various publications are referenced, including referenced inparenthesis. The disclosures of all publications mentioned in this application in their entireties are hereby incorporated by reference into this application in order to provide additional description of the art to which this invention pertains and of the features in the art which can be employed with this invention. BACKGROUND OF THE INVENTION
[0003] Image-guided targeted alpha-particle therapy (alpha-TRT) has emerged as an effectiveintervention for several cancers, and the use of alpha-TRT for metastatic cancers could improve outcomesfor the thousands of patients. The use of macromolecules such as monoclonal antibodies (mAbs) astargeting vectors for delivery of therapeutic radiation is promising, but radiation-induced hematopoietictoxicity typically limits the efficacy of directly radiolabeled macromolecules (Vilma, 2021, Altai 2017 andJallinoja 2023).
[0004] The present invention developed pretargeting technology that uses a molecular “host” (CB7)that is conjugated to a mAb (e.g., CB7-mAb) and a bifunctional small-molecule “guest” radioligand with ahost-specific binding structure.
[0005] The present invention is built upon the advantages of robust stability of CB7-modifiedmonoclonal antibodies (mAbs) within the body, the adaptable nature of the pretargeting platform, and the extended half-life of203Pb (51.9 hours). Leveraging these features, the ability to track the in vivo behavior of pretargeting radioligands for theranostic applications across the span of 10 half-lives of212Pb (with a half-life of 10.6 hours) is anticipated.BRIEF SUMMARY OF THE INVENTION
[0006] The present invention provides a compound having the structure:, wherein Y1, Y2, Y3, and Y4are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, and wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1 and R2 are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2 or -OCF3;a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0007] The present invention provides a compound having the structure:, wherein Y1, Y2, Y3, and Y4 are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, and 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3;a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0008] The present invention provides a compound having the structure:wherein Y1, Y2, Y3, and Y4are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or -NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker;R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0009] The present invention provides a method of detecting cells in a subject comprises administeringan effective amount of the compound having the structure to the subject,, wherein Y1, Y2, Y3, and Y4are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or -NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl-cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0010] The present invention provides a compound having the structure:, wherein Y1, Y2, and Y3, are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; andwherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7-phosphaadamantane, or a salt or an ester thereof.
[0011] The present invention provides a compound having the structure:R, wherein Y1, Y2, Y3and Y4, are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1 and R2 are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7-phosphaadamantane, or a salt or an ester thereof.BRIEF DESCRIPTION OF THE DRAWINGS
[0012] Figure 1(a)The reaction scheme for the synthesis of PSC-PEG3-ADMA; 1(b) ChemicalStructure of PSC-PEG3-ADMA,TCMC-PEG3-ADMA and DOTA-PEG3- ADMA.
[0013] Figure 2. In vivo biodistribution of pre-targeted 203Pb-PSC-PEG3-ADMA with 6 days afterinjecting CB7-M5A in BxPC3 tumor bearing nude mice at 4h, 8h and 24h.DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides a compound having the structure:wherein Y1, Y2, Y3, and Y4 are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or -NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3;a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0015] The present invention provides a compound having the structure:, wherein Y1, Y2, Y3, and Y4 are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6alkyl), or -NH-(C1-C6alkyl), more preferably R4is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker;R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0016] The present invention provides a compound having the structure:wherein Y1, Y2, Y3, and Y4are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or -NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-;L is a chemical linker; R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0017] The present invention provides a compound having the structure:wherein Y1, Y2, and Y3, are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl-cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7-phosphaadamantane, or a salt or an ester thereof.
[0018] The present invention provides a compound having the structure:R, wherein Y1, Y2, Y3 and Y4, are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2,wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1 and R2 are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7-phosphaadamantane, or a salt or an ester thereof.
[0019] In some embodiments, R4 is -OH, -NH2, -O-(C1-C6 alkyl), or -NH-(C1-C6 alkyl), morepreferably R4 is -OH or -NH2.
[0020] In some embodiments, the targeting moiety A is a molecule or group of molecules, or a proteinor group of proteins that is used to direct a drug or other therapeutic agent to a specific target, like a cell or tissue.
[0021] In some embodiments, the targeting moiety A is a moiety with specificity for a target proteinon the surface of a cell.
[0022] In some embodiments, the targeting moiety A is a moiety with specificity for a target antigenon the surface of a cell.
[0023] In some embodiments, the targeting moiety A is a moiety with specificity for a target antibodyon the surface of a cell.
[0024] In some embodiments, the targeting moiety A is a molecule, a peptide, an antigen, an antibodyor a derivative or fragment thereof.
[0025] In some embodiments, the targeting moiety A is a protein.
[0026] In some embodiments, the targeting moiety A is a ligand.
[0027] In some embodiments, the targeting moiety A is a guest molecule.
[0028] In some embodiments, the guest molecule A 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane.
[0029] In some embodiments, A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2,-NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3.
[0030] In some embodiments, A is substituted with -NH2, -alkyl-NH2, -NH-alkyl, or alkyl.
[0031] In some embodiments, A is substituted with -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 alkynal, -OH,-NH2, -N-(C1-C6 alkyl)2, -N+-(C1-C6 alkyl)3 , -alkyl-N-(C1-C6 alkyl)2, -alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
[0032] In some embodiments, A is substituted with N+(CH3)3.
[0033] In some embodiments, A is substituted or unsubstituted diamantane, 4,9-diamino diamantane,bicyclo[2.2.2]octane, iceane, triamantane, tetramantane, pentamantane, isotetramantane, cyclohexamantane, super-adamantane, or 1,3,5,7-tetramethyl-1,3,5,7-tetrasilaadamantane.
[0034] In some embodiments, A is substituted or unsubstituted diamantane, triamantane, tetramantane,or pentamantane.
[0035] In some embodiments, A is substituted or unsubstituted diamantane.
[0036] In some embodiments, A is diamantane.
[0037] In some embodiments, A is diamantane substituted with N+(CH3)3.
[0038] In some embodiments, A has the structure:
[0039] In some embodiments, n and m are each independently 0, 1, 2, 3, 4, 5, or 6.
[0040] In some embodiments, n and m are each independently 1, 2, or 3.
[0041] In some embodiments, n and m are each independently 1.
[0042] In some embodiments, n is 1, 2, or 3.
[0043] In some embodiments, m is 1, 2, or 3.
[0044] In some embodiments, n is 1 or 2.
[0045] In some embodiments, m is 1 or 2.
[0046] In some embodiments, n is 1.
[0047] In some embodiments, m is 1.
[0048] In some embodiments, n is 0.
[0049] In some embodiments, m is 0.
[0050] In some embodiments, n and m are the same.
[0051] In some embodiments, n and m are different.
[0052] In some embodiments, R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
[0053] In some embodiments, R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl,or C1-C6 alkynyl.
[0054] In some embodiments, R1 and R2 are each independently C1-C6 alkyl or C1-C6 alkenyl.
[0055] In some embodiments, R1 and R2 are different.
[0056] In some embodiments, R1 and R2 are same.
[0057] In some embodiments, R1 and R2 are each C1-C6 alkyl.
[0058] In some embodiments, R1 and R2 are each C1-5 alkyl.
[0059] In some embodiments, R1 and R2 are each C1-3 alkyl.
[0060] In some embodiments, R1 and R2 are each methyl.
[0061] In some embodiments, R1 and R2 are each ethyl.
[0062] In some embodiments, X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl-thiourea, alkenyl-aryl-thiourea, or alkenyl -heteroaryl-thiourea.
[0063] In some embodiments, X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, or alkyl-cycloalkyl-thiourea.
[0064] In some embodiments, X is alkyl-aryl-thiourea, or alkyl-heteroaryl-thiourea.
[0065] In some embodiments, X is alkyl-aryl-thiourea.
[0066] In some embodiments, 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 a combination thereof.
[0067] In some embodiments, the chemical linker L is an alkyl linker, an alkyne linker, alkynal linkeror a polyethylene glycol (PEG) or a combination thereof.
[0068] In some embodiments, the chemical linker L is an alkyl or a PEG or a combination thereof.
[0069] In some embodiments, the chemical linker L is a PEG.
[0070] In some embodiments, the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
[0071] In some embodiments of chemical linker L, b is 1, 2, 3, 4, 5, 6, or 7.
[0072] In some embodiments of chemical linker L, b is 1, 3, or 7.
[0073] In some embodiments of chemical linker L, b is 3.
[0074] In some embodiments of chemical linker L, b is 7.
[0075] In some embodiments, the chemical linker L has the following structure:, wherein b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 3, or 7.
[0076] In some embodiments of chemical linker L, b is 1, 2 or 3.
[0077] In some embodiments of chemical linker L, b is 2.
[0078] In some embodiments of chemical linker L, b is 1, 3 or 7.
[0079] In some embodiments of chemical linker L, b is 3.
[0080] In some embodiments, each occurrence of R4 is -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.
[0081] In some embodiments, each occurrence of R4 is -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, -alkyl-CF3, or -Si(alkyl)3.
[0082] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, amide,aryl, heteroaryl, or -alkyl-CF3.
[0083] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, oramide.
[0084] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, or -NH-alkyl.
[0085] In some embodiments, R4 is -OH.
[0086] In some embodiments, R4 is -NH2.
[0087] In some embodiments, Y1, Y2, Y3, and Y4 are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl- N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl- CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2.
[0088] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, -alkyl-CONH2, -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.
[0089] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, -alkyl-CONH2, -alkyl-CO2H, -alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2.
[0090] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-CO2H.
[0091] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-CONH2,
[0092] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-CO2NH2.
[0093] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-N(alkyl-CO2H)2.
[0094] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CO2H.
[0095] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CO2NH2.
[0096] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CONH2.
[0097] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-N(alkyl-CO2H)2.
[0098] In some embodiments, at least two of Y1, Y2, Y3, and Y4 are the same.
[0099] In some embodiments, at least three of Y1, Y2, Y3, and Y4 are the same.
[0100] In some embodiments, Y1, Y2, Y3, and Y4 are the same.
[0101] In some embodiments, at least one of Y1, Y2, Y3 and Y4 is H.
[0102] In some embodiments, none of Y1, Y2, Y3 and Y4 are H.
[0103] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl- N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl- CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2.
[0104] In some embodiments, Y1, Y2, and Y3 are each independently-H, -alkyl-CONH2, -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.
[0105] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, alkyl-CO2H,or alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2.
[0106] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CO2H.
[0107] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CONH2.
[0108] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CO2NH2.
[0109] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-N(alkyl-CO2H)2.
[0110] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2H.
[0111] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2NH2.
[0112] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CONH2.
[0113] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-N(alkyl-CO2H)2.
[0114] In some embodiments, at least two of Y1, Y2, and Y3 are the same.
[0115] In some embodiments, Y1, Y2, and Y3 are the same.
[0116] In some embodiments, at least one of Y1, Y2, and Y3 is H.
[0117] In some embodiments, none of Y1, Y2, and Y3 are H.[
[0121] In some embodiments, Y1, Y2, Y3, and Y4 are each independently, ,
[0122] In some embodiments, Y1, Y2, Y3, and Y4 are each independently, ,[
[0128] In some embodiments, Y1, Y2, and Y3 are each independently ,
[0129] In some embodiments, Y1, Y2, and Y3 are each
[0130] In some embodiments, Y1, Y2, and Y3 are each
[0131] In some embodiments, Y
[0132] In some embodiments, Y
[0133] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
[0134] In some embodiments, 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.
[0135] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane or ferrocene.
[0136] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane ordiamantane.
[0137] In some embodiments, the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl,-OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
[0138] In some embodiments, the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), or -N-(alkyl).
[0139] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane.
[0140] In some embodiments, the guest molecule A is substituted or unsubstituted diamantane.
[0141] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene.
[0142] In some embodiments, the guest molecule A is unsubstituted adamantane.
[0143] In some embodiments, the guest molecule A is substituted adamantane.
[0144] In some embodiments, the guest molecule A is 4,9-diamino diamantane.
[0145] In some embodiments, the guest molecule A is unsubstituted ferrocene.
[0146] In some embodiments, the guest molecule A is unsubstituted diamantane.
[0147] In some embodiments, the guest molecule A is substituted diamantane.
[0148] In some embodiments, the substituted diamantane has the following structure:.
[0149] In some embodiments, the guest molecule A is substituted ferrocene.
[0150] In some embodiments, 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.
[0151] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), or -NH-(C1-C6 alkyl).
[0152] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, or -alkyl-N-(C1-C6 alkyl).
[0153] In some embodiments, the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl).
[0154] In some embodiments, the substituted ferrocene has the following structure:
[0155] In some embodiments, 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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; L is a chemical linker; and A is a target moiety, or a salt or an ester thereof.
[0156] In some embodiments, the present invention provides a compound having the structure:A, 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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;L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0157] In some embodiments, 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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; L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0158] In some embodiments, the targeting moiety A is a molecule or group of molecules, or a proteinor group of proteins that is used to direct a drug or other therapeutic agent to a specific target, like a cell or tissue.
[0159] In some embodiments, the targeting moiety A is a moiety with specificity for a target proteinon the surface of a cell.
[0160] In some embodiments, the targeting moiety A is a moiety with specificity for a target antigenon the surface of a cell.
[0161] In some embodiments, the targeting moiety A is a moiety with specificity for a target antibodyon the surface of a cell.
[0162] In some embodiments, the targeting moiety A is a molecule, a peptide, an antigen, an antibodyor a derivative or fragment thereof.
[0163] In some embodiments, the targeting moiety A is a protein.
[0164] In some embodiments, the targeting moiety A is a ligand.
[0165] In some embodiments, the targeting moiety A is a guest molecule.
[0166] In some embodiments, the guest molecule A 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane.
[0167] In some embodiments, A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2,-NH-alkyl, -CHF2, -CF3, -OCHF2, or -OCF3.
[0168] In some embodiments, A is substituted with -NH2, -alkyl-NH2, -NH-alkyl, or alkyl.
[0169] In some embodiments, n and m are each independently 0, 1, 2, 3, 4, 5, or 6.
[0170] In some embodiments, n and m are each independently 1, 2, or 3.
[0171] In some embodiments, n and m are each 1.
[0172] In some embodiments, n is 1, 2, or 3.
[0173] In some embodiments, m is 1, 2, or 3.
[0174] In some embodiments, n is 1 or 2.
[0175] In some embodiments, m is 1 or 2.
[0176] In some embodiments, n is 1.
[0177] In some embodiments, m is 1.
[0178] In some embodiments, n and m are the same.
[0179] In some embodiments, n and m are different.
[0180] In some embodiments, a is 0, 1, 2, 3, 4, 5, or 6.
[0181] In some embodiments, a is 0, 1, 2, or 3.
[0182] In some embodiments, a is 1 or 2.
[0183] In some embodiments, a is 1.
[0184] In some embodiments, R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, -OCHF2or -OCF3.
[0185] In some embodiments, R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl,or C1-C6alkynyl.
[0186] In some embodiments, R1 and R2 are each independently C1-C6 alkyl or C1-C6 alkenyl.
[0187] In some embodiments, R1 and R2 are same.
[0188] In some embodiments, R1 and R2 are different.
[0189] In some embodiments, R1 and R2 are each C1-C6 alkyl.
[0190] In some embodiments, R1 and R2 are each C1-5 alkyl.
[0191] In some embodiments, R1 and R2 are each C1-3 alkyl.
[0192] In some embodiments, R1 and R2 are each methyl.
[0193] In some embodiments, R1 and R2 are each ethyl.
[0194] In some embodiments, 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.
[0195] In some embodiments, 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.
[0196] In some embodiments, each occurrence of R4 is independently -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, amide, aryl, heteroaryl, or alkyl-CF3.
[0197] In some embodiments, each occurrence of R4 is independently OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, or amide.
[0198] In some embodiments, each occurrence of R4 is independently -OH, -NH2, alkyl, -O-alkyl, or-NH-alkyl.
[0199] In some embodiments, each occurrence of R4 is independently -OH, or -NH2.
[0200] In some embodiments, R4 is -OH.
[0201] In some embodiments, R4 is -NH2.
[0202] In some embodiments, Y1, Y2, and 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-CO2H)2, - alkyl-N(alkylaryl-CO2R4)2, -alkyl-N(alkylheteroaryl-CO2R4)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl- OH)(alkyl-CO2H), -alkyl-Nalkylheteroaryl-OH)(alkyl-CO2H), or -alkylheteroaryl- P(O)(OH)2.
[0203] In some embodiments, Y1, Y2, and Y3 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.
[0204] In some embodiments, Y1, Y2, and Y3 are each independently -alkyl-CO2H, or -alkyl-CO2NH2,or -alkyl-N(alkyl-CO2H)2.
[0205] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CO2H.
[0206] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CO2NH2.
[0207] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CONH2.
[0208] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-N(alkyl-CO2H)2.
[0209] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2H.
[0210] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2NH2.
[0211] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CONH2.
[0212] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-N(alkyl-CO2H)2
[0213] In some embodiments, at least two of Y1, Y2, and Y3 are the same.
[0214] In some embodiments, Y1, Y2, and Y3 are the same.
[0215] In some embodiments, at least one of Y1, Y2, and Y3 is H.
[0216] In some embodiments, none of Y1, Y2, and Y3 are H.
[0217] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H,,[[.
[0220] In some embodiments, , Y1, Y2, Y3, and Y4 are each independently, ,
[0221] In some embodiments, , Y1, Y2, Y3, and Y4 are each independently, ,
[0222] In some embodiments, Y1, Y2, and Y3 are each independently,
[0223] In some embodiments, Y1, Y2, and Y3 are each
[0224] In some embodiments, Y1, Y , and Y are each23 .
[0225] In some embodiments, Y
[0226] In some embodiments, Y
[0227] In some embodiments, 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.
[0228] In some embodiments, the chemical linker L is an alkyl linker, an alkyne linker, alkynal linkeror a polyethylene glycol (PEG) or combinations thereof.
[0229] In some embodiments, the chemical linker L is an alkyl or a PEG or combinations thereof.
[0230] In some embodiments, the chemical linker L is a PEG.
[0231] In some embodiments, the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
[0232] In some embodiments of chemical linker L, b is 1, 2, 3, 4, 5, 6, or 7.
[0233] In some embodiments of chemical linker L, b is 1, 3, or 7.
[0234] In some embodiments of chemical linker L, b is 3.
[0235] In some embodiments of chemical linker L, b is 7.
[0236] In some embodiments, the chemical linker L has the following structure:, wherein b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 3, or 7.
[0237] In some embodiments of chemical linker L, b is 1, 3 or 7.
[0238] In some embodiments of chemical linker L, b is 3.
[0239] In some embodiments, each occurrence of R4 is -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.
[0240] In some embodiments, each occurrence of R4 is -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
[0241] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, amide,aryl, heteroaryl, or alkyl-CF3.
[0242] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, oramide.
[0243] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, or -NH-alkyl.
[0244] In some embodiments, each occurrence of R4 is -OH, or -NH2.
[0245] In some embodiments, R4 is -OH.
[0246] In some embodiments, R4 is -NH2.
[0247] In some embodiments, A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2,-NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3.
[0248] In some embodiments, A is substituted with -NH2, -alkyl-NH2, -NH-alkyl, or alkyl.
[0249] In some embodiments, 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.
[0250] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,ferrocene, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane.
[0251] In some embodiments, 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.
[0252] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane , 4,9-diamino diamantane or ferrocene.
[0253] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane ordiamantane.
[0254] In some embodiments, the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl,-OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
[0255] In some embodiments, the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), or -N-(alkyl).
[0256] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane.
[0257] In some embodiments, the guest molecule A is substituted or unsubstituted diamantane.
[0258] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene.
[0259] In some embodiments, the guest molecule A is unsubstituted adamantane.
[0260] In some embodiments, the guest molecule A is substituted adamantane.
[0261] In some embodiments, the guest molecule A is 4,9-diamino diamantane.
[0262] In some embodiments, the guest molecule A is unsubstituted ferrocene.
[0263] In some embodiments, the guest molecule A is unsubstituted diamantane.
[0264] In some embodiments, the guest molecule A is substituted diamantane.
[0265] In some embodiments, the substituted diamantane has the following structure:
[0266] In some embodiments, the guest molecule A is substituted ferrocene.
[0267] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6alkyl), -OH, -O-(C1-C6alkyl), -NH-(C1-C6alkyl), -CHF2, -CF3, -OCHF2, or -OCF3.
[0268] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6alkyl), -OH, -O-(C1-C6alkyl), or -NH-(C1-C6alkyl).
[0269] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, or -alkyl-N-(C1-C6alkyl).
[0270] In some embodiments, the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl).
[0271] In some embodiments, the substituted ferrocene has the following structure:.
[0272] In some embodiments, the compound has 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 each independently 1 or 2.
[0273] In some embodiments, the present invention provides a compound having the structure: :wherein(a) Y1, Y2, Y3, Y4 are each independently -alkyl-CONH2, -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; preferably, Y1, Y2, Y3, Y4are each independently -alkyl-CONH2, -alkyl-CO2H, -alkyl-N- (CO2R4)2, -alkyl-N-(alkyl-CO2R4)2,or -alkyl-N(alkyl-CO2H)2; more preferably, Y1, Y2, Y3, Y4are each independently -alkyl-CONH2, or -alkyl- CO2H; more preferably, alkyl is -C1-C5 alkyl; more preferably alkyl is -C1-C3 alkyl; more preferably alkyl is -CH2;(b) Z is -NH-, or alkyl;when Z is -NH-, then X is -alkyl-aryl-thiourea-, -alkyl-heteroaryl-thiourea-, -alkyl-cycloalkyl- thiourea-, -alkenyl-aryl-thiourea-, or -alkenyl-heteroaryl-thiourea-, preferably, X is -alkyl-aryl-thiourea-, -alkyl-heteroaryl-thiourea-, or -alkyl-cycloalkyl- thiourea-, more preferably, X is -alkyl-aryl-thiourea-, or -alkyl-heteroaryl-thiourea-, more preferably, X is -alkyl-aryl-thiourea-; more preferably, alkyl is -CH3; more preferably, aryl is phenyl; when Z is alkyl, preferably Z is C1-C5 alkyl; more preferably Z is -C1-C3 alkyl; more preferably Z is -CH2;(c) the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or polyethylene glycol(PEG) or combinations thereof, preferably, the chemical linker L is an alkyl or PEG, more preferably, the chemical linker L is PEG.(d) R1 and R2 are each independently -H, halogen, -C1-C6 alkyl, -C1-C6 alkenyl, or -C1-C6 alkynyl;preferably, R1 and R2 are each independently -C1-C6 alkyl or -C1-C6 alkenyl; more preferably, R1 and R2 are same; more preferably, R1 and R2 are each -C1-6 alkyl; more preferably, R1and R2are each -C1-5alkyl; more preferably, R1and R2are each -C1-4alkyl; more preferably, R1and R2are each -C1-3alkyl; more preferably, R1and R2are each methyl or ethyl; more preferably, R1and R2are each methyl;(e) a, n and m are each independently 0, 1, 2, or 3; and / or(f) A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, bicyclo[2.2.2]octane,iceane, triamantane, tetramantane, pentamantane, isotetramantane, cyclohexamantane, super- adamantane, or 1,3,5,7-tetramethyl-1,3,5,7-tetrasilaadamantane; preferably, A is substituted or unsubstituted diamantane, triamantane, tetramantane, or pentamantane; more preferably, A is substituted or unsubstituted diamantane; preferably, the substitution is -C1-C6alkyl, -C1-C6alkenyl, -C1-C6alkynal, -OH, -NH2, -N-(C1-C6alkyl)2, -N+-(C1-C6alkyl)3, -alkyl-N-(C1-C6alkyl)2, -alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, - CF3, -OCHF2, or -OCF3.
[0274] In some embodiments,(preferably Y1, Y2, Y3, and Y4are each independently ,,more preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4 are each independentlymore preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4are each independently (, wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 2, or 3; more preferably b is 2; (c) m is 0;(d) n is 0; and / or(e) A is unsubstituted diamantane or diamantane substituted with -C1-C6 alkyl, -C1-C6 alkenyl,-C1-C6 alkynal, -OH, -NH2, -N-(C1-C6 alkyl)2, -N+-(C1-C6 alkyl)3 , -alkyl-N-(C1-C6 alkyl)2, -alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or - OCF3; more preferably, A is diamantane substituted with N+(CH3)3; more preferably, A is
[0275] In some embodiments, the present invention provides a compound having the structure:, wherein (a) L has the structure:, wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 2, or 3; more preferably b is 2; (b) R1 and R2 are each -C1-3 alkyl; more preferably, R1 and R2 are each methyl or ethyl; morepreferably, R1 and R2 are each methyl; (c) m is 0;(d) n is 0; and / or(e) A is unsubstituted diamantane or diamantane substituted with -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 alkynal, -OH, -NH2, -N-(C1-C6 alkyl)2, -N+-(C1-C6 alkyl)3 , -alkyl-N-(C1-C6 alkyl)2, - alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3; more preferably, A is diamantane substituted with N+(CH3)3; more preferably, A is
[0276] In some embodiments, the compound has the structure:
[0277] In some embodiments, the compound has the structure:.
[0278] In some embodiments, the compound has the structure:,,,,,,.
[0279] In some embodiments, the compound has the structure:.
[0280] In some embodiments, the compound has the structure:.
[0281] The present invention provides a metal complex comprising the compound disclosed herein,wherein the compound coordinates to a metal.
[0282] The present invention provides a metal complex having the structure:, whereinM is the metal; Y1, Y2, and Y3, are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; 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, or alkynyl-cycloalkyl-thiourea; L is a chemical linker; R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0283] The present invention provides a metal complex having the structure:whereinM is the metal; Y1, Y2, Y3 and Y4 are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; 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, or alkynyl-cycloalkyl-thiourea; L is a chemical linker;R1and R2are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0284] The present invention provides a metal complex having the structure:, wherein M is the metal; Y1, Y2, and Y3, are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl- CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl- P(O)(OH)2, -alkylaryl-P(O)(OH)2 or -alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1-C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl-cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; 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, or alkynyl-cycloalkyl-thiourea; L is a chemical linker; R1and R2are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, - OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
[0285] The present invention provides a metal complex having the structure:, wherein M is the metal; Y1, Y2, and Y3, are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl- CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl- P(O)(OH)2, -alkylaryl-P(O)(OH)2or -alkylheteroaryl-P(O)(OH)2, wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-;wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1 and R2 are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, - OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane; or a salt or an ester thereof.
[0286] The present invention provides a metal complex having the structure:, wherein M is the metal; Y1, Y2, Y3and Y4, are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl- CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl- P(O)(OH)2, -alkylaryl-P(O)(OH)2or -alkylheteroaryl-P(O)(OH)2, wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1 and R2 are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, - OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane; or a salt or an ester thereof.
[0287] In some embodiments, the targeting moiety A is a molecule or group of molecules, or a proteinor group of proteins that is used to direct a drug or other therapeutic agent to a specific target, like a cell or tissue.
[0288] In some embodiments, the targeting moiety A is a moiety with specificity for a target proteinon the surface of a cell.
[0289] In some embodiments, the targeting moiety A is a moiety with specificity for a target antigenon the surface of a cell.
[0290] In some embodiments, the targeting moiety A is a moiety with specificity for a target antibodyon the surface of a cell.
[0291] In some embodiments, the targeting moiety A is a molecule, a peptide, an antigen, an antibodyor a derivative or fragment thereof.
[0292] In some embodiments, the targeting moiety A is a protein.
[0293] In some embodiments, the targeting moiety A is a ligand.
[0294] In some embodiments, the targeting moiety A is a guest molecule.
[0295] In some embodiments, the guest molecule A 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane.
[0296] In some embodiments, A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2,-NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3.
[0297]
[0298] In some embodiments, A is substituted with -NH2, -alkyl-NH2, -NH-alkyl, or alkyl.
[0299] In some embodiments, n and m are each independently 0, 1, 2, 3, 4, 5, or 6.
[0300] In some embodiments, n and m are each independently 1, 2, or 3.
[0301] In some embodiments, n and m are each independently 1.
[0302] In some embodiments, n is 1, 2, or 3.
[0303] In some embodiments, m is 1, 2, or 3.
[0304] In some embodiments, n is 1 or 2.
[0305] In some embodiments, m is 1 or 2.
[0306] In some embodiments, n is 1.
[0307] In some embodiments, m is 1.
[0308] In some embodiments, n and m are the same.
[0309] In some embodiments, n and m are different.
[0310] In some embodiments, R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, -OCHF2or -OCF3.
[0311] In some embodiments, R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl,or C1-C6alkynyl.
[0312] In some embodiments, R1 and R2 are each independently C1-C6 alkyl or C1-C6 alkenyl.
[0313] In some embodiments, R1 and R2 are different.
[0314] In some embodiments, R1 and R2 are same.
[0315] In some embodiments, R1 and R2 are each C1-C6 alkyl.
[0316] In some embodiments, R1 and R2 are each C1-5 alkyl.
[0317] In some embodiments, R1 and R2 are each C1-3 alkyl.
[0318] In some embodiments, R1 and R2 are each methyl.
[0319] In some embodiments, R1 and R2 are each ethyl.
[0320] In some embodiments, X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl-thiourea, alkenyl-aryl-thiourea, or alkenyl -heteroaryl-thiourea.
[0321] In some embodiments, X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, or alkyl-cycloalkyl-thiourea.
[0322] In some embodiments, X is alkyl-aryl-thiourea, or alkyl-heteroaryl-thiourea.
[0323] In some embodiments, X is alkyl-aryl-thiourea.
[0324] In some embodiments, 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.
[0325] In some embodiments, the chemical linker L is an alkyl linker, an alkyne linker, alkynal linkeror a polyethylene glycol (PEG) or combinations thereof.
[0326] In some embodiments, the chemical linker L is an alkyl or a PEG or combinations thereof.
[0327] In some embodiments, the chemical linker L is a PEG.
[0328] In some embodiments, the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
[0329] In some embodiments of chemical linker L, b is 1, 2, 3, 4, 5, 6, or 7.
[0330] In some embodiments of chemical linker L, b is 1, 3, or 7.
[0331] In some embodiments of chemical linker L, b is 3.
[0332] In some embodiments of chemical linker L, b is 7.
[0333] In some embodiments, the chemical linker L has the following structure:, wherein b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7.
[0334] In some embodiments of chemical linker L, b is 1, 3 or 7.
[0335] In some embodiments of chemical linker L, b is 3.
[0336] In some embodiments, each occurrence of R4 is -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.
[0337] In some embodiments, each occurrence of R4 is -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
[0338] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, amide,aryl, heteroaryl, or alkyl-CF3.
[0339] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, oramide.
[0340] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, or -NH-alkyl.
[0341] In some embodiments, R4 is -OH.
[0342] In some embodiments, R4 is -NH2.
[0343] In some embodiments, Y1, Y2, Y3, and Y4 are each independently-H, alkyl-CONH2, 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(alkyl- CO2H)2, alkyl-N(alkylaryl-OH)(alkyl-CO2H), alkyl-Nalkylheteroaryl-OH)(alkyl-CO2H), or alkylheteroaryl- P(O)(OH)2.
[0344] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, alkyl-CONH2, 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.
[0345] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, alkyl-CONH2, alkyl-CO2H, or alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2.
[0346] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is alkyl-CO2H.
[0347] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is alkyl-CONH2.
[0348] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is alkyl-CO2NH2.
[0349] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is alkyl-N(alkyl-CO2H)2.
[0350] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CO2H.
[0351] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CO2NH2.
[0352] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CONH2.
[0353] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-N(alkyl-CO2H)2.
[0354] In some embodiments, at least two of Y1, Y2, Y3, and Y4 are the same.
[0355] In some embodiments, at least three of Y1, Y2, Y3, and Y4 are the same.
[0356] In some embodiments, Y1, Y2, Y3, and Y4 are the same.
[0357] In some embodiments, at least one of Y1, Y2, Y3 and Y4 is H.
[0358] In some embodiments, none of Y1, Y2, Y3 and Y4 are H.
[0359] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, 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(alkyl- CO2H)2, alkyl-N(alkylaryl-OH)(alkyl-CO2H), alkyl-Nalkylheteroaryl-OH)(alkyl-CO2H), or alkylheteroaryl- P(O)(OH)2.
[0360] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, 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.
[0361] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, alkyl-CO2H,or alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2.
[0362] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CO2H.
[0363] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CO2NH2.
[0364] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-CONH2.
[0365] In some embodiments, at least one of Y1, Y2, and Y3 is -alkyl-N(alkyl-CO2H)2.
[0366] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2H.
[0367] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2NH2.
[0368] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CONH2.
[0369] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-N(alkyl-CO2H)2.
[0370] In some embodiments, at least two of Y1, Y2, and Y3 are the same.
[0371] In some embodiments, Y1, Y2, and Y3 are the same.
[0372] In some embodiments, at least one of Y1, Y2, and Y3 is H.
[0373] In some embodiments, none of Y1, Y2, and Y3 are H.[
[0384] In some embodiments, Y1, Y2, and Y3 are each independently ,
[0385] In some embodiments, Y1, Y2, and Y3 are each
[0386] In some embodiments, Y1, Y2, and Y3 are each
[0387] In some embodiments, Y
[0388] In some embodiments, Y
[0389] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
[0390] In some embodiments, 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.
[0391] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane or ferrocene.
[0392] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane ordiamantane.
[0393] In some embodiments, the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl,-OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
[0394] In some embodiments, the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), or -N-(alkyl).
[0395] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane.
[0396] In some embodiments, the guest molecule A is substituted or unsubstituted diamantane.
[0397] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene.
[0398] In some embodiments, the guest molecule A is unsubstituted adamantane.
[0399] In some embodiments, the guest molecule A is substituted adamantane.
[0400] In some embodiments, the guest molecule A is 4,9-diamino diamantane.
[0401] In some embodiments, the guest molecule A is unsubstituted ferrocene.
[0402] In some embodiments, the guest molecule A is unsubstituted diamantane.
[0403] In some embodiments, the guest molecule A is substituted diamantane.
[0404] In some embodiments, the substituted diamantane has the following structure:.
[0405] In some embodiments, the guest molecule A is substituted ferrocene.
[0406] In some embodiments, 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.
[0407] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), or -NH-(C1-C6 alkyl).
[0408] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, or -alkyl-N-(C1-C6 alkyl).
[0409] In some embodiments, the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl).
[0410] In some embodiments, the substituted ferrocene has the following structure:.
[0411] The present invention provides a metal complex having the structure:, wherein M is a metal ion; 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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; L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0412] The present invention provides a metal complex having the structure:, wherein M is a metal ion; 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1;each occurrence of R4is 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 L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0413] The present invention provides a metal complex having the structure:, wherein M is a metal ion; 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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 L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0414] The present invention provides a metal complex having the structure:.
[0415] The present invention provides a metal complex having the structure:A.
[0416] The present invention provides a metal complex having the structure:.
[0417] In some embodiments, the targeting moiety A is a molecule or group of molecules, or a proteinor group of proteins that is used to direct a drug or other therapeutic agent to a specific target, like a cell or tissue.
[0418] In some embodiments, the targeting moiety A is a moiety with specificity for a target proteinon the surface of a cell.
[0419] In some embodiments, the targeting moiety A is a moiety with specificity for a target antigenon the surface of a cell.
[0420] In some embodiments, the targeting moiety A is a moiety with specificity for a target antibodyon the surface of a cell.
[0421] In some embodiments, the targeting moiety A is a molecule, a peptide, an antigen, an antibodyor a derivative or fragment thereof.
[0422] In some embodiments, the targeting moiety A is a protein.
[0423] In some embodiments, the targeting moiety A is a ligand.
[0424] In some embodiments, the targeting moiety A is a guest molecule.
[0425] In some embodiments, the guest molecule A 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane.
[0426] In some embodiments, alkyl is C1-6 alkyl, preferably, alkyl is C1-3 alkyl, more preferably, alkylis methyl or ethyl; more preferably alkyl is methyl.
[0427] In some embodiments, aryl is phenyl, p-toluenyl (4-methylphenyl), naphthyl,tetrahydronaphthyl; indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl, preferably, aryl is phenyl, p- toluenyl (4-methylphenyl), or naphthyl, more preferably, aryl is phenyl.
[0428] In some embodiments, the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 3, or 7; preferably, the compound has the following structure:
[0429] The present invention provides a metal complex having the structure:.
[0430] The present invention provides a metal complex having the structure:.
[0431] The present invention provides a metal complex having the structure:.
[0432] The present invention provides a metal complex having the structure:.
[0433] The present invention provides a metal complex having the structure:,,,,.
[0434] The present invention provides a metal complex having the structure:,.
[0435] The present invention provides a metal complex having the structure:,.
[0436] In some embodiments, the metal ion is Lead-203 (203Pb), Lead-212 (212Pb), Copper-62 (62Cu),Copper-64 (64Cu), Copper-67 (67Cu), Gallium-68 (68Ga) Scandium-44 (44Sc), Scandium-47 (47Sc), Scandium-43 (43Sc), Lead-203 (203Pb), Lead-212 (212Pb), Lanthanum-132 (132La), Lanthanum-135 (135La), Yttrium-86 (86Y), Yttrium-90 (90Y), Lutetium 177 (177Lu), Terbium -149 (149Tb), Terbium-152 (152Tb), Terbium-155 (155Tb) or Terbium-161 (161Tb).
[0437] In some embodiments, the metal ion is Lead-203 (203Pb), Lead-212 (212Pb), Copper-62 (62Cu),Copper-64 (64Cu), Copper-67 (67Cu), Scandium-44 (44Sc), Scandium-47 (47Sc), or Scandium-43 (43Sc).
[0438] In some embodiments, the metal ion is Lead-203 (203Pb), or Lead-212 (212Pb).
[0439] The present invention provides a pharmaceutical composition comprising the metal complexdisclosed herein and a host molecule attached to a marker.
[0440] In some embodiments, the marker is a tumor marker or a cancer marker.
[0441] In some embodiments, the marker is a prostate-specific antigen (PSA), prostatic acidphosphatase (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).
[0442] In some embodiments, the marker is a prostate-specific antigen (PSA), cancer antigen 125 (CA125), 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).
[0443] In some embodiments, the marker is a prostate-specific antigen (PSA) or carcinoembryonicantigen (CEA).
[0444] In some embodiments, the marker is a carcinoembryonic antigen (CEA).
[0445] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril,cucurbit[7]uril, cucurbit[8]uril, cucurbit
[0010] uril, cucurbit
[0014] uril, cyclodextrin, or calix-[5]-arenes.
[0446] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril,cucurbit[7]uril, cucurbit[8]uril, or cucurbit
[0010] uril.
[0447] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril,cucurbit[7]uril, or cucurbit[8]uril.
[0448] In some embodiments, the host molecule comprises cucurbit[7]uril, or cucurbit[8]uril.
[0449] In some embodiments, the host molecule is cucurbit[7]uril.
[0450] In some embodiments, the interaction between the host and the guest molecule is a non-covalent interaction.
[0451] In some embodiments, the non-covalent interaction is ion-ion interaction, ion-dipoleinteraction, dipole-dipole interaction, hydrogen bonding, cation-π interaction, π-π interaction, van der Waals interaction or hydrophobic interaction.
[0452] In some embodiments, the interaction is ion-ion interaction or van der Waals interaction.
[0453] In some embodiments, the metal complex and the host molecule form a high affinity host-guestcomplex.
[0454] The present invention provides a method of detecting cells in a subject comprises administeringan effective amount of metal complex having the structure:, wherein M is a metal ion; Y1, Y2, and Y3are each, independently, --H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, and wherein each occurrence of R4is 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; preferably, R4is -OH, -NH2, -O-(C1- C6alkyl), or NH-(C1-C6alkyl), more preferably R4is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; 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, or alkynyl-cycloalkyl-thiourea; wherein L is a chemical linker; R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof, to the subject.
[0455] In some embodiments, the method further comprises administering a host molecule attached toa marker to the subject.
[0456] The present invention provides a method of detecting cells in a subject comprises administeringan effective amount of metal complex having the structure:, wherein M is a metal ion; Y1, Y2, Y3, and Y4are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, and wherein each occurrence of R4is 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; preferably, R4is -OH, -NH2, -O-(C1- C6alkyl), or NH-(C1-C6alkyl), more preferably R4is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; 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, or alkynyl-cycloalkyl-thiourea; wherein L is a chemical linker;R1and R2are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof; to the subject.
[0457] In some embodiments, the method further comprises administering a host molecule attached toa marker to the subject.
[0458] The present invention provides a method of detecting cells in a subject comprises administeringan effective amount of metal complex having the structure:, wherein M is a metal ion; Y1, Y2, and Y3are each, independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, and 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; preferably, R4 is -OH, -NH2, -O-(C1- C6 alkyl), or NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; 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, or alkynyl-cycloalkyl-thiourea; wherein L is a chemical linker; R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof, to the subject.
[0459] In some embodiments, the method further comprises administering a host molecule attached toa marker to the subject.
[0460] In some embodiments, A is substituted with -OH, -NH2, halogen, alkyl, -O-alkyl, -alkyl-NH2,-NH-alkyl, -CHF2, -CF3, -OCHF2, -OCF3.
[0461] In some embodiments, A is substituted with -NH2, -alkyl-NH2, -NH-alkyl, or alkyl.
[0462] In some embodiments, n and m are each independently 0, 1, 2, 3, 4, 5, or 6.
[0463] In some embodiments, n and m are each independently 1, 2, or 3.
[0464] In some embodiments, n and m are each independently 1.
[0465] In some embodiments, n is 1, 2, or 3.
[0466] In some embodiments, m is 1, 2, or 3.
[0467] In some embodiments, n is 1 or 2.
[0468] In some embodiments, m is 1 or 2.
[0469] In some embodiments, n is 1.
[0470] In some embodiments, m is 1.
[0471] In some embodiments, n and m are the same.
[0472] In some embodiments, n and m are different.
[0473] In some embodiments, R1 and R2 are each independently H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, -CF3, -OCHF2or -OCF3.
[0474] In some embodiments, R1 and R2 are each independently H, halogen, C1-C6 alkyl, C1-C6 alkenyl,or C1-C6alkynyl.
[0475] In some embodiments, R1 and R2 are each independently C1-C6 alkyl or C1-C6 alkenyl.
[0476] In some embodiments, R1 and R2 are different.
[0477] In some embodiments, R1 and R2 are each C1-C6 alkyl.
[0478] In some embodiments, R1 and R2 are each C1-5 alkyl.
[0479] In some embodiments, R1 and R2 are each C1-3 alkyl.
[0480] In some embodiments, R1 and R2 are each methyl.
[0481] In some embodiments, R1 and R2 are each ethyl.
[0482] In some embodiments, X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, alkyl-cycloalkyl-thiourea, alkenyl-aryl-thiourea, or alkenyl -heteroaryl-thiourea.
[0483] In some embodiments, X is alkyl-aryl-thiourea, alkyl-heteroaryl-thiourea, or alkyl-cycloalkyl-thiourea.
[0484] In some embodiments, X is alkyl-aryl-thiourea, or alkyl-heteroaryl-thiourea.
[0485] In some embodiments, X is alkyl-aryl-thiourea.
[0486] In some embodiments, 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.
[0487] In some embodiments, the chemical linker L is an alkyl linker, an alkyne linker, alkynal linkeror a polyethylene glycol (PEG) or combinations thereof.
[0488] In some embodiments, the chemical linker L is an alkyl or a PEG or combinations thereof.
[0489] In some embodiments, the chemical linker L is a PEG.
[0490] In some embodiments, the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
[0491] In some embodiments of chemical linker L, b is 1, 2, 3, 4, 5, 6, or 7.
[0492] In some embodiments of chemical linker L, b is 1, 3, or 7.
[0493] In some embodiments of chemical linker L, b is 3.
[0494] In some embodiments of chemical linker L, b is 7.
[0495] In some embodiments, the chemical linker L has the following structure:, wherein b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, m is 1, 3, or 7.
[0496] In some embodiments of chemical linker L, b is 1, 3 or 7.
[0497] In some embodiments of chemical linker L, b is 3.
[0498] In some embodiments, each occurrence of R4 is -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.
[0499] In some embodiments, each occurrence of R4 is -H, -OH, -NH2, halogen, alkyl, -O-alkyl, -NH-alkyl, amide, alkenyl, alkynyl, alkyl-aryl, alkyl-heteroaryl, aryl, heteroaryl, alkyl-CF3, or -Si(alkyl)3.
[0500] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, amide,aryl, heteroaryl, or alkyl-CF3.
[0501] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, -NH-alkyl, oramide.
[0502] In some embodiments, each occurrence of R4 is -OH, -NH2, alkyl, -O-alkyl, or -NH-alkyl.
[0503] In some embodiments, R4 is -OH.
[0504] In some embodiments, R4 is -NH2.
[0505] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, alkyl-CONH2, 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(alkyl- CO2H)2, alkyl-N(alkylaryl-OH)(alkyl-CO2H), alkyl-Nalkylheteroaryl-OH)(alkyl-CO2H), or alkylheteroaryl- P(O)(OH)2.
[0506] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, alkyl-CONH2, 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.
[0507] In some embodiments, Y1, Y2, Y3, and Y4 are each independently -H, alkyl-CONH2, alkyl-CO2H, or alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2.
[0508] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-CO2H.
[0509] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-CONH2.
[0510] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-CO2NH2.
[0511] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -alkyl-N(alkyl-CO2H)2.
[0512] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CO2H.
[0513] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CO2NH2.
[0514] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-CONH2.
[0515] In some embodiments, at least one of Y1, Y2, Y3, and Y4 is -CH2-N(alkyl-CO2H)2.
[0516] In some embodiments, at least two of Y1, Y2, Y3, and Y4 are the same.
[0517] In some embodiments, at least three of Y1, Y2, Y3, and Y4 are the same.
[0518] In some embodiments, Y1, Y2, Y3, and Y4 are the same.
[0519] In some embodiments, at least one of Y1, Y2, Y3 and Y4 is H.
[0520] In some embodiments, none of Y1, Y2, Y3 and Y4 are H.
[0521] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, 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(alkyl- CO2H)2, alkyl-N(alkylaryl-OH)(alkyl-CO2H), alkyl-Nalkylheteroaryl-OH)(alkyl-CO2H), or alkylheteroaryl- P(O)(OH)2.
[0522] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, 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.
[0523] In some embodiments, Y1, Y2, and Y3 are each independently -H, alkyl-CONH2, alkyl-CO2H,or alkyl-CO2NH2, or alkyl-N(alkyl-CO2H)2.
[0524] In some embodiments, at least one of Y1, Y2, and Y3 is alkyl-CO2H.
[0525] In some embodiments, at least one of Y1, Y2, and Y3 is alkyl-CONH2.
[0526] In some embodiments, at least one of Y1, Y2, and Y3 is alkyl-CO2NH2.
[0527] In some embodiments, at least one of Y1, Y2, and Y3 is alkyl-N(alkyl-CO2H)2.
[0528] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2H.
[0529] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CO2NH2.
[0530] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-CONH2.
[0531] In some embodiments, at least one of Y1, Y2, and Y3 is -CH2-N(alkyl-CO2H)2.
[0532] In some embodiments, at least two of Y1, Y2, and Y3 are the same.
[0533] In some embodiments, Y1, Y2, and Y3 are the same.
[0534] In some embodiments, at least one of Y1, Y2, and Y3 is H.
[0535] In some embodiments, none of Y1, Y2, and Y3 are H.[
[0545] In some embodiments, Y1, Y2, and Y3 are each independently, ,
[0546] In some embodiments, Y1, Y2, and Y3 are each independently
[0547] In some embodiments, Y1, Y2, and Y3 are each
[0548] In some embodiments, Y1, Y2, and Y3 are each
[0549] In some embodiments, Y
[0550] In some embodiments, Y
[0551] In some embodiments, the targeting moiety A is a molecule or group of molecules, or a proteinor group of proteins that is used to direct a drug or other therapeutic agent to a specific target, like a cell or tissue.
[0552] In some embodiments, the targeting moiety A is a moiety with specificity for a target proteinon the surface of a cell.
[0553] In some embodiments, the targeting moiety A is a moiety with specificity for a target antigenon the surface of a cell.
[0554] In some embodiments, the targeting moiety A is a moiety with specificity for a target antibodyon the surface of a cell.
[0555] In some embodiments, the targeting moiety A is a molecule, a peptide, an antigen, an antibodyor a derivative or fragment thereof.
[0556] In some embodiments, the targeting moiety A is a protein.
[0557] In some embodiments, the targeting moiety A is a ligand.
[0558] In some embodiments, the targeting moiety A is a guest molecule.
[0559] In some embodiments, the guest molecule A 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, phosphoruspentoxide, phosphorus trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane.
[0560] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane.
[0561] In some embodiments, 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.
[0562] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane or ferrocene.
[0563] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane ordiamantane.
[0564] In some embodiments, the guest molecule A is substituted with halogen, alkyl, alkenyl, alkynyl,-OH, -O-(alkyl), -N-(alkyl), -CHF2, -CF3, -OCHF2 or -OCF3.
[0565] In some embodiments, the guest molecule A is substituted with halogen, alkyl, -O-(alkyl), or -N-(alkyl).
[0566] In some embodiments, the guest molecule A is substituted or unsubstituted adamantane.
[0567] In some embodiments, the guest molecule A is substituted or unsubstituted diamantane.
[0568] In some embodiments, the guest molecule A is substituted or unsubstituted ferrocene.
[0569] In some embodiments, the guest molecule A is unsubstituted adamantane.
[0570] In some embodiments, the guest molecule A is substituted adamantane.
[0571] In some embodiments, the guest molecule A is 4,9-diamino diamantane.
[0572] In some embodiments, the guest molecule A is unsubstituted ferrocene.
[0573] In some embodiments, the guest molecule A is unsubstituted diamantane.
[0574] In some embodiments, the guest molecule A is substituted diamantane.
[0575] In some embodiments, the substituted diamantane has the following structure:.
[0576] In some embodiments, the guest molecule A is substituted ferrocene.
[0577] In some embodiments, 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.
[0578] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, -alkyl-N-(C1-C6 alkyl), -OH, -O-(C1-C6 alkyl), or -NH-(C1-C6 alkyl).
[0579] In some embodiments, the substituted ferrocene is substituted with C1-C6 alkyl, or -alkyl-N-(C1-C6 alkyl).
[0580] In some embodiments, the substituted ferrocene is substituted with -alkyl-N-(C1-C6 alkyl).
[0581] In some embodiments, the substituted ferrocene has the following structure:
[0582] In some embodiments, the metal complex has the structure:, wherein M is a metal ion; 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1;each occurrence of R4is 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; L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0583] In some embodiments, the metal complex has the structure:, wherein M is a metal ion; 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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 L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0584] In some embodiments, the metal complex has the structure:, wherein M is a metal ion; 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 each 1; a is 0, 1, 2, 3, 4, 5, or 6; preferably a is 1, 2, or 3; more preferably, a is 1; each occurrence of R4is 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 L is a chemical linker; and A is a targeting moiety, or a salt or an ester thereof.
[0585] In some embodiments, the metal complex has the structure:.
[0586] In some embodiments, the metal complex has the structure:.
[0587] In some embodiments, the metal complex has the structure:.
[0588] In some embodiments, the targeting moiety A is a molecule or group of molecules, or a proteinor group of proteins that is used to direct a drug or other therapeutic agent to a specific target, like a cell or tissue.
[0589] In some embodiments, the targeting moiety A is a moiety with specificity for a target proteinon the surface of a cell.
[0590] In some embodiments, the targeting moiety A is a moiety with specificity for a target antigenon the surface of a cell.
[0591] In some embodiments, the targeting moiety A is a moiety with specificity for a target antibodyon the surface of a cell.
[0592] In some embodiments, the targeting moiety A is a molecule, a peptide, an antigen, an antibodyor a derivative or fragment thereof.
[0593] In some embodiments, the targeting moiety A is a protein.
[0594] In some embodiments, the targeting moiety A is a ligand.
[0595] In some embodiments, the targeting moiety A is a guest molecule.
[0596] In some embodiments, the guest molecule A 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane.
[0597] In some embodiments, alkyl is C1-6 alkyl, preferably, alkyl is C1-3 alkyl, more preferably, alkylis methyl or ethyl; more preferably alkyl is methyl.
[0598] In some embodiments, aryl is phenyl, p-toluenyl (4-methylphenyl), naphthyl,tetrahydronaphthyl; indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl, preferably, aryl is phenyl, p- toluenyl (4-methylphenyl), or naphthyl, more preferably, aryl is phenyl.
[0599] In some embodiments, the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 3, or 7.
[0600] In some embodiments, the metal complex has the structure:.
[0601] In some embodiments, the metal complex has the structure:.
[0602] In some embodiments, the metal complex has the structure:.
[0603] In some embodiments, the metal complex has the structure:.
[0604] In some embodiments, the metal complex has the structure:,,,,.
[0605] In some embodiments, the metal ion is Lead-203 (203Pb), Lead-212 (212Pb), Copper-62 (62Cu),Copper-64 (64Cu), Copper-67 (67Cu), Gallium-68 (68Ga) Scandium-44 (44Sc), Scandium-47 (47Sc), Scandium-43 (43Sc), Lead-203 (203Pb), Lead-212 (212Pb), Lanthanum-132 (132La), Lanthanum-135 (135La), Yttrium-86 (86Y), Yttrium-90 (90Y), Lutetium 177 (177Lu), Terbium -149 (149Tb), Terbium-152 (152Tb), Terbium-155 (155Tb) or Terbium-161 (161Tb).
[0606] In some embodiments, the metal ion is Lead-203 (203Pb), Lead-212 (212Pb), Copper-62 (62Cu),Copper-64 (64Cu), Copper-67 (67Cu), Scandium-44 (44Sc), Scandium-47 (47Sc), or Scandium-43 (43Sc).
[0607] In some embodiments, the metal ion is Lead-203 (203Pb), or Lead-212 (212Pb).
[0608] In some embodiments, the marker is a tumor marker or a cancer marker.
[0609] In some embodiments, the marker is a prostate-specific antigen (PSA), prostatic acidphosphatase (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).
[0610] In some embodiments, the marker is a prostate-specific antigen (PSA), cancer antigen 125 (CA125), 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).
[0611] In some embodiments, the marker is a prostate-specific antigen (PSA) or carcinoembryonicantigen (CEA).
[0612] In some embodiments, the marker is a carcinoembryonic antigen (CEA).
[0613] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril,cucurbit[7]uril, cucurbit[8]uril, cucurbit
[0010] uril, cucurbit
[0014] uril, cyclodextrin, or calix-[5]-arenes.
[0614] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril,cucurbit[7]uril, cucurbit[8]uril, or cucurbit
[0010] uril.
[0615] In some embodiments, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril,cucurbit[7]uril, or cucurbit[8]uril.
[0616] In some embodiments, the host molecule comprises cucurbit[7]uril, or cucurbit[8]uril.
[0617] In some embodiments, the host molecule is cucurbit[7]uril.
[0618] In some embodiments, the interaction between the host and the guest molecule is a non-covalent interaction.
[0619] In some embodiments, the non-covalent interaction is ion-ion interaction, ion-dipoleinteraction, dipole-dipole interaction, hydrogen bonding, cation-π interaction, π-π interaction, van der Waals interaction or hydrophobic interaction.
[0620] In some embodiments, the interaction is ion-ion interaction or van der Waals interaction.
[0621] In some embodiments, the metal complex and the host molecule form a high affinity host-guestcomplex.
[0622] The present invention provides a method of detecting cells in a subject comprises administeringan effective amount of the modified marker with a host molecule disclosed herein to the subject who contains a guest molecule.
[0623] The present invention provides a method of detecting cells in a subject comprisingadministering an effective amount of the pharmaceutical composition disclosed herein to the subject and imaging the subject with a molecular imaging device to detect the composition in the subject.
[0624] The present invention provides a method of imaging cells in a subject comprising:1) administering to the subject an effective amount of the composition disclosed herein, wherein the composition specifically accumulates at the cells in the subject; 2) detecting in the subject the location of the composition; and 3) obtaining an image of the cells in the subject based on the location of the composition in the subject.
[0625] The present invention provides a method of detecting the presence of cells in a subject whichcomprises determining if an amount of the composition disclosed herein is present in the subject at a period of time after administration of the composition to the subject, thereby detecting the presence of the cells based on the amount of the composition determined to be present in the subject.
[0626] In some embodiments, the method further comprises administering to the subject a hostmolecule.
[0627] In some embodiments, the metal complex and the host molecule are administered concurrently,or wherein the host molecule is administered first, and the metal complex is administered after a period of time.
[0628] In some embodiments, the period of time is 24 hours, 48 hours, 72, hours, 96 hours, 120 hours,or 144 hours.
[0629] In some embodiments, the period of time is 72 hours.
[0630] In some embodiments, the cells are cancer cells or tumor cells.
[0631] In some embodiments, the cancer cells or tumor cells have elevated levels of proteins orantigens, or both.
[0632] In some embodiments, the cancer is lung cancer, breast cancer, prostate cancer, cervical cancer,pancreatic cancer, colon cancer, ovarian cancer, stomach cancer, esophagus cancer, skin cancer, heart cancer, liver cancer, bronchial cancer, testicular cancer, kidney cancer, bladder cancer, spleen cancer, thymus cancer, thyroid cancer, brain cancer, or gall bladder cancer.
[0633] In some embodiments, the cancer is pancreatic cancer.
[0634] In some embodiments, the tumor is bone tumor, brain tumor, malignant soft tissue tumor, organtumor, ovarian germ cell tumor, gland tumor, lymphatic tumor, or skin tumor.
[0635] In some embodiments, the subject is a mammal.
[0636] In some embodiments, the subject is a human.
[0637] In some embodiments, the molecular imaging device is a PET imaging device.
[0638] The present invention provides a use of an effective amount of metal complex disclosed hereinto detect cells within a subject, wherein the subject contains a host molecule.
[0639] The present invention provides a use of an effective amount of a host molecule attached to amarker disclosed herein to detect cells in a subject, wherein the subject contains a guest molecule.
[0640] The present invention provides a use of an effective amount of the composition disclosed hereinto image a subject with a molecular imaging device to detect cells in a subject.
[0641] The present invention provides a composition comprising the metal complex disclosed hereinto detect cells in a subject.
[0642] The present invention provides a composition comprising the metal complex disclosed hereinto image cells in a subject.
[0643] The compounds of the present invention include all hydrates, solvates, and complexes of thecompounds 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. The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469–1474, (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
[0644] Exemplary functional groups of Y1, Y2, Y3, and Y4 are described in U.S. Patent ApplicationPublication No. 2021 / 0276971 A1, International Application No. US / 2022 / 078389, International Application No. PCT / US2023 / 064637, and International Application No. PCT / US2023 / 073725 the contents of which are hereby incorporated by reference.
[0645] Compounds and metal complexes disclosed and tested in U.S. Patent Application PublicationNo. 2021 / 0276971 A1, International Application No. US / 2022 / 078389, and International Application No. PCT / US2023 / 064637 can be used to attach to a guest molecule as disclosed in the subject application. The contents of U.S. Patent Application Publication No. 2021 / 0276971 A1, International Application No. US / 2022 / 078389, International Application No. PCT / US2023 / 064637, and International Application No. PCT / US2023 / 073725 are hereby incorporated by reference.
[0646] Compounds and metal complexes disclosed and tested in U.S. Patent Application PublicationNo. 2021 / 0276971 A1, International Application No. US / 2022 / 078389, and International Application No. PCT / US2023 / 064637 can be used to attach to a guest molecule as disclosed in the subject application for PET imaging in a subject. The contents of U.S. Patent Application Publication No. 2021 / 0276971 A1, International Application No. US / 2022 / 078389, International Application No. PCT / US2023 / 064637, and International Application No. PCT / US2023 / 073725 are hereby incorporated by reference.
[0647] The compounds of the subject invention may have spontaneous tautomeric forms. In caseswherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
[0648] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atomshaving less than four bonds to non-hydrogen atoms. However, it is understood that enough hydrogen atoms exist on said carbon atoms to satisfy the octet rule.
[0649] This invention also provides isotopic variants of the compounds disclosed herein, includingwherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.
[0650] It is understood that the structures described in the embodiments of the methods hereinabovecan be the same as the structures of the compounds described hereinabove.
[0651] It is understood that where a numerical range is recited herein, the present inventioncontemplates each integer between, and including, the upper and lower limits, unless otherwise stated.
[0652] Except where otherwise specified, if the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
[0653] The subject invention is also intended to include all isotopes of atoms occurring on thecompounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
[0654] It will be noted that any notation of a carbon in structures throughout this application, whenused without further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein.
[0655] It will also be noted that any notation of a hydrogen in structures throughout this application,when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H, or3H. Furthermore, any compounds containing2H or3H may specifically have the structure of any of the compounds disclosed herein.
[0656] Isotopically-labeled compounds can generally be prepared by conventional techniques knownto those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
[0657] In the compounds used in the method of the present invention, the substituents may besubstituted or unsubstituted, unless specifically defined otherwise.
[0658] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle,bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl and aminocarbonyl and aminothiocarbonyl.
[0659] It is understood that substituents and substitution patterns on the compounds used in the methodof the present 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 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.
[0660] In choosing the compounds used in the method of the present invention, one of ordinary skillin the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
[0661] As used herein, the term “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 measuredaccurately and reproducibly. Medical signs stand in contrast to medical symptoms, which are limited to those indications of health or illness perceived by patients themselves. In 1998, the National Institutes of Health Biomarkers Definitions Working Group defined a 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.” A joint venture on chemical safety, the International Programme on Chemical Safety, led by the World Health Organization (WHO) and in coordination with the United Nations and the International Labor Organization, has defined 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. 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.
[0662] As used herein, the term “Guest-Host” refers to host guest interactions involving two moleculesor materials that can form complexes through unique structural relationships and noncovalent binding. Also referred to as molecular recognition, this type of interaction is widely found in biorecognition processes, such as enzyme–inhibitor and antigen–antibody interactions.
[0663] As used herein, host–guest chemistry describes complexes that are composed of two or moremolecules or ions that are held together in unique structural relationships by forces other than those of full covalent bonds. Host–guest chemistry encompasses the idea of molecular recognition and interactions through non-covalent bonding.
[0664] As used herein, the host molecule is a molecule (a 'host') binding another molecule (a 'guest')to produce a 'host–guest' complex or supermolecule. Commonly the host is a large molecule or aggregate such as an enzyme or synthetic cyclic compound possessing a sizeable, central hole or cavity.
[0665] As used herein, a "guest molecule" refers to a molecule that is bound by a larger, host moleculethrough non-covalent interactions. The host molecule typically has a cavity or binding pocket where the guest molecule can fit and interact. This interaction is often described as an "inclusion compound" where the guest is enclosed or incorporated into the host.
[0666] As used herein the term “Prostate-specific antigen (PSA)” is always present in lowconcentrations in the blood of adult males. An elevated PSA level in the blood may indicate prostate cancer, but other conditions such as benign prostatic hyperplasia (BPH) and prostatitis can also raise PSA levels. PSA levels are used to evaluate how a patient has responded to treatment and to check for tumor recurrence.
[0667] As used herein the term “Prostatic acid phosphatase (PAP)” originates in the prostate and isnormally present in small amounts in the blood. In addition to prostate cancer, elevated levels of PAP may indicate testicular cancer, leukemia, and non-Hodgkin's lymphoma, as well as some noncancerous conditions.
[0668] As used herein, ovarian cancer is the most common cause of elevated CA 125, but cancers ofthe 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.
[0669] As used herein “Carcinoembryonic antigen (CEA)” is normally found in small amounts in theblood. Colorectal cancer is the most common cancer that raises this tumor marker. Several other cancers can also raise levels of carcinoembryonic antigen.
[0670] As used herein “Alpha-fetoprotein (AFP)” is normally elevated in pregnant women since it isproduced by the fetus. However, AFP is not usually found in the blood of adults. In men, and in women who are not pregnant, an elevated level of AFP may indicate liver cancer or cancer of the ovary or testicle. Noncancerous conditions may also cause elevated AFP levels.
[0671] As used herein “Human chorionic gondadotropin (HCG)” is another substance that appearsnormally in pregnancy and is produced by the placenta. If pregnancy is ruled out, HCG may indicate cancer in the testis, ovary, liver, stomach, pancreas, and lung. Marijuana use can also raise HCG levels.
[0672] As used herein “CA 19-9” marker is associated with cancers in the colon, stomach, and bileduct. 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.
[0673] As used herein “CA 15-3” marker is most useful in evaluating the effect of treatment for womenwith 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.
[0674] As used herein “CA 27-29” marker, like CA 15-3, is used to follow the course of treatment inwomen 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.
[0675] As used herein “Lactate dyhydrogenase (LDH)” is a protein that normally appears throughoutthe body in small amounts. Many cancers can raise LDH levels, so it is not useful in identifying a specific kind of cancer. Measuring LDH levels can be helpful in monitoring treatment for cancer. Noncancerous conditions that can raise LDH levels include heart failure, hypothyroidism, anemia, and lung or liver disease.
[0676] As used herein “Neuroson-specific enolase (NSE)” is associated with several cancers, but it isused most often to monitor treatment in patients with neuroblastoma or small cell lung cancer.
[0677] Targeting Agent
[0678] The targeting moiety may comprise, consist of, or consist essentially of an antibody, peptideor small molecule.
[0679] The targeting moiety may comprise, consist of, or consist essentially of Brentuximab(targets cell-membrane protein CD30), Inotuzumab targets CD22), Gemtuzumab (targets CD33), Milatuzumab (targets CD74), Trastuzumab (targets HER2 receptor), Glembatumomab (targets transmembrane glycoprotein NMB - GPNMB), Lorvotuzumab (targets CD56), or Labestuzumab (targets carcinoembryonic cell adhesion molecule 5) or derivatives or fragments thereof.
[0680] The targeting moiety may comprise, consist of, or consist essentially of DUPA [(2-[3-(1, 3-dicarboxy propyl)ureido] pentanedioic acid)] (targets prostate-specific membrane antigen (PSMA)), or derivatives or fragments thereof.
[0681] The targeting moiety may comprise, consist of, or consist essentially of bombesin (targets G-protein-coupled receptors BBR1, -2, and -3) or somatostatin (targets Somatostatin receptor subtypes 1-5), or derivatives or fragments thereof.
[0682] The targeting moiety is capable of selectively binding to the population of cells to be visualizeddue to preferential expression on the targeted cells of a receptor for the targeting moiety. The binding site for the targeting moiety can include receptors or other proteins that are uniquely expressed, overexpressed, or preferentially expressed by the population of cells to be visualized. A surface-presented protein uniquely expressed, overexpressed, or preferentially expressed by the cells to be visualized is a receptor not present or present at lower amounts on other cells providing a means for selective, rapid, and sensitive visualization of the cells targeted for diagnostic imaging using the conjugates of the present invention.
[0683] Exemplary targeting moieties are described in U.S. Patent Nos. 10,005,820 B2, 9,801,951 B2or U.S. Patent Application Publication No.2015 / 0105540 A1 the contents of which are hereby incorporated by reference.
[0684] Chemical Linker
[0685] The term "chemical linker" refers to a chemical moiety or bond that covalently attaches two ormore molecules, such as a targeting moiety and an imaging moiety. The linker may be a cleavable linkers, e.g. pH-sensitive (acid-labile) linker, disulfide linker, a peptide linker, a β-glucuronide linkers or a hydrazine linker. The linker may be a non-cleavable linker, e.g. thioether, maleimidocaproyl, maleimidomethyl cyclohexane-1carboxylate, alkyl, alkylamido or amide linker.
[0686] Covalent bonding of the imaging agent, chemical linker and targeting moiety can occur throughthe formation of amide, ester or imino bonds between acid, aldehyde, hydroxy, amino, or hydrazo groups. For example, a carboxylic acid on the targeting moiety can be activated using carbonyldiimidazole or standard carbodiimide coupling reagents such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and thereafter reacted with the other component of the conjugate, or with a linker, having at least one nucleophilic group, i.e. hydroxy, amino, hydrazo, or thiol, to form the vitamin-chelator conjugate coupled, with or without a linker, through ester, amide, or thioester bonds.
[0687] Linkage of a targeting moiety to the imaging moiety may be achieved by any means known tothose in the art, such as genetic fusion, covalent chemical attachment, noncovalent attachment (e.g., adsorption) or a combination of such means. Selection of a method for linking a Targeting Moiety to an imaging moiety will vary depending, in part, on the chemical nature of the targeting moiety.
[0688] Linkage may be achieved by covalent attachment, using any of a variety of appropriatemethods. For example, the targeting moiety and imaging moiety may be linked using bifunctional reagents (linkers) that are capable of reacting with both the targeting moiety and imaging moiety and forming a bridge between the two.
[0689] The term “non-covalent linker” is used in accordance with its ordinary meaning and refers to adivalent moiety which includes at least two molecules that are not covalently linked to each other but do interact with each other via a non-covalent bond (e.g. electrostatic interactions (e.g. ionic bond, hydrogen bond, halogen bond) or van der Waals interactions (e.g. dipole-dipole, dipole-induced dipole, London dispersion).
[0690] The terms “cleavable linker” or “cleavable moiety” as used herein refers to a divalent ormonovalent, respectively, moiety which is capable of being separated (e.g., detached, split, disconnected, hydrolyzed, a stable bond within the moiety is broken) into distinct entities. A cleavable linker is cleavable(e.g., specifically cleavable) in response to external stimuli (e.g., enzymes, nucleophilic / basic reagents, reducing agents, photo-irradiation, electrophilic / acidic reagents, organometallic and metal reagents, or oxidizing reagents). A chemically cleavable linker refers to a linker which is capable of being split in response to the presence of a chemical (e.g., acid, base, oxidizing agent, reducing agent, Pd(0), tris-(2- carboxyethyl)phosphine, dilute nitrous acid, fluoride, tris(3-hydroxypropyl)phosphine), sodium dithionite (Na2S2O4), hydrazine (N2H4)). A chemically cleavable linker is non-enzymatically cleavable. In embodiments, the cleavable linker is cleaved by contacting the cleavable linker with a cleaving agent. In embodiments, the cleaving agent is sodium dithionite (Na2S2O4), weak acid, hydrazine (N2H4), Pd(0), or light-irradiation (e.g., ultraviolet radiation).
[0691] A photocleavable linker (e.g., including or consisting of a o-nitrobenzyl group) refers to a linkerwhich is capable of being split in response to photo-irradiation (e.g., ultraviolet radiation). An acid- cleavable linker refers to a linker which is capable of being split in response to a change in the pH (e.g., increased acidity). A base-cleavable linker refers to a linker which is capable of being split in response to a change in the pH (e.g., decreased acidity). An oxidant-cleavable linker refers to a linker which is capable of being split in response to the presence of an oxidizing agent. A reductant-cleavable linker refers to a linker which is capable of being split in response to the presence of an reducing agent (e.g., Tris(3- hydroxypropyl)phosphine). In embodiments, the cleavable linker is a dialkylketal linker, an azo linker, an allyl linker, a cyanoethyl linker, a 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl linker, or a nitrobenzyl linker.
[0692] The term “orthogonally cleavable linker” or “orthogonal cleavable linker” as used herein referto a cleavable linker that is cleaved by a first cleaving agent (e.g., enzyme, nucleophilic / basic reagent, reducing agent, photo-irradiation, electrophilic / acidic reagent, organometallic and metal reagent, oxidizing reagent) in a mixture of two or more different cleaving agents and is not cleaved by any other different cleaving agent in the mixture of two or more cleaving agents. For example, two different cleavable linkers are both orthogonal cleavable linkers when a mixture of the two different cleavable linkers are reacted with two different cleaving agents and each cleavable linker is cleaved by only one of the cleaving agents and not the other cleaving agent. In embodiments, an orthogonally is a cleavable linker that following cleavage the two separated entities (e.g., fluorescent dye, bioconjugate reactive group) do not further react and form a new orthogonally cleavable linker.
[0693] Exemplary linkers are described in U.S. Patent Application No.2012 / 0322741 A1, U.S. PatentApplication No. 2018 / 0289828 A1 and U.S. Patent No. 8,461,117 B2 the contents of which are hereby incorporated by reference.
[0694] Antibody
[0695] An "antibody" as used herein is defined broadly as a protein that characteristicallyimmunoreacts with an epitope (antigenic determinant) of an antigen. As is known in the art, the basic structural unit of an antibody is composed of two identical heavy chains and two identical light chains, in which each heavy and light chain consists of amino terminal variable regions and carboxy terminal constant regions. The antibodies of the present invention include polyclonal antibodies, monoclonal antibodies (mAbs), chimeric antibodies, CDR-grafted antibodies, humanized antibodies, human antibodies, catalytic antibodies, multispecific antibodies, as well as fragments, regions or derivatives thereof provided by known techniques, including, for example, enzymatic cleavage, peptide synthesis or recombinant techniques.
[0696] As used herein, "monoclonal antibody" means an antibody obtained from a population ofsubstantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations that typically include different antibodies directed against different determinants, each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler and Milstein, Nature 256:495-97 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The monoclonal antibodies may also be isolated from phage display libraries using the techniques described, for example, in Clackson et al., Nature 352:624-28 (1991) and Marks et al., J. Mol. Biol.222(3):581-97 (1991).
[0697] The term "hybridoma" or "hybridoma cell line" refers to a cell line derived by cell fusion, orsomatic cell hybridization, between a normal lymphocyte and an immortalized lymphocyte tumor line. In particular, B cell hybridomas are created by fusion of normal B cells of defined antigen specificity with a myeloma cell line, to yield immortal cell lines that produce monoclonal antibodies. In general, techniques for producing human B cell hybridomas, are well known in the art [Kozbor et al., Immunol. Today 4:72 (1983); Cole et al., in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc.77-96 (1985)].
[0698] The term "epitope" refers to a portion of a molecule (the antigen) that is capable of being boundby a binding agent, e.g., an antibody, at one or more of the binding agent's antigen binding regions. Epitopes usually consist of specific three-dimensional structural characteristics, as well as specific charge characteristics.
[0699] "Humanized antibodies" means antibodies that contain minimal sequence derived from non-human immunoglobulin sequences. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hyper variable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. See, for example, U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205, each herein incorporated by reference. In some instances, framework residues of the human immunoglobulin are replaced by corresponding non-human residues (see, for example, U.S. Pat. Nos. 5,585,089; 5,693,761; 5,693,762, each herein incorporated by reference). Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance (e.g., to obtain desired affinity). In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details see Jones et al., Nature 331:522-25 (1986); Riechmann et al., Nature 332:323-27 (1988); and Presta, Curro Opin. Struct. Biol.2:593-96 (1992), each of which is incorporated herein by reference.
[0700] Also encompassed by the term “antibody” are xenogeneic or modified antibodies produced ina non-human mammalian host, more particularly a transgenic mouse, characterized by inactivated endogenous immunoglobulin (Ig) loci. In such transgenic animals, competent endogenous genes for the expression of light and heavy subunits of host immunoglobulins are rendered non-functional and substituted with the analogous human immunoglobulin loci. These transgenic animals produce human antibodies in the substantial absence of light or heavy host immunoglobulin subunits. See, for example, U.S. Pat. No. 5,939,598, the entire contents of which are incorporated herein by reference.
[0701] Those skilled in the art will be aware of how to produce antibody molecules of the presentinvention. For example, polyclonal antisera or monoclonal antibodies can be made using standard methods. To produce monoclonal antibodies, antibody producing cells (lymphocytes) can be harvested from an immunized animal and fused with myeloma cells by standard somatic cell fusion procedures thus immortalizing these cells and yielding hybridoma cells. Such techniques are well known in the art. Hybridoma cells can be screened immunochemically for production of antibodies which are specifically reactive with the oligopeptide, and monoclonal antibodies isolated.
[0702] Target Cells
[0703] The term "target cells" refers to the cells that are involved in a pathology and so are preferredtargets for imaging or therapeutic activity. Target cells can be, for example and without limitation, one or more of the cells of the following groups: primary or secondary tumor cells (the metastases), stromal cells of primary or secondary tumors, neoangiogenic endothelial cells of tumors or tumor metastases, macrophages, monocytes, polymorphonuclear leukocytes and lymphocytes, and polynuclear agents infiltrating the tumors and the tumor metastases. The term "targeting moiety" and "targeting agent" refer to an antibody, aptamer, peptide, small molecule or other substance that binds specifically to a target. A targeting moiety may be an antibody targeting moiety (e.g. antibodies or fragments thereof) or a non- antibody targeting moiety (e.g. aptamers, peptides, small molecules or other substances that bind specifically to a target).
[0704] The term "target tissue" refers to target cells (e.g., tumor cells) and cells in the environment ofthe target cells.
[0705] The term "cancer" refers to any of a number of diseases characterized by uncontrolled,abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (e.g., metastasize), as well as any of a number of characteristic structural and / or molecular features. A "cancerous cell" or "cancer cell" is understood as a cell having specific structural properties, which can lack differentiation and be capable of invasion and metastasis. Examples of cancers are, breast, lung, brain, bone, liver, kidney, colon, and prostate cancer
[0706] Exemplary targets are described in Avicenna J Med Biotechnol. 2019 Jan-Mar; 11(1): 3–23,Nature Reviews Drug Discovery Volume 16, pages 315–337 (2017), the contents of which are hereby incorporated by reference.
[0707] As used herein, the term "amino acid" refers to any natural or unnatural amino acid includingits salt form, ester derivative, protected amine derivative and / or its isomeric forms. Amino Acids comprise, by way of non-limiting example: Agmatine, Alanine Beta-Alanine, Arginine, Asparagine, Aspartic Acid, Cysteine, Glutamine, Glutamic Acid, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Phenyl Beta-Alanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine. The amino acids may be L or D amino acids.
[0708] The terms "peptide", "polypeptide", peptidomimetic and "protein" are used to refer to apolymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers. These terms also encompass the term "antibody". "Peptide" isoften used to refer to polymers of fewer amino acid residues than "polypeptides" or "proteins". A protein can contain two or more polypeptides, which may be the same or different from one another.
[0709] As used herein, the term "oligopeptide" refers to a peptide comprising of between 2 and 20amino acids and includes dipeptides, tripeptides, tetrapeptides, pentapeptides, etc.
[0710] An amino acid or oligopeptide may be covalently bonded to an amine of another moleculethrough an amide linkage, resulting in the loss of an “OH” from the amino acid or oligopeptide.
[0711] As used herein, the term “activity” refers to the activation, production, expression, synthesis,intercellular effect, and / or pathological or aberrant effect of the referenced molecule, either inside and / or outside of a cell. Such molecules include, but are not limited to, cytokines, enzymes, growth factors, pro- growth factors, active growth factors, and pro-enzymes. Molecules such as cytokines, enzymes, growth factors, pro-growth factors, active growth factors, and pro-enzymes may be produced, expressed, or synthesized within a cell where they may exert an effect. Such molecules may also be transported outside of the cell to the extracellular matrix where they may induce an effect on the extracellular matrix or on a neighboring cell. It is understood that activation of inactive cytokines, enzymes and pro-enzymes may occur inside and / or outside of a cell and that both inactive and active forms may be present at any point inside and / or outside of a cell. It is also understood that cells may possess basal levels of such molecules for normal function and that abnormally high or low levels of such active molecules may lead to pathological or aberrant effects that may be corrected by pharmacological intervention.
[0712] This invention also provides isotopic variants of the compounds disclosed herein, includingwherein the isotopic atom is2H and / or wherein the isotopic atom13C. Accordingly, in the compounds provided herein hydrogen can be enriched in the deuterium isotope. It is to be understood that the invention encompasses all such isotopic forms.
[0713] It is understood that the structures described in the embodiments of the methods hereinabovecan be the same as the structures of the compounds described hereinabove.
[0714] It is understood that where a numerical range is recited herein, the present inventioncontemplates each integer between, and including, the upper and lower limits, unless otherwise stated.
[0715] Except where otherwise specified, if the structure of a compound of this invention includes anasymmetric carbon atom, it is understood that the compound occurs as a racemate, racemic mixture, and isolated single enantiomer. All such isomeric forms of these compounds are expressly included in this invention. Except where otherwise specified, each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomerscan be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.
[0716] The subject invention is also intended to include all isotopes of atoms occurring on thecompounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
[0717] It will be noted that any notation of a carbon in structures throughout this application, whenused without further notation, are intended to represent all isotopes of carbon, such as12C,13C, or14C. Furthermore, any compounds containing13C or14C may specifically have the structure of any of the compounds disclosed herein.
[0718] It will also be noted that any notation of a hydrogen in structures throughout this application,when used without further notation, are intended to represent all isotopes of hydrogen, such as1H,2H, or3H. Furthermore, any compounds containing2H or3H may specifically have the structure of any of the compounds disclosed herein.
[0719] Isotopically-labeled compounds can generally be prepared by conventional techniques knownto those skilled in the art using appropriate isotopically-labeled reagents in place of the non-labeled reagents employed.
[0720] In the compounds used in the method of the present invention, the substituents may besubstituted or unsubstituted, unless specifically defined otherwise.
[0721] In the compounds used in the method of the present invention, alkyl, heteroalkyl, monocycle,bicycle, aryl, heteroaryl and heterocycle groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
[0722] It is understood that substituents and substitution patterns on the compounds used in the methodof the present 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 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.
[0723] In choosing the compounds used in the method of the present invention, one of ordinary skillin the art will recognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
[0724] As used herein, "alkyl" is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, C1-Cnas in “C1–Cnalkyl" is defined to include groups having 1, 2......, n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl and so on. An embodiment can be C1-C12alkyl, C2-C12alkyl, C3-C12alkyl, C4-C12alkyl and so on. ”Alkoxy" represents an alkyl group as described above attached through an oxygen bridge.
[0725] The term "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. Thus, C2-Cn alkenyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 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 C6 alkenyl, respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C2-C12 alkenyl, C3-C12 alkenyl, C4-C12 alkenyl and so on.
[0726] The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present. Thus, C2-Cn alkynyl is defined to include groups having 1, 2...., n-1 or n carbons. For example, "C2-C6 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.
[0727] “Alkylene”, “alkenylene” and “alkynylene” shall mean, respectively, a divalent alkane, alkeneand 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.
[0728] As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms and at least 1 heteroatom within the chain or branch.
[0729] As used herein, "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.
[0730] As herein, "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).
[0731] As used herein, "monocycle" includes any stable polyatomic carbon ring of up to 10 atoms andmay be unsubstituted or substituted. Examples of such non-aromatic monocycle elements include but are not limited to: cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocycle elements include but are not limited to: phenyl.
[0732] As used herein, "bicycle" includes any stable polyatomic carbon ring of up to 10 atoms that isfused to a polyatomic carbon ring of up to 10 atoms with each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicycle elements include but are not limited to: decahydronaphthalene. Examples of such aromatic bicycle elements include but are not limited to: naphthalene.
[0733] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbonring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
[0734] As used herein, the term “polycyclic” refers to unsaturated or partially unsaturated multiplefused ring structures, which may be unsubstituted or substituted.
[0735] The term “arylalkyl” refers to alkyl groups as described above wherein one or more bonds tohydrogen 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. Examples of arylalkyl moieties include, but are not limitedto, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
[0736] The term "heteroaryl", as used herein, represents a stable monocyclic, bicyclic or polycyclicring 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, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra- hydroquinoline. In cases where the 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.
[0737] The term “alkylheteroaryl” refers to alkyl groups as described above wherein one or morebonds to hydrogen contained therein are replaced by a bond to an heteroaryl group as described above. It is understood that an “alkylheteroaryl” group is connected to a core molecule through a bond from the alkylgroup and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH2-(C5H4N), -CH2-CH2-(C5H4N) and the like.
[0738] The term "heterocycle" or “heterocyclyl” refers to a mono- or poly-cyclic ring system whichcan 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. Preferably 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). Examples of 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.
[0739] The alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl substituents may be substitutedor unsubstituted, unless specifically defined otherwise. In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl groups can be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
[0740] As used herein, the term “halogen” refers to F, Cl, Br, and I.
[0741] The terms “substitution”, “substituted” and “substituent” refer to a functional group asdescribed 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. Examples of 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 methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or pluraly. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
[0742] It is understood that substituents and substitution patterns on the compounds of the instantinvention 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.
[0743] In choosing the compounds of the present invention, one of ordinary skill in the art willrecognize that the various substituents, i.e. R1, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity.
[0744] The various R groups attached to the aromatic rings of the compounds disclosed herein may beadded to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the content of which is hereby incorporated by reference.
[0745] The compounds used in the method of the present invention may be prepared by techniqueswell known in organic synthesis and familiar to a practitioner ordinarily skilled in the art. However, these may not be the only means by which to synthesize or obtain the desired compounds.
[0746] The compounds used in the method of the present invention may be prepared by techniquesdescribed 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) 5thEdition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5thEdition (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.
[0747] Another aspect of the invention comprises a compound used in the method of the presentinvention as a pharmaceutical composition.
[0748] In some embodiments, a pharmaceutical composition comprising the compound of the presentinvention and a pharmaceutically acceptable carrier.
[0749] As used herein, the term “pharmaceutically active agent” means any substance or compoundsuitable 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. Department Of Health AndHuman Services, 30thedition, 2010), which are hereby incorporated by reference. Pharmaceutically active agents 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.
[0750] The compounds used in the method of the present invention may be in a salt form. As usedherein, a “salt” is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These 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. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19).
[0751] The compounds of the present invention may also form salts with basic amino acids such alysine, arginine, etc. and with basic sugars such as N-methylglucamine, 2-amino-2-deoxyglucose, etc. and any other physiologically non-toxic basic substance.
[0752] As used herein, “administering” an agent may be performed using any of the various methodsor 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.
[0753] The compounds used in the method of the present invention may be administered in variousforms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
[0754] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptablesolvent, 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.
[0755] The dosage of the compounds administered in treatment will vary depending upon factors suchas the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
[0756] A dosage unit of the compounds used in the method of the present invention may comprise asingle compound or mixtures thereof with additional antitumor agents. The compounds can be administeredin 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.
[0757] The compounds used in the method of the present invention can be administered in admixturewith 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. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulatedand 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. Examples of 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.
[0758] Techniques and compositions for making dosage forms useful in the present invention aredescribed 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. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.
[0759] Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. 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.
[0760] The compounds used in the method of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as lecithin, sphingomyelin, proteolipids, protein-encapsulated vesicles or from cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions.
[0761] The compounds used in the method of the present invention may also be coupled to solublepolymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
[0762] Gelatin capsules may contain the active ingredient compounds and powdered carriers, such aslactose, 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.
[0763] For oral administration in liquid dosage form, the oral drug components are combined with anyoral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of 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.
[0764] Liquid dosage forms for oral administration can contain coloring and flavoring to increasepatient acceptance. In general, water, asuitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteralsolutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
[0765] The compounds used in the method of the present invention may also be administered inintranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.
[0766] Parenteral and intravenous forms may also include minerals and other materials such as solutoland / or ethanol to make them compatible with the type of injection or delivery system chosen.
[0767] The compounds and compositions of the present invention can be administered in oral dosageforms 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.
[0768] Specific examples of pharmaceutically acceptable carriers and excipients that may be used toformulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sept.2, 1975. 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. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugsand the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.
[0769] The active ingredient can be administered orally in solid dosage forms, such as capsules,tablets, powders, and chewing gum; or in liquid dosage forms, such as elixirs, syrups, and suspensions, including, but not limited to, mouthwash and toothpaste. It can also be administered parentally, in sterile liquid dosage forms.
[0770] Solid dosage forms, such as capsules and tablets, may be enteric-coated to prevent release ofthe active ingredient compounds before they reach the small intestine. Materials that may be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate- methacrylic acid copolymers.
[0771] The compounds and compositions of the invention can be coated onto stents for temporary orpermanent implantation into the cardiovascular system of a subject.
[0772] Variations on those general synthetic methods will be readily apparent to those of ordinary skillin the art and are deemed to be within the scope of the present invention.
[0773] Each embodiment disclosed herein is contemplated as being applicable to each of the otherdisclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.
[0774] This invention will be better understood by reference to the Experimental Details which follow,but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.
[0775] The present involves host-guest chemistry, CB7-Adma driven pre-targeting platform. Threecopper-64-labeled Adma guest molecules (1-3) were synthesized and characterized. The in vivo profile of the ligands in pre-targeting strategy were evaluated with using a CB7-modified carcinoembryonic antigen (CEA) targeting humanized full-length antibody (CB7-M5A) as the secondary pre-targeting agent. The pre- targeting studies were performed in CEA+ and CEA- human pancreatic cancer mouse xenografts. The biodistribution of the pre-targeted Adma-radioligand was compared to that of a zirconium-89-labeled directly radiolabeled antibody. The dosimetry of the two antibody-based imaging approaches were compared. It was hypothesized that the highly stability, mutual high affinity and human compatibility of the proposed CB7-Adma pre-targeting agents provide a great basis for a pre-targeting platform.
[0776] Definitions
[0777] Unless otherwise defined, all technical and / or scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
[0778] In the discussion unless otherwise stated, adjectives such as “substantially” and “about”modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of and any combination of items it conjoins.
[0779] It should be understood that the terms “a” and “an” as used above and elsewhere herein referto “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a,” “an” and “at least one” are used interchangeably in this application.
[0780] For purposes of better understanding the present teachings and in no way limiting the scope ofthe teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
[0781] In the description and claims of the present application, each of the verbs, “comprise,”“include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb arenot necessarily a complete listing of components, elements or parts of the subject or subjects of the verb. Other terms as used herein are meant to be defined by their well-known meanings in the art. General
[0782] For the foregoing embodiments, each embodiment disclosed herein is contemplated as beingapplicable to each of the other disclosed embodiments.
[0783] As used herein, all headings are simply for organization and are not intended to limit thedisclosure in any manner. The content of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention.
[0784] Additional objects, advantages, and novel features of the present invention will becomeapparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.
[0785] It is appreciated that certain features of the invention, which are, for clarity, described in thecontext of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
[0786] Examples are provided below to facilitate a more complete understanding of the invention. Thefollowing examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only. EXAMPLES Example 1
[0787] Examples are provided below to facilitate a more complete understanding of the invention. Thefollowing examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only.
[0788] The present invention synthesized various radioligands, namely 203Pb-PSC-PEG3-Adma, 203Pb-TCMC-PEG3-Adma, and203Pb-DOTA-PEG3-Adma, all of which contained an Adma guest component, a PEG3linker, and different chelators. The present invention conducted analyses on these radioligands to assess their partition coefficient (log D), in vitro plasma stability, binding to plasma proteins, and blood half-life.
[0789] In the context of in vivo pretargeting, the guest radioligand was evaluated using a xenograftmouse model with CB7-modified carcinoembryonic antigen (CEA) targeting full-length antibody (CB7- M5A) as the pretargeting agent. For this purpose, the tumor-bearing female nude mice was divided into three experimental groups (n=4 / cohort) with BxPC3 (CEA+) tumors. These mice were first injected with CB7-M5A (0.83 nmol; 125 μg in 250 μL PBS 7.4) via the tail vein, creating a 6-day interval before administering the small guest radioligand (referred to as a "lagtime" of 6 days).
[0790] Subsequently, a single dose of 203Pb-PSC-PEG3-Adma radioligand (1.4 nmol; 2.4 –2.8 MBqin 200 μL PBS 7.4) was introduced via the tail vein 6 days after the CB7-M5A injection. Biodistribution assessments were carried out at a total of three time points: 4 hours, 8 hours, and 24 hours after the administration of the radioligand.
[0791] Table 1. Characterization of 203Pb- labelled RadioligandsThe distribution coefficient (log D), in vitro PBS stability, plasma stability and blood half life of203 Pb- PSC-PEG3-Adma, 203Pb-TCMC-PEG3-Adma, 203 Pb-DOTA-PEG3-Adma.
[0792] The present invention successfully synthesized three novel radioligands designed for image-guided pretargeted alpha-TRT, achieving excellent radiochemical yield and purity. Through comprehensive in vitro characterization, the robustness of these radioligands, confirming their suitability for subsequent in vivo pretargeting applications was established.
[0793] Significantly, the host: guest pretargeting strategy demonstrated remarkable promise in an invivo cancer model utilizing a CB7-conjugated anti-CEA monoclonal antibody (mAb). Notably, the lag timeof 6 days exceeds the typical capabilities of other platforms. The observed tumor-to-normal tissue uptake ratios were notably high, underscoring the exceptional performance of our approach.
[0794] It was suggested that the CB7-Adma pretargeting methodology holds potential for therapeuticapplications with reduced radiation toxicity. Ongoing efforts are dedicated to optimizing the radioligands and adapting them for use with Pb-212, an isotope central to alpha-TRT. In this context, the PSC chelator stands out for its substantial advantages over existing chelators designed for Pb isotopes. Example 2
[0795] Synthetic procedure of PSC-PEG2-Diamantaneamine (PSC-PEG2-Diadma)
[0796] Step 1: Synthesis of Compound 3
[0797] To a stirred solution of compound 1 (25 mg, 0.123 mmol) in DMSO (2 mL) was addedtriethylamine (70 µL, 0.492 mmol) at room temperature, and the reaction mixture was stirred for 15 min. Subsequently, mesyl-protected PEG compound 2 (161 mg, 0.492 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h. Reaction progress was monitored by low-resolution LC- MS. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure and the crude product obtained.
[0798] Step 2: Synthesis of Compound 4
[0799] The crude residue from Step 1 was dissolved in minimum methanol (0.5 mL), and NaOHpellets (7 mg, 0.184 mmol) were added. The reaction mixture was stirred at room temperature for 15 min. Methyl iodide (1 mL, excess) was then added dropwise, and stirring was continued for 16 h. After completion (as confirmed by LC-MS), the reaction mixture was concentrated under reduced pressure to remove excess methyl iodide. The residue was dissolved in water (500 µL) and purified by preparative HPLC (100Å LC column 250 x 10 mm (Phenomenex) column) to yield the product 4 as a sticky solid (8.5 mg, 15 % yield), with a retention time of 17.27 min.
[0800] Step 3: Deprotection of Compound 4 and synthesis of PSC-PEG2-Diadm
[0801] Pure compound 4 (7.5 mg, 0.016 mmol) was suspended in a 1:1 (v / v) mixture of trifluoroaceticacid (TFA) and dichloromethane (DCM) (0.5 mL) and stirred at room temperature for 2 h. Upon completion, the solvents were removed under reduced pressure, and the resulting residue was resuspendedin DMSO (1 mL). N,N-Diisopropylethylamine (DIPEA; 15 µL, 0.08 mmol) was added, and the solution was stirred for 15 min. Subsequently, p-SCN-Bn-PSC (8.9 mg, 0.016 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h while maintaining the pH between 8.2 and 8.5. After completion (monitored by LC-MS), DMSO was removed under reduced pressure, and the crude residue was dissolved in water (500 µL) and purified by preparative HPLC. The desired product was obtained as a colorless sticky solid (6.8 mg, 46.5 % yield) with a retention time of 12.43–13.13 min.
[0802] LRMS (ESI⁺) m / z calcd for C₄₆H₇₄N₉O₈S⁺ [M]⁺: 913.21; found: 456.9 [M / 2] ⁺Example 3
[0803] Synthetic procedure of PSC-PEG2-Diamantaneamine (PSC-PEG2-Didiadma)
[0804] Step 1: Synthesis of Compound 3a
[0805] To a stirred solution of compound 1a (25 mg, 0.114 mmol) in DMSO (2 mL) was addedtriethylamine (60 µL, 0.458 mmol) at room temperature, and the reaction mixture was stirred for 15 min. Subsequently, mesyl-protected PEG compound 2 (150 mg, 0.458 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 h. Reaction progress was monitored by low-resolution LC- MS. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure and the crude product obtained.
[0806] Step 2: Synthesis of Compound 4a
[0807] The crude residue from Step 1 was dissolved in minimum methanol (0.5 mL), and NaOHpellets (6.8 mg, 0.172 mmol) were added. The reaction mixture was stirred at room temperature for 15 min. Methyl iodide (1 mL, excess) was then added dropwise, and stirring was continued for 16 h. After completion (as confirmed by LC-MS), the reaction mixture was concentrated under reduced pressure to remove excess methyl iodide. The residue was dissolved in water (500 µL) and purified by preparative HPLC (100Å LC column 250 x 10 mm (Phenomenex) column) to yield the product 4 as a sticky solid (8.6 mg, 14.4 % yield), with a retention time of 9-10 min.
[0808] Step 3: Deprotection of Compound 4a and synthesis of PSC-PEG2-Didiadma
[0809] Pure compound 4 (7.6 mg, 0.014 mmol) was suspended in a 1:1 (v / v) mixture of trifluoroaceticacid (TFA) and dichloromethane (DCM) (0.5 mL) and stirred at room temperature for 2 h. Upon completion, the solvents were removed under reduced pressure, and the resulting residue was resuspended in DMSO (1 mL). N,N-Diisopropylethylamine (DIPEA; 12.2 µL, 0.07 mmol) was added, and the solution was stirred for 15 min. Subsequently, p-SCN-Bn-PSC (8.01 mg, 0.014 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h while maintaining the pH between 8.2 and 8.5. After completion (monitored by LC-MS), DMSO was removed under reduced pressure, and the crude residue was dissolved in water (500 µL) and purified by preparative HPLC. The desired product was obtained as a colorless sticky solid (9.4 mg, 69.1 % yield) with a retention time of 8:13-8:5 min.
[0810] LRMS (ESI⁺) m / z calcd for C49H82N10O8S2+[M]⁺: 970.60; found: 485.5 [M / 2] ⁺REFERENCES 1. Vilma I.J. Jallinoja, Jacob L. Houghton Journal of Nuclear Medicine Sep 2021, 62 (9) 1200- 1206; DOI: 10.2967 / jnumed.120.260687 2. Altai M, Membreno R, Cook B, Tolmachev V, Zeglis BM. Pretargeted Imaging and Therapy. J Nucl Med. 2017 Oct;58(10):1553-1559. doi: 10.2967 / jnumed.117.189944. Epub 2017 Jul 7. PMID: 28687600; PMCID: PMC5632733. 3. Jallinoja VIJ, Abbriano CH, Bhatt K, Kaur A, Schlyer DJ, Yazaki PJ, Carney BD, Houghton JL. Pretargeting with Cucurbituril-Adamantane Host-Guest Pair in Xenograft Models. J Nucl Med.2023 Aug;64(8):1203-1209. doi: 10.2967 / jnumed.122.265008. Epub 2023 Apr 6. PMID: 37024305; PMCID: PMC10394317.
Claims
CLAIMS What is claimed is:
1. A compound having the structure:wherein Y1, Y2, Y3, and Y4are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2 or - alkylheteroaryl-P(O)(OH)2, 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker; R1 and R2 are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2 or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, wherein when the compound has the structure:then A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, tetramantane, pentamantane, bicyclo[2.2.2]octane, iceane, triamantane, isotetramantane, 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7- phosphaadamantane, or a salt or an ester thereof.
2. The compound of claim 1 having the structure:wherein Y1, Y2, Y3, and Y4are each independently, -H, -alkyl-CONH2, -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-CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl-N(alkylaryl-OH)(alkyl-CO2H), - alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, -alkylaryl-P(O)(OH)2or - alkylheteroaryl-P(O)(OH)2, wherein each occurrence of R4is 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; Z is -NH-, alkyl, or -alkyl-NH-; wherein when Z is -NH-, then 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-, or -alkynyl- cycloalkyl-thiourea-; and wherein when Z is alkyl or -alkyl-NH-, then X is -aryl-thiourea-, -heteroaryl-thiourea-, - cycloalkyl-thiourea-, -alkenyl-aryl-thiourea-, -alkenyl-heteroaryl-thiourea-, -alkenyl- cycloalkyl-thiourea-, -alkynyl-aryl-thiourea-, -alkynyl-heteroaryl-thiourea-, or -alkynyl- cycloalkyl-thiourea-; L is a chemical linker;R1and R2are each independently -H, halogen, alkyl, alkenyl, alkynyl, -OH, -O-(alkyl), -CHF2, - CF3, -OCHF2or -OCF3; a, n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and A is a targeting moiety, or a salt or an ester thereof.
3. The compound of claim 2, wherein Y1, Y2, Y3, and Y4 are each independently -alkyl-CONH2, -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- CO2R4)2, -alkyl-N(alkylaryl-OH)2, -alkyl-N(alkylheteroaryl-OH)2, -alkyl-N(alkyl-CO2H)2, -alkyl- N(alkylaryl-OH)(alkyl-CO2H), -alkyl-N(alkylheteroaryl-OH)(alkyl-CO2H), -alkyl-P(O)(OH)2, - alkylaryl-P(O)(OH)2 or -alkylheteroaryl-P(O)(OH)2; preferably, Y1, Y2, Y3, Y4 are each independently -alkyl-CONH2, -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; more preferably, Y1, Y2, Y3, Y4 are each independently -alkyl-CONH2, -alkyl-CO2H, -alkyl-N- (CO2R4)2, -alkyl-N-(alkyl-CO2R4)2, or -alkyl-N(alkyl-CO2H)2; more preferably, Y1, Y2, Y3, Y4 are each independently -alkyl-CONH2, or -alkyl-CO2H; more preferably, alkyl is -C1-C5alkyl; more preferably alkyl is -C1-C3alkyl; more preferably alkyl is -CH2or wherein at least two of Y1, Y2and Y3are same; or wherein at least two of Y1, Y2, Y3and Y4are same; preferably, at least three of Y1, Y2, Y3and Y4are same.
4. The compound of any one of claims 2-3, wherein the targeting moiety A is a molecule or a protein,preferably, A is a molecule, more preferably, A is a guest molecule, more preferably, A is a 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 trioxide, tetramethylenedisulfotetramine, tetrodotoxin, or 1,3,5-Triaza-7-phosphaadamantane.
5. The compound of any one of claims 2-4, wherein(a) when Z is -NH-, then X is -alkyl-aryl-thiourea-, -alkyl-heteroaryl-thiourea-, -alkyl-cycloalkyl- thiourea-, -alkenyl-aryl-thiourea-, or -alkenyl-heteroaryl-thiourea-, preferably, X is -alkyl-aryl-thiourea-, -alkyl-heteroaryl-thiourea-, or -alkyl-cycloalkyl-thiourea-, more preferably, X is -alkyl-aryl-thiourea-, or -alkyl-heteroaryl-thiourea-, more preferably, X is -alkyl-aryl-thiourea-; more preferably, alkyl is -C1-C5 alkyl; more preferably alkyl is -C1-C3 alkyl; more preferably alkyl is -CH2; (b) Z is -NH-, or alkyl; preferably, alkyl is -C1-C5 alkyl; more preferably, alkyl is -C1-C3 alkyl, more preferably alkyl is -CH2; and / or (c) R4 is -OH, -NH2, -O-(C1-C6 alkyl), or -NH-(C1-C6 alkyl), more preferably R4 is -OH or -NH2.
6. The compound of any one of claims 2-5, wherein 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; preferably, the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or polyethylene glycol (PEG) or combinations thereof, more preferably, the chemical linker L is an alkyl or PEG, more preferably, the chemical linker L is PEG.
7. The compound of any one of claims 2-6, wherein R1 and R2 are each independently -H, halogen, -C1-C6alkyl, -C1-C6alkenyl, or -C1-C6alkynyl; preferably, R1and R2are each independently -C1-C6alkyl or -C1-C6alkenyl; more preferably, R1and R2are same; more preferably, R1and R2are each -C1-6alkyl; more preferably, R1and R2are each -C1-5alkyl; more preferably, R1and R2are each -C1-4alkyl; more preferably, R1and R2are each -C1-3alkyl; more preferably, R1 and R2 are each methyl or ethyl; more preferably, R1 and R2 are each methyl.
8. The compound of any one of claims 2-7, wherein n and m are each independently 0, 1, 2, 3, 4, 5,or 6; preferably, n and m are each independently 0, 1, 2, or 3; more preferably, n and m are each independently 0, 1 or 2.
9. The compound of any one of claims 2-8, wherein a is 0, 1, 2, 3, 4, 5, or 6; preferably, a is 1, 2, or3; more preferably, a is 1.
10. The compound of any one of claims 2-9, wherein A is substituted or unsubstituted adamantane,diamantane, 4,9-diamino diamantane, ferrocene, bicyclo[2.2.2]octane, buckminsterfullerene (C60), iceane, triamantane, isotetramantane, ferrocene-modified peracetic acid, pentamantane, or cyclohexamantane; preferably, A is adamantane, ferrocene, 4,9-diamino diamantane, bicyclo[2.2.2]octane, iceane, diamantane, triamantane, isotetramantane, pentamantane, or cyclohexamantane, more preferably, A is adamantane, 4,9-diamino diamantane, or ferrocene, more preferably, A is adamantane.
11. The compound of claim 10, wherein the substituted ferrocene is substituted with -C1-C6 alkyl, -alkyl-N-(C1-C6alkyl), -OH, -O-(C1-C6alkyl), -NH-(C1-C6alkyl), -CHF2, -CF3, -OCHF2, or - OCF3; preferably, the substituted ferrocene is substituted with -C1-C6alkyl, -alkyl-N-(C1-C6alkyl), - OH, -O-(C1-C6alkyl), or -NH-(C1-C6alkyl); more preferably, the substituted ferrocene is substituted with -C1-C6alkyl, or -alkyl-N-(C1-C6alkyl); more preferably, the substituted ferrocene is substituted with -alkyl-N-(C1-C6alkyl);more preferably, the substituted ferrocene is12. The compound of any one of claims 2-11, whereinY1, Y2, Y3, and Y4 are each independently -H,, , ,more preferably, Y1, Y2, Y3, and Y4 are each independentlymore preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4 are each independently13. The compound of any one of claims 2-12, wherein the compound has the structure:,wherein R4 is -H, -OH, -NH2, halogen, -C1-C6 alkyl, -OH, -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, - CF3, -OCHF2, or -OCF3; preferably, R4 is -OH, -NH2, -O-(C1-C6 alkyl), or NH-(C1-C6 alkyl), more preferably, R4 is -OH or -NH2.
14. The compound of any one of claims 2-13, wherein the compound has 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 each independently 1 or 2.
15. The compound of any one of claims 2-14, whereina) alkyl is C1-6 alkyl, preferably, alkyl is C1-3 alkyl, more preferably, alkyl is methyl or ethyl;more preferably alkyl is methyl; and / or b) aryl is phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydronaphthyl; indanyl,biphenyl, phenanthryl, anthryl or acenaphthyl, preferably, aryl is phenyl, p-toluenyl (4- methylphenyl), or naphthyl, more preferably, aryl is phenyl.
16. The compound of claim 6, wherein the chemical linker L has the following structure:wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 3, or 7; preferably, the compound has the following structure:.
17. The compound of any one of claims 2-16 having the structure:,,,,,,preferably, the compound has the structure:.
18. The compound of claim 1 having the structure:wherein (g) Y1, Y2, Y3, Y4 are each independently -alkyl-CONH2, -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; preferably, Y1, Y2, Y3, Y4are each independently -alkyl-CONH2, -alkyl-CO2H, -alkyl-N- (CO2R4)2, -alkyl-N-(alkyl-CO2R4)2,or -alkyl-N(alkyl-CO2H)2; more preferably, Y1, Y2, Y3, Y4are each independently -alkyl-CONH2, or -alkyl- CO2H; more preferably, alkyl is -C1-C5alkyl; more preferably alkyl is -C1-C3alkyl; more preferably alkyl is -CH2; (h) Z is -NH-, or alkyl;when Z is -NH-, then X is -alkyl-aryl-thiourea-, -alkyl-heteroaryl-thiourea-, -alkyl-cycloalkyl- thiourea-, -alkenyl-aryl-thiourea-, or -alkenyl-heteroaryl-thiourea-, preferably, X is -alkyl-aryl-thiourea-, -alkyl-heteroaryl-thiourea-, or -alkyl-cycloalkyl- thiourea-, more preferably, X is -alkyl-aryl-thiourea-, or -alkyl-heteroaryl-thiourea-, more preferably, X is -alkyl-aryl-thiourea-; more preferably, alkyl is -CH3; more preferably, aryl is phenyl; when Z is alkyl, preferably Z is C1-C5alkyl; more preferably Z is -C1-C3alkyl; more preferably Z is -CH2; (i) the chemical linker L is an alkyl linker, an alkyne linker, alkynal linker or polyethylene glycol(PEG) or combinations thereof, preferably, the chemical linker L is an alkyl or PEG, more preferably, the chemical linker L is PEG. (j) R1 and R2 are each independently -H, halogen, -C1-C6 alkyl, -C1-C6 alkenyl, or -C1-C6 alkynyl;preferably, R1 and R2 are each independently -C1-C6 alkyl or -C1-C6 alkenyl;more preferably, R1and R2are same; more preferably, R1and R2are each -C1-6alkyl; more preferably, R1and R2are each -C1-5alkyl; more preferably, R1and R2are each -C1-4alkyl; more preferably, R1and R2are each -C1-3alkyl; more preferably, R1and R2are each methyl or ethyl; more preferably, R1and R2are each methyl;(k) a, n and m are each independently 0, 1, 2, or 3; and / or(l) A is substituted or unsubstituted diamantane, 4,9-diamino diamantane, bicyclo[2.2.2]octane,iceane, triamantane, tetramantane, pentamantane, isotetramantane, cyclohexamantane, super- adamantane, or 1,3,5,7-tetramethyl-1,3,5,7-tetrasilaadamantane; preferably, A is substituted or unsubstituted diamantane, triamantane, tetramantane, or pentamantane; more preferably, A is substituted or unsubstituted diamantane; preferably, the substitution is -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 alkynal, -OH, -NH2, -N-(C1-C6 alkyl)2, -N+-(C1-C6 alkyl)3 , -alkyl-N-(C1-C6 alkyl)2, -alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, - CF3, -OCHF2, or -OCF3.
19. The method of claim 18, wherein(a) Y1, Y2, Y3, and Y4 are each independently -H,, , ,, , , , , ,more preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4are each independentlymore preferably, Y1, Y2, Y3, and Y4 are each independently (, wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 2, or 3; more preferably b is 2; (c) m is 0;(d) n is 0; and / or(e) A is unsubstituted diamantane or diamantane substituted with -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6alkynal, -OH, -NH2, -N-(C1-C6alkyl)2, -N+-(C1-C6alkyl)3, -alkyl-N-(C1-C6alkyl)2, - alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3; more preferably, A is diamantane substituted with N+(CH3)3; more preferably, A is20. The compound of claim 14 having the structure:, wherein (f) L has the structure:, wherein b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; preferably b is 1, 2, 3, 4, 5, 6, or 7; more preferably, b is 1, 2, or 3; more preferably b is 2; (g) R1 and R2 are each -C1-3 alkyl; more preferably, R1 and R2 are each methyl or ethyl; morepreferably, R1 and R2 are each methyl; (h) m is 0;(i) n is 0; and / or(j) A is unsubstituted diamantane or diamantane substituted with -C1-C6 alkyl, -C1-C6 alkenyl, -C1-C6 alkynal, -OH, -NH2, -N-(C1-C6 alkyl)2, -N+-(C1-C6 alkyl)3 , -alkyl-N-(C1-C6 alkyl)2, - alkyl-N+-(C1-C6 alkyl)3 -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), -CHF2, -CF3, -OCHF2, or -OCF3; more preferably, A is diamantane substituted with N+(CH3)3; more preferably, A is21. The compound of any one of claims 18-20 having the structure:,,.
22. A metal complex comprising the compound of any one of claims 1-21, wherein the compound coordinatesto a metal ion.
23. The metal complex of claim 18 having the structure:,,,24. The metal complex of any one of claims 22-23, wherein the metal ion is Lead-203 (203Pb), Lead-212 (212Pb),Copper-62 (62Cu), Copper-64 (64Cu), Copper-67 (67Cu), Gallium-68 (68Ga) Scandium-44 (44Sc), Scandium- 47 (47Sc), Scandium-43 (43Sc), Lead-203 (203Pb), Lead-212 (212Pb), Lanthanum-132 (132La), Lanthanum- 135 (135La), Yttrium-86 (86Y), Yttrium-90 (90Y), Lutetium 177 (177Lu), Terbium -149 (149Tb), Terbium-152 (152Tb), Terbium-155 (155Tb) or Terbium-161 (161Tb); preferably, the metal ion is Lead-203 (203Pb), Lead-212 (212Pb), Copper-62 (62Cu), Copper-64 (64Cu), Copper-67 (67Cu), Scandium-44 (44Sc), Scandium-47 (47Sc), or Scandium-43 (43Sc); more preferably, the metal ion is Lead-203 (203Pb), or Lead-212 (212Pb).
25. A composition comprising the metal complex of any one of claims 22-24; preferably, the composition is apharmaceutical composition.
26. The composition of claim 25, wherein the composition further comprises a host molecule attached to amarker, preferably, the marker is a tumor marker or a cancer marker.
27. The composition of claim 26, wherein the marker is a prostate-specific antigen (PSA), prostatic acidphosphatase (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); preferably, the marker is a 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);more preferably the marker is a prostate-specific antigen (PSA) or carcinoembryonic antigen (CEA); more preferably, the marker is a carcinoembryonic antigen (CEA).
28. The composition of any one of claims 26-27, wherein 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; preferably, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, cucurbit[8]uril, or cucurbit[10]uril; more preferably, the host molecule comprises cucurbit[5]uril, cucurbit[6]uril, cucurbit[7]uril, or cucurbit[8]uril; more preferably, the host molecule comprises cucurbit[7]uril, or cucurbit[8]uril; more preferably, the host molecule is cucurbit[7]uril.
29. The composition of any one of claims 26-28, wherein the interaction between the host and the guestmolecule is a non-covalent interaction, preferably, the non-covalent interaction is ion-ion interaction, ion- dipole interaction, dipole-dipole interaction, hydrogen bonding, cation-π interaction, π-π interaction, van der Waals interaction or hydrophobic interaction; more preferably, the interaction is ion-ion interaction or van der Waals interaction.
30. The composition of any one of claims 26-29, wherein the metal complex and the host molecule form a highaffinity host-guest complex.
31. A method of detecting cells in a subject comprising administering an effective amount of the compound ofany one of claims 1-21, the metal complex of any one of claims 22-24, or the composition of any one of claims 25-30 to the subject; preferably, the method further comprises administering to the subject a host molecule attached to a marker.
32. A method of detecting cells in a subject comprising administering an effective amount of the compound ofany one of claims 1-21, the metal complex of any one of claims 22-24, or the composition of any one of claims 25-30 to the subject, preferably, the method further comprises administering to the subject a host molecule attached to a marker.
33. A method of detecting cells in a subject comprising administering an effective amount the compound ofany one of claims 1-21, the metal complex of any one of claims 22-24, or the composition of any one ofclaims 25-30 to the subject and imaging the subject with a molecular imaging device to detect the composition in the subject, preferably, the method further comprises administering to the subject a host molecule attached to a marker.
34. A method of imaging cells in a subject comprising:1) administering to the subject an effective amount of the compound of any one of claims 1-21, the metal complex of any one of claims 22-24, or the composition of any one of claims 25-30, wherein the composition specifically accumulates at the cells in the subject; 2) detecting in the subject the location of the composition; and 3) obtaining an image of the cells in the subject based on the location of the composition in the subject.
35. A method of detecting the presence of cells in a subject which comprises determining if an amount of thecomposition of any one of claims 25-30 is present in the subject at a period of time after administration of the composition to the subject, thereby detecting the presence of the cells based on the amount of the composition determined to be present in the subject.
36. The method of any one of claims 31-35, wherein the metal complex and the host molecule are administeredconcurrently, or wherein the host molecule is administered first, and the metal complex is administered after a period of time.
37. The method of claim 36, wherein the period of time is 24 hours, 48 hours, 72, hours, 96 hours, 120 hours,or 144 hours; preferably, the period of time is 72 hours.
38. The method of any one of claims 31-37, wherein the cells are cancer cells or tumor cells.
39. The method of claim 38, wherein the cancer cells or tumor cells have elevated levels of proteins or antigens,or both.
40. The method of any one of claims 38-39, wherein the cancer is lung cancer, breast cancer, prostate cancer,cervical cancer, pancreatic cancer, colon cancer, ovarian cancer, stomach cancer, esophagus cancer, skin cancer, heart cancer, liver cancer, bronchial cancer, testicular cancer, kidney cancer, bladder cancer, spleen cancer, thymus cancer, thyroid cancer, brain cancer, or gall bladder cancer.
41. The method of any one of claims 38-39, wherein the tumor is bone tumor, brain tumor, malignant soft tissuetumor, organ tumor, ovarian germ cell tumor, gland tumor, lymphatic tumor, or skin tumor.
42. The method of any one of claims 31-41, wherein the subject is a mammal, preferably, the subject is ahuman.
43. The method of claim 33, wherein the molecular imaging device is a PET imaging device.