NZ719939B2 - Compounds for positron emission tomography - Google Patents
Compounds for positron emission tomographyInfo
- Publication number
- NZ719939B2 NZ719939B2 NZ719939A NZ71993914A NZ719939B2 NZ 719939 B2 NZ719939 B2 NZ 719939B2 NZ 719939 A NZ719939 A NZ 719939A NZ 71993914 A NZ71993914 A NZ 71993914A NZ 719939 B2 NZ719939 B2 NZ 719939B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- conjugate
- acid
- cozh
- methyl
- nota
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title abstract description 84
- 238000002600 positron emission tomography Methods 0.000 title abstract description 26
- 239000000203 mixture Substances 0.000 claims abstract description 99
- 229960005261 Aspartic Acid Drugs 0.000 claims abstract description 9
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 9
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 9
- 239000004472 Lysine Substances 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 47
- 230000036499 Half live Effects 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 17
- 239000000969 carrier Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000002552 dosage form Substances 0.000 claims description 6
- 229920000570 polyether Polymers 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229920001184 polypeptide Polymers 0.000 claims description 5
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 4
- 210000003205 Muscles Anatomy 0.000 claims description 2
- 125000003929 folic acid group Chemical group 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims 2
- 230000027455 binding Effects 0.000 abstract description 67
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 abstract description 64
- 101700036477 FOLH1 Proteins 0.000 abstract description 50
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- 239000003795 chemical substances by application Substances 0.000 abstract description 31
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- 229910052751 metal Inorganic materials 0.000 abstract description 27
- 239000002184 metal Substances 0.000 abstract description 27
- 230000001717 pathogenic Effects 0.000 abstract description 26
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- 101700008337 PSMA Proteins 0.000 abstract 4
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 abstract 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 118
- 125000005647 linker group Chemical group 0.000 description 103
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 92
- -1 hydroxy, amino Chemical group 0.000 description 92
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 55
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 52
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- 229920005989 resin Polymers 0.000 description 52
- 229910052796 boron Inorganic materials 0.000 description 50
- 210000004027 cells Anatomy 0.000 description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 50
- 238000004128 high performance liquid chromatography Methods 0.000 description 45
- 239000002253 acid Substances 0.000 description 43
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- 229910001868 water Inorganic materials 0.000 description 40
- 125000000217 alkyl group Chemical group 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 239000002904 solvent Substances 0.000 description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 29
- JFCQEDHGNNZCLN-UHFFFAOYSA-N Glutaric acid Chemical class OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 27
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- 125000003118 aryl group Chemical group 0.000 description 17
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 17
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 16
- 125000004429 atoms Chemical group 0.000 description 16
- 230000001808 coupling Effects 0.000 description 16
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- 150000002500 ions Chemical class 0.000 description 16
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 14
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- 125000003342 alkenyl group Chemical group 0.000 description 13
- 230000000875 corresponding Effects 0.000 description 13
- 239000003085 diluting agent Substances 0.000 description 13
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
- 210000003734 Kidney Anatomy 0.000 description 12
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 12
- FEMOMIGRRWSMCU-UHFFFAOYSA-N Ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 125000004432 carbon atoms Chemical group C* 0.000 description 11
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
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- VIAFLMPQBHAMLI-UHFFFAOYSA-N PyBOP Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 VIAFLMPQBHAMLI-UHFFFAOYSA-N 0.000 description 10
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- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 10
- 125000003710 aryl alkyl group Chemical group 0.000 description 10
- 238000003776 cleavage reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
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- JOAQINSXLLMRCV-UHFFFAOYSA-N 4-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}benzoic acid Chemical compound C1=NC2=NC(N)=NC(O)=C2N=C1CNC1=CC=C(C(O)=O)C=C1 JOAQINSXLLMRCV-UHFFFAOYSA-N 0.000 description 3
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- MSTNYGQPCMXVAQ-KIYNQFGBSA-N Tetrahydrofolic acid Chemical class N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 description 3
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- BUGBHKTXTAQXES-UHFFFAOYSA-N selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Inorganic materials [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
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- 125000003003 spiro group Chemical group 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003455 sulfinic acids Chemical class 0.000 description 1
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 201000009594 systemic scleroderma Diseases 0.000 description 1
- APPXMECEIFEZAO-SFHVURJKSA-N tert-butyl N-[(5S)-5-(9H-fluoren-9-ylmethoxycarbonylamino)-6-oxohexyl]carbamate Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C=O)C3=CC=CC=C3C2=C1 APPXMECEIFEZAO-SFHVURJKSA-N 0.000 description 1
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 230000032895 transmembrane transport Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 201000006704 ulcerative colitis Diseases 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/60—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances involving radioactive labelled substances
Abstract
Described herein are compounds, compositions, and methods for diagnosing and/or monitoring pathogenic disease using positron emission tomography. Also described are conjugates of the formula B-L-P, wherein B is a radical of a targeting agent selected from vitamin receptor binding ligands (such as folate), PSMA binding ligands, or PSMA inhibitors; L is a divalent linker comprising aspartic acid, lysine, or arginine, and P is a radical of an imaging agent or radiotherapy agent, such as a radionuclide or radionuclide containing group, or a radical of a compound capable of binding a radionuclide, such as a metal chelating group. late), PSMA binding ligands, or PSMA inhibitors; L is a divalent linker comprising aspartic acid, lysine, or arginine, and P is a radical of an imaging agent or radiotherapy agent, such as a radionuclide or radionuclide containing group, or a radical of a compound capable of binding a radionuclide, such as a metal chelating group.
Description
COMPOUNDS FOR POSITRON EMISSION APHY
REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. § 119(e) of United States
Provisional ation Serial Nos. 61/904,387, filed November 14, 2013, 61/904400, filed
November 14, 2013, and 61/909,822, filed November 27, 2013, the disclosure of each of
which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
The invention described herein pertains to compounds, compositions, and
methods for diagnosing and/or monitoring diseases and disease states using radionuclides. In
ular, the invention described herein pertains to nds, compositions, and methods
for diagnosing and/or monitoring pathogenic disease states using radionuclides for positron
emission tomography (PET).
OUND AND SUMMARY OF THE INVENTION
PET is a nuclear imaging methodology that detects pairs of gamma rays
emitted indirectly by a positron-producing radionuclide. Because the two d gamma
rays travel in exactly opposite directions, it is possible to locate their site of origin and
thereby truct a three-dimensional image of all positron emitters from a computer
analysis of the origins of emitted gamma rays. Compared to other radioimaging modalities,
such as SPECT, PET reportedly shows higher sensitivity (about 2 orders of magnitude),
better spatial resolution (about 5 mm), greater signal to noise, and superior tracer
quantification in both preclinical and clinical applications. In addition, in st to the
about 90 minutes required for body scans for a standard SPECT imaging, PET image
acquisition may be routinely performed in about 20 minutes. Moreover, in viva PET imaging
generally requires only subnanomolar (10'10 to 10'”) concentrations of racer, which
reportedly zes ial damage to other biological systems. y, PET allows for
quantitative dynamic imaging, which may facilitate kinetic studies of target engagement
through receptor occupancy. It has been discovered herein that PET agents may be ed
to predetermined tissues using Vitamin receptors and/or prostate-specific membrane antigen
(PSMA).
For example, vitamin receptors are overexpressed on certain pathogenic cells,
including many cancer cell types, activated macrophages, and activated monocytes. In
particular, folate ors are overexpressed in many cancers. The folate receptor, a 38 KD
GPI—anchored protein that binds the vitamin folic acid with high affinity (<1 nM), is
overexpressed on many malignant tissues, ing ovarian, breast, bronchial, and brain
cancers. It is estimated that 95% of all ovarian carcinomas overexpress the folate receptor.
In contrast, with the exception of kidney, choroid plexus, and placenta, normal tissues
express low or nondetectable levels of the folate receptor. Most cells also use an unrelated
reduced folate carrier to acquire the necessary folic acid.
Folate receptors are also overexpressed on activated hages, and
activated monocytes. Further, it has also been reported that the folate receptor B, the
nonepithelial isoform of the folate receptor, is expressed on activated, but not resting,
synovial macrophages. Activated hages can participate in the immune response by
nonspecifically engulfing and killing foreign pathogens within the macrophage, by displaying
degraded peptides from n ns on the macrophage cell surface where they can be
recognized by other immune cells, and by secreting cytokines and other factors that modulate
the function of T and B lymphocytes, resulting in further stimulation of immune responses.
However, activated macrophages can also bute to the pathophysiology of disease in
some instances. For example, activated macrophages can contribute to atherosclerosis,
toid tis, autoimmune disease states, and graft versus host disease, among other
disease states.
Following or binding of vitamins to vitamin receptors, such as folic acid
and analogs and tives of folic acid to folate receptors, rapid endocytosis delivers the
vitamin into the cell, where it is unloaded in an endosomal compartment at lower pH.
Importantly, nt conjugation of small molecules, proteins, and even liposomes to
vitamins and other vitamin receptor binding ligands does not block the ability of the ligand to
bind to its receptor, and therefore, such ligand conjugates can readily be delivered to and can
enter cells by receptor-mediated endocytosis. Accordingly, diagnostic, imaging, and
eutic agents can be targeted to vitamin receptors, including the folate receptor, for
delivery into vitamin receptor expressing cells.
The prostate is a male uctive organ that functions to e and store
seminal fluid, which provides nutrients and fluids for the survival of sperm introduced into
the vagina during reproduction. Like other tissues, the prostate gland may develop either
malignant (cancerous) or benign (non-cancerous) . Prostate cancer is reportedly one
of the most common male cancers in western societies, and is the second leading form of
malignancy among American men.
Prostate-specific membrane antigen (PSMA) is a biomarker that is
pressed on prostate cancer. PSMA is over-expressed in the malignant prostate tissues
when compared to other organs in the human body such as , proximal small intestine,
and salivary glands. PSMA is also expressed on the neovasculature within many non-
prostate solid tumors, including lung, colon, breast, renal, liver and pancreatic carcinomas,
but not on normal vasculature. However, PSMA is expressed minimally in brain. PSMA is a
type II cell surface membrane-bound glycoprotein with ~110 kD molecular weight, including
an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43),
and an extensive extracellular domain (amino acids 44-750). Though the functions of the
intracellular segment and the transmembrane domains are currently reported to be
insignificant, the extracellular domain is involved in several distinct activities. For example,
PSMA plays a role in the central nervous system, where it lizes N—acetyl—aspartyl
glutamate (NAAG) into glutamic and N-acetyl aspartic acid. PSMA also plays a role in the
proximal small ine where it removes ed glutamate from poly-y—glutamated folate
and (x-linked glutamate from peptides and small les.
Though the particular function of PSMA on prostate cancer cells remains
unresolved, PSMA is known to undergo rapid internalization into the cell, similar to cell
surface bound ors like vitamin receptors. PSMA is internalized through clathrin-coated
pits and subsequently can either e to the cell surface or go to lysosomes. Accordingly,
stic, g, and therapeutic agents can be targeted to PSMA for delivery into PSMA
sing cells, such as prostate cancer cells.
It has been ered herein that the nds and itions described
herein are useful for targeting and delivering radionuclides for diagnosing and/or monitoring
various diseases and disease states caused by pathogenic cell populations. In addition, it has
been discovered that the compounds and compositions described herein are also useful for
targeting and delivering radionuclides for treating various diseases and disease states caused
by pathogenic cell populations in radiotherapy.
In one illustrative and non-limiting embodiment of the invention described
herein, compounds and compositions described herein are used for diagnosing and/or
monitoring, or treating various diseases and disease states caused by pathogenic cell
populations. In another illustrative embodiment, methods are described herein for
stering compounds and compositions described herein for diagnosing and/or
monitoring, or treating various es and disease states caused by pathogenic cell
populations. In another embodiment, uses of compounds and compositions are described
herein for manufacturing ments for diagnosing and/or monitoring, or treating various
diseases and disease states caused by pathogenic cell populations. In another embodiment,
kits are bed herein for preparing and/or using compounds and compositions described
herein for diagnosing andj’or monitoring, or treating various diseases and e states
caused by enic cell populations.
BRIEF DESCRIPTION OF THE DRAWINGS
shows a rtem biodistribution study of F-QC07017 and
18F-AIF—QC07043 folate—NOTA—Al-lsF conjugates in s tissues at 90 minutes post
injection in nude mice bearing KB tumor xenografts. For each tissue, the histogram is in
groups of 4 from left to right: 18F—AIF-QC07017, 18F—AIF—QC07017 + excess folic acid, 18F-
AIF-QC07043, F-QC07043 + excess folic acid.
shows a postmortem tribution study of 18F—AIF-QCO'iOl7
folate-NOTA-Al-ISF conjugate in various tissues at 90 minutes post injection in nude mice
bearing KB tumor xenografts or A549 tumor xenografts. It is to be understood that the
vertical axis has been expanded and that the kidney data is truncated. For each tissue, the
histogram is in groups of 4 from left to right: 18F—AIF-QC07017 against A549 tumor
xenografts, 18F—AIF—QCO?017 + excess folic acid against A549 tumor xenografts, 18F—AIF-
7 against KB tumor xenografts, 18F—AIF-QC07017 + excess folic acid against KB
tumor xenografts.
shows a postmortem biodistribution study of 18F—AIF-QC07O43
folate-NOTA-Al-‘SF conjugate in various tissues at 90 minutes post injection in nude mice
bearing KB tumor xenografts or A549 tumor xenografts. It is to be understood that the
vertical axis has been expanded and that the kidney data is truncated. For each tissue, the
histogram is in groups of 4 from left to right: 18F—AIF-QC07043 against A549 tumor
xenografts, 18F—AIF-QCO?043 + excess folic acid t A549 tumor xenografts, 18F-AIF—
QC07043 against KB tumor xenografts, F-QC07O43 + excess folic acid against KB
tumor xenografts.
shows a postmortem biodistribution study of 18F—AIF-QC07017 and
18F-AIF-QC07043 folate—NOTA-Al-ISF conjugates, compared to 99mTc-EC20 in KB tumor
xenograft tissues at 90 minutes post ion in nude mice. The histogram from left to right:
99mTc-EC20 against KB tumor xenografts, 99mTc-EC20 + excess folic acid against KB tumor
xenografts, 18F—AIF—QCO?017 against KB tumor xenografts, 18F—AIF—QCO?017 + excess folic
acid against KB tumor xenografts, 18F—AIF-QC07043 t KB tumor xenografts, 18F-AIF—
QC07043 + excess folic acid against KB tumor xenografts.
shows a postmortem biodistribution study of 18F—AIF-QC0'1'017 and
18F-AIF-QC07043 folate-NOTA-Al-lSF conjugates, compared to 99mTc-EC20 in A549 tumor
xenograft tissues at 90 minutes post injection in nude mice. The histogram from left to right:
99mTc-EC20 against A549 tumor xenografts, 99mTc—EC20 + excess folic acid against A549
tumor xenografts, 18F—AIF—QC07017 against A549 tumor xenografts, 18F-AIF-QC07017 +
excess folic acid against A549 tumor afts, 18F—AIF-QCO7043 t A549 tumor
xenografts, 18F—AIF-QC07043 + excess folic acid against A549 tumor xenografts.
DETAILED DESCRIPTION
In each of the foregoing and each of the ing embodiments, it is to be
understood that the formulae include and represent not only all pharmaceutically acceptable
salts of the nds, but also e any and all hydrates and/or solvates of the compound
formulae. It is appreciated that certain functional groups, such as the hydroxy, amino, and
like groups form complexes and/or coordination compounds with water and/or s
solvents, in the various al forms of the compounds. Accordingly, the formulae
described herein are to be understood to include and represent those s hydrates and/or
solvates. It is also to be understood that the non-hydrates and/or non-solvates of the
compound formulae are described by such formula, as well as the hydrates and/or solvates of
the compound formulae.
As used herein, the term “composition” generally refers to any product
sing the ied ingredients in the specified amounts, as well as any product which
results, directly or indirectly, from combinations of the specified ingredients in the specified
amounts. It is to be understood that the compositions bed herein may be prepared from
isolated compounds described herein or from salts, solutions, hydrates, solvates, and other
forms of the compounds described herein. It is appreciated that certain functional groups,
such as the hydroxy, amino, and like groups form complexes and/or coordination compounds
with water and/or various solvents, in the various al forms of the compounds. It is also
to be understood that the compositions may be prepared from various amorphous, non-
amorphous, partially crystalline, crystalline, and/or other morphological forms of the
compounds described herein. It is also to be understood that the compositions may be
prepared from various hydrates and/or solvates of the nds described .
Accordingly, such pharmaceutical itions that recite compounds described herein are
to be understood to include each of, or any combination of, the various morphological forms
and/or solvate or hydrate forms of the compounds described herein. In addition, it is to be
understood that the itions may be prepared from various co—crystals of the compounds
bed herein.
ratively, compositions may include one or more carriers, diluents, and/or
excipients. The compounds described herein, or compositions containing them, may be
formulated in a therapeutically effective amount in any conventional dosage forms
appropriate for the methods described herein. The compounds described herein, or
compositions containing them, including such formulations, may be administered by a wide
y of conventional routes for the methods described herein, and in a wide variety of
dosage formats, utilizing known procedures (see generally, Remington: The Science and
Practice of cy, (21St ed., 2005)).
In each of the foregoing and each of the ing embodiments, it is also to
be understood that the formulae include and represent each possible isomer, such as
isomers and geometric isomers, both individually and in any and all possible mixtures.
In each of the foregoing and each of the following embodiments, it is also to be understood
that the formulae include and represent any and all crystalline forms, partially crystalline
forms, and non crystalline and/or ous forms of the compounds.
Illustrative embodiments of the invention are described by the following
clauses:
A conjugate of the formula
B—L—P
or a pharmaceutically acceptable salt f, wherein B is a l of a targeting agent
selected from vitamin receptor binding ligands, PSMA binding ligands, and PSMA inhibitors,
L is a divalent linker, and P is a radical of an imaging agent or radiotherapy agent, such as a
radionuclide or radionuclide containing group, or a precursor thereof, or a radical of a
nd capable of binding a radionuclide or radionuclide containing group, such as a
metal chelating group.
The conjugate of the preceding clause wherein the targeting agent is a l
of a folate receptor binding ligand.
The conjugate of any one of the preceding clauses wherein the targeting agent
is a radical of a folic acid.
The ate of any one of the preceding clauses comprising —Asp.
The conjugate of any one of the preceding clauses comprising folate—Asp-Arg.
The conjugate of any one of the preceding clauses comprising folate—Arg.
The conjugate of any one of the preceding clauses wherein the linker
comprises a polypeptide.
The conjugate of any one of the preceding clauses wherein the linker
comprises a polypeptide sing lysine, arginine, or aspartic acid, or a combination
thereof.
The conjugate of any one of the preceding clauses n the linker
comprises a lysine.
The conjugate of any one of the preceding clauses wherein the linker
comprises Lys.
The ate of any one of the preceding clauses wherein the linker
comprises s.
The conjugate of any one of the preceding clauses wherein the linker
comprises Arg-Arg-Lys.
The conjugate of any one of the preceding clauses wherein the linker
comprises Asp-Arg-Arg-Lys.
The conjugate of any one of the preceding clauses wherein the linker does not
include a polyamine radical, such as a polyamine diradical of the formula NH—(CH2)2—NH.
The conjugate of any one of the preceding clauses wherein P comprises the
formula
N\)—\COZH
HOZC—/
or a derivative thereof comprising a chelated metal.
The ate of any one of the preceding clauses comprising the formula
*QNmN/Rflos
<COZH <002H
* HNJLN
H NV COZH ::—\COZH
HOzC—/ HOZC—/
or a derivative thereof comprising a chelated metal.
The conjugate of any one of the preceding clauses comprising folate—PEG.
The conjugate of any one of the ing clauses comprising folate—PEGz.
The conjugate of any one of the ing clauses comprising folate—PEGs.
The conjugate of any one of the preceding clauses sing folate—PEGu.
The conjugate of any one of the ing clauses wherein the linker
comprises [(CH2)20]n, [(CHz)zO]n-(CH2)2-C(O), [(CH2)20]n-(CHz)2-C(O)NH, [(CH2)20]n-
(CH2)2—C(O)NH—(CH2)2, [(CH2)2O]2—(CH2)n—C(O)NH—(CH2)2NH, where n is an integer from
1 to about 12.
The conjugate of any one of the preceding clauses wherein the linker
comprises [(CH2)2O]2, [(CH2)20]6, or [(CH2)2O]12.
The ate of any one of the preceding clauses wherein the linker
comprises (CH2)2O-(CH2)2-C(O), 2O]2-(CH2)2-C(O), 2O]6-(CH2)2-C(O), or
[(CH2)20]12-(CH2)2—C(O).
The conjugate of any one of the preceding clauses wherein the linker
comprises (CH2)zO—(CH2)2—C(O)NH, [(CHz)zO]2—(CHz)z—C(O)NH, [(CH2)zO]6—(CH2)2—
C(O)NH, or [(CH2)2O]12—(CH2)z—C(O)NH.
The ate of any one of the preceding clauses wherein the linker
comprises (CH2)zO—(CH2)2-C(O)NH—(CH2)2, [(CH2)2O]2—(CH2)z—C(O)NH—(CH2)2,
[(CH2)zO]6—(CH2)2—C(O)NH—(CH2)2, or [(CHz)zO]12—(CH2)2—C(O)NH—(CH2)2.
The conjugate of any one of the preceding clauses wherein the linker
ses (CH2)2O—(CH2)2—C(O)NH—(CH2)2NH, [(CH2)2O]2—(CH2)2—C(O)NH—(CH2)2NH,
[(CHz)20]6—(CH2)2—C(O)NH—(CH2)2NH, or [(CH2)2O]12—(CH2)2—C(O)NH—(CH2)2NH.
The conjugate of any one of the preceding clauses wherein the linker
comprises NH[(CH2)2O]n, NH[(CH2)zO]n—(CH2)z—C(O), NH[(CH2)2O]n—(CH2)2—C(O)NH,
NH[(CH2)2O]n—(CH2)2—C(O)NH-(CH2)2, NH[(CH2)2O]n—(CH2)2—C(O)NH-(CH2)2NH, where n
is an integer from 1 to about 12.
The ate of any one of the preceding clauses wherein the linker
comprises NH(CH2)zO, NH[(CH2)2O]2, 2)ZO]6, NH[(CH2)2O]12.
The conjugate of any one of the preceding clauses wherein the linker
comprises NH(CH2)zO—(CH2)2—C(O), NH[(CH2)20]2—(CHz)z—C(O), NH[(CH2)zO]6—(CH2)2—
C(O), or NH[(CH2)2O]12-(CH2)z-C(O).
The conjugate of any one of the preceding clauses wherein the linker
comprises NH(CH2)2O—(CH2)z—C(O)NH, NH[(CH2)2O]2—(CH2)2—C(O)NH, NH[(CH2)2O]6—
(CH2)2—C(O)NH, or NH[(CH2)20]12—(CH2)2—C(O)NH.
The conjugate of any one of the preceding clauses wherein the linker
ses NH(CH2)2O—(CH2)2—C(O)NH—(CH2)2, NH[(CH2)2O]2—(CH2)2—C(O)NH—(CH2)2,
NH[(CH2)20]6-(CH2)2-C(O)NH-(CH2)2, or NH[(CH2)2O]12-(CH2)2—C(O)NH—(CH2)2.
The conjugate of any one of the preceding clauses n the linker
comprises NH(CH2)20—(CH2)2—C(O)NH—(CH2)2NH, NH[(CH2)zO]2—(CHz)z—C(O)NH—
(CH2)2NH, NH[(CH2)2O]6-(CH2)2—C(O)NH—(CH2)2NH, or NH[(CH2)2O]12—(CH2)2—C(O)NH—
(CH2)2NH.
The conjugate of any one of the preceding clauses wherein the linker
ses NH[(CH2)2O]n-(CH2)2NH, where n is an integer from 1 to about 12.
The conjugate of any one of the preceding clauses wherein the linker
comprises NH(CH2)zO-(CH2)2NH, NH[(CH2)zO]z-(CH2)2NH, NH[(CH2)zO]6-(CH2)2NH, or
2)20]12-(CH2)2NH.
The conjugate of any one of the preceding s wherein the linker
comprises NH[(CH2)zO]n-(CHz)2NH-C(O)—(CH2)z-C(O), where n is an integer from 1 to
about 12.
The conjugate of any one of the preceding clauses wherein the linker
comprises NH(CH2)20—(CH2)2NH—C(O)—(CH2)2—C(O), NH[(CH2)zO]2—(CH2)2NH—C(O)—
(CH2)2—C(O), NH[(CH2)zO]6—(CH2)2NH—C(O)—(CH2)2—C(O), or NH[(CH2)zO]12—(CH2)2NH—
C(O)—(CH2)2—C(O).
The conjugate of any one of the preceding clauses comprising the a
<COZH <C02H
* O N/R * HN N/R
—\—NH ENN—\\)—\COZH —\—NH ENN—\ViCOZH
OW or 0%
or a derivative f comprising a chelated metal.
The conjugate of any one of the preceding clauses where P comprises the
* HN <COZH
“IQ—\COZH
or a derivative thereof comprising a chelated metal.
The conjugate of any one of the preceding clauses comprising the formula
HOZC/—HOZC> HOZCF
or H020>
or a derivative f comprising a chelated metal.
The conjugate of any one of the preceding clauses wherein the targeting agent
is a radical of a PSMA binding ligand or PSMA inhibitor.
The conjugate of any one of the preceding s wherein the targeting agent
is a radical of a PSMA inhibitor.
The ate of any one of the preceding clauses comprising the formula
“TNfl’lLNH *
H0200,
wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or
YNWHWCJ)‘NH*
HOZC/ll,H'hirN
COZH or
HOZC/II,HH/H
wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or,JTT
COZH '
H020,”HH/N
COZH 01.
COZH NTNH *
HN\n/N
O COZH
where W is O or S.
The conjugate of any one of the preceding clauses wherein the linker
comprises a polypeptide.
The conjugate of any one of the preceding clauses wherein the linker
comprises a polypeptide comprising phenylalanine, , arginine, or aspartic acid, or a
combination thereof.
The conjugate of any one of the preceding clauses wherein the linker
comprises a lysine.
The conjugate of any one of the ing clauses wherein the linker
ses Lys.
The ate of any one of the preceding s wherein the linker
comprises Arg-Lys.
The conjugate of any one of the preceding clauses wherein the linker
comprises Asp-Arg-Lys.
The conjugate of any one of the preceding clauses wherein the linker
comprises Arg-Asp-Arg.
The ate of any one of the preceding clauses wherein the linker
comprises Arg-Asp-Arg-Lys.
The conjugate of any one of the preceding clauses wherein the linker
comprises Phe-Arg-Asp.
The conjugate of any one of the preceding clauses wherein the linker
comprises Phe-Arg—Asp-Arg.
The conjugate of any one of the preceding clauses n the linker
comprises Phe-Arg—Asp-Arg-Lys.
The conjugate of any one of the preceding clauses wherein the linker
comprises Phe-Phe-Arg.
The ate of any one of the preceding clauses wherein the linker
comprises Phe—Phe-Arg—Asp.
WO 73678
The conjugate of any one of the preceding clauses wherein the linker
comprises Phe-Phe—Arg-Asp-Arg.
The conjugate of any one of the preceding clauses wherein the linker
ses e—Arg-Asp-Arg-Lys.
The ate of any one of the preceding clauses wherein the radical of the
radionuclide or radionuclide containing group, or precursor thereof, or compound capable of
binding a radionuclide or radionuclide containing group comprises a radical of NOTA.
The conjugate of any one of the preceding clauses wherein P comprises the
formula
<COZH <COZH
[NE * HNWNQWCOZHE“? ,/_/N\) COZH
or a derivative thereof comprising a chelated metal.
The conjugate of any one of the preceding clauses comprising the formula
, HN <COZH
HO2C EN”
N;_/N\)—\COZH
or a derivative f comprising a chelated metal.
The conjugate of any one of the preceding s comprising the formula
O O
N n n ‘3
HOZC JLN 0 O
wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The conjugate of any one of the preceding clauses comprising the formula
COZH N N/\/
i0 H H
0 0
H020 N N cogH
The conjugate of any one of the preceding s wherein the linker
comprises the formula
H |
* HNNNW
The conjugate of any one of the ing clauses wherein the linker
comprises the formula
H (I)
The conjugate of any one of the preceding clauses wherein the linker
comprises the formula
no u ‘3
0 fiHNWO
The conjugate of any one of the preceding clauses wherein one or more of the
phenylalanines is L—phenylalanine.
The conjugate of any one of the preceding clauses comprising the formula
<COZH (COZH
m m
*0XNEEM)“COZH M—\—N;"' [,N\)—\COZH
O or O 01‘
<COZH
* HN HN
Phofl—\—NHOEN\)_\COZH
or a derivative thereof comprising a chelated metal.
The conjugate of any one of the ing clauses where P comprises the
formula
* HN <COZH
”Q1002H
or a derivative thereof comprising a chelated metal.
The conjugate of any one of the preceding clauses comprising the formula
0 0
NH COZH NH (COZH
0 [mmNV O [NE
COzH N\) COZH
HOZC/—>N N
H020 >
HOZC or HozC or
* HN\_\ <COZH
EN:—\COZH
HOZC/—H020>
NH <COZH
HN [N31CO2H
HOZCFH020>
or a derivative thereof comprising a chelated metal.
The conjugate of any one of the preceding clauses wherein the radionuclide is
a positron emitting uclide.
The conjugate of any one of the preceding clauses wherein the radionuclide is
a metal ion.
The conjugate of any one of the ing clauses n the radionuclide is
a metal salt.
The conjugate of any one of the preceding clauses comprising an aluminum
halide, such as an aluminum fluoride, um chloride, um bromide, or aluminum
The conjugate of any one of the preceding clauses comprising an um
fluoride.
The conjugate of any one of the preceding clauses comprising an aluminum
18F-fluoride.
The conjugate of any one of the preceding clauses comprising an aluminum
iodide.
The conjugate of any one of the preceding clauses comprising an aluminum
”SI-iodide.
The conjugate of any one of the preceding clauses comprising a gallium ion.
The conjugate of any one of the preceding s comprising a 66Ga ion.
The conjugate of any one of the preceding s comprising a 68Ga ion.
The conjugate of any one of the preceding clauses comprising a zirconium ion.
The conjugate of any one of the preceding clauses comprising 21 89Zr ion.
The conjugate of any one of the preceding clauses comprising a copper ion.
The conjugate of any one of the preceding s sing a 64Cu ion.
The conjugate of any one of the preceding clauses wherein the radionuclide is
a radiotherapy agent, such as iodine, including 1311, lutetium, including 177Lu, m,
including 90Y, strontium, including 89Sr, samarium, including 153Sm, and the like, or a
radiotherapy agent containing group.
The conjugate of any one of the preceding clauses comprising a lutetium ion,
such as a 177Lu ion.
The conjugate of any one of the preceding clauses comprising a yttrium ion,
such as a 90Y ion.
A conjugate of the formulae
COZH 0<N\N/>
/dNNN/\/firN\/\O/\/o\/\N’lk/N\_/¥C02Hcho7o17
HO {N3fLg
HNJE250%22%wa0007029
HN N\ N
A I H QC07043
N N
O 0 O
ul=02H H O H NI N‘ _<OH
O H/\/\n/N \/\ /\/ \/\O
N 0 O NJ
HN \ N
/]\\ I H O
N N folate-C-NETA
or a pharmaceutically acceptable salt thereof.
A conjugate of the formulae
0 §OZH H O
o :fi\:§;~nl;j>
”W \/\o/\/ \/\N ‘ (LCOZH
“N N\
| IAN folate-NOTA-Al13F (0007017)
J\\N N/ COZH
o COZH 0 (N3
MNwo’l'VOWNHwnk/NL/ LCOZHM N
ZNHNjL/[ZjflH o o
FA-PEG12-N0TA-Al-13F ate (oco7o43)
M = Al-18F or “Ga
folate-C-NETA-M M=Al-15F or 68Ga O¥
or a pharmaceutically acceptable salt thereof.
A conjugate of the formulae
0 flrCOZH
N N“ N
co H2 N
i JL H H 13(— NJ
0 bow
H020 N N COZH
H H
DUPA-EAOA-Phe-Phe-NOTA
cogH E
H020 N N COZH
H H
DUPA-C-NETA OH
or a pharmaceutically acceptable salt thereof.
A conjugate of the formulae
COZH E
HOZC H H COZH M=586a64CuorAl-“F
DUPA-EAOA-Phe-Phe-NOTA-S‘CuIAl-18F ’
C02H E
H020 N N COZH
H H
DUPA-C-NETA-M OH
M = Al-18F,6sGa,177Lu or 90Y
or a pharmaceutically acceptable salt thereof.
The conjugate of any one of the ing clauses wherein P comprises the
formula
N+Me3 x-
wherein X" is the conjugate base of an acid, such as trifluoromethanesulfonic acid.
The conjugate of any one of the preceding clauses sing the formula
N+Me3 X'
CN or
* HN\/\O/\/O\/\N
N+Me3 X'
where X’ is a conjugate base of an acid, such as trifluoromethanesulfonic acid.
The conjugate of any one of the preceding clauses n P comprises the
formula
The conjugate of any one of the preceding clauses wherein P ses the
formula
The conjugate of any one of the preceding clauses comprising the formula
0 O
* HN\/\o/\/O\/\N
* O/\/O\/\N
H H
F F
ON or ON
The conjugate of any one of the preceding clauses sing the formula
0 O
* HN\/\O/\/O\/\N
* O/\/O\/\N
H H
18F 18F
ON or ON
The conjugate of any one of the preceding clauses wherein P comprises the
formula *NH-C(CH20H)3.
The conjugate of any one of the ing clauses comprising a boron
fluoride.
The conjugate of any one of the preceding clauses sing a boron 18F-
fluoride.
A pharmaceutical composition comprising one or more of the conjugates of
any one of the preceding clauses, in combination with one or more carriers, diluents, or
excipients, or a combination thereof.
A unit dose or unit dosage form composition comprising a diagnostically
effective amount of one or more of the conjugates of any one of the preceding clauses,
ally in combination with one or more carriers, diluents, or excipients, or a combination
thereof for diagnosing and/or ring a pathogenic cell population, such as a cancer or
inflammatory disease.
A unit dose or unit dosage form composition comprising a therapeutically
effective amount of one or more of the ates of any one of the preceding clauses,
optionally in combination with one or more carriers, diluents, or excipients, or a combination
thereof for ng a pathogenic cell population, such as a cancer or atory disease.
A composition for diagnosing and/or monitoring a disease or disease state
caused at least in part by a pathogenic cell population, such as a cancer or inflammatory
disease, in a host animal, the composition comprising a diagnostically effective amount of
one or more of the conjugates of any one of the preceding clauses; or a pharmaceutical
composition comprising a diagnostically effective amount of one or more of the conjugates of
any one of the preceding clauses, optionally further comprising one or more carriers, diluents,
or ents, or a combination thereof.
A composition for treating a e or disease state caused at least in part by a
pathogenic cell population, such as a cancer or inflammatory disease, in a host animal, the
composition comprising a eutically effective amount of one or more of the conjugates
of any one of the preceding clauses; or a ceutical composition comprising a
therapeutically effective amount of one or more of the conjugates of any one of the preceding
clauses, optionally further comprising one or more carriers, diluents, or excipients, or a
combination thereof.
A method for diagnosing and/or monitoring a e or disease state caused at
least in part by a pathogenic cell population, such as a cancer or inflammatory disease, in a
host animal, the method comprising the step of administering to the host animal a
diagnostically effective amount of one or more of the conjugates of any one of the preceding
clauses; or a pharmaceutical composition comprising a diagnostically effective amount of one
or more of the conjugates of any one of the preceding clauses, optionally further comprising
one or more carriers, diluents, or excipients, or a combination thereof.
A method for treating a disease or disease state caused at least in part by a
pathogenic cell population, such as a cancer or atory disease, in a host animal, the
method comprising the step of administering to the host animal a therapeutically effective
amount of one or more of the conjugates of any one of the preceding clauses; or a
pharmaceutical composition comprising a therapeutically effective amount of one or more of
the conjugates of any one of the preceding s, optionally further comprising one or more
carriers, diluents, or ents, or a combination thereof.
Use of one or more of the ates of any one of the preceding clauses; or a
ceutical ition comprising one or more of the conjugates of any one of the
preceding clauses, optionally further comprising one or more carriers, diluents, or excipients,
or a combination thereof, in the manufacture of a medicament for diagnosing and/or
monitoring a disease or disease state caused at least in part by a pathogenic cell tion,
such as a cancer or inflammatory disease, in a host animal.
Use of one or more of the ates of any one of the preceding clauses; or a
ceutical composition comprising one or more of the conjugates of any one of the
preceding clauses, optionally further comprising one or more carriers, diluents, or excipients,
or a combination thereof, in the manufacture of a medicament for treating a disease or e
state caused at least in part by a pathogenic cell population, such as a cancer or inflammatory
disease, in a host animal.
A kit comprising one or more of the conjugates of any one of the preceding
clauses, or a pharmaceutical ition thereof, optionally further comprising one or more
carriers, diluents, or excipients, or a combination thereof; an al solvent; an optional
reaction container, and a set of instructions for preparing one or more radionuclides and
ing the one or more radionuclides with the one or more of the conjugates to prepare an
imaging agent, diagnostic agent, or therapeutic agent.
A kit comprising one or more of the conjugates of any one of the preceding
s, or a pharmaceutical composition thereof, optionally further comprising one or more
carriers, diluents, or excipients, or a combination thereof; an optional solvent; an optional
reaction container, and a set of instructions for preparing one or more radionuclides and
combining the one or more radionuclides with the one or more of the conjugates to prepare an
imaging agent, diagnostic agent, or therapeutic agent.
It is to be understood that in each instance where a compound or al
formula includes an atom or locus that is marked with or includes a (*), the (*) indicates that
the compound or chemical formula is a radical having an open valence at that atom or locus,
and that atom or locus is the location for attachment of another radical.
In another illustrative embodiment, the conjugate, composition, unit dose,
method, use, or kit of any other embodiment described herein comprises a compound of
formula
or a derivative thereof comprising a chelated metal; or a radical of the foregoing, where each
R is in each instance independently selected to form a carboxylic acid or salt thereof, ester, or
amide, and R1, R2, and R3, are each independently ed from en, and alkyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally
substituted.
In another illustrative embodiment, the conjugate, composition, unit dose,
method, use, or kit of any other ment described herein comprises 1,4,7,10-
tetraazacyclododecane-l,4,7,10-tetraacetic acid (DOTA) or a derivative thereof comprising a
chelated metal; or a l of the ing.
In r illustrative embodiment, the conjugate, composition, unit dose,
method, use, or kit of any other embodiment described herein comprises a compound of
a
R1< R2
ISM_\
Roc—/
or a derivative thereof comprising a chelated metal; or a radical of the ing, where each
R is in each instance independently selected to form a carboxylic acid or salt thereof, ester, or
amide, and R1, R2, and R3, are each independently selected from hydrogen, and alkyl,
cycloalkyl, aryl, kyl, heteroaryl, and heteroarylalkyl, each of which is optionally
substituted, such as the following illustrative compounds:
R1 <COZH
N/R/R2
H0204
R1 R2
: NH2 H
* H20
n H
* H20
H H
O TNH2S * H20
ONH2 COZH
* H2O * H20 W
“j rCOZH
: | N
S * H20,
* H20 EOZH
H NH2 rCOZH
T ,N
S * H20
* H C W
2 COZH
“WCOZH (COZH
: N
O * H20,
* H20 EOZH
COZH COZH
f f
* H20] W
=\- H2C’ W
COZH COZH
HOchNAcozH rCOzH
* HCl;
* HZC’NW
002“ COZH
or a carboxylic acid salt or carboxamide derivative (CONHz) thereof, or a radical of any of
the ing; or a derivative thereof comprising a chelated metal.
In another illustrative embodiment, the conjugate, composition, unit dose,
method, use, or kit of any other embodiment described herein comprises a compound of
formula
N/YR4 R5
HOZC—/
or a derivative thereof comprising a ed metal; or a radical of the foregoing, where R4
and R5 are selected from hydrogen, and alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl, each of which is optionally substituted, such as the following illustrative
or a carboxylic acid salt or carboxamide derivative (CONHz) thereof, or a radical of any of
the ing; or a derivative f comprising a chelated metal.
In another illustrative embodiment, the conjugate, composition, unit dose,
method, use, or kit of any other embodiment described herein comprises a compound of
formula
* H2C-CO2H
NODA—HA
0N02 * HC/VCOZH
* H20
NODA—MPN
* H2C N02
NODA—EPN
NODA—MBA
* H20 COZH
NODA—MPAA NODA—EBA
O O OH
*HZCMNMN O
H / * H20
0 NODA—MPH
NODA—BAEM
m”“20 mwgfiO /
* H20
* H2C O
NODA—MPAED NODA—MPAEM
Q 0
0 \
flNA/NH o
* H2C
NODA—MBEM
* HZCMN
NODA-BM
NODA-EA
* H20\
NODA-butyne
N=N\ COZH
* Hzck/
* mNVOTVNa30
NODA-MPAPEG3N3
* HZC/\©\ 0
NODA-EPA-succinyl
imozN
*HZC N
* H20
L—NETA ((R) or (S) or (RS))
or a carboxylic acid salt or carboxamide derivative ) thereof, or a radical of any of
the foregoing; or a derivative thereof comprising a chelated metal.
In r illustrative embodiment, the conjugate, composition, unit dose,
method, use, or kit of any other embodiment described herein comprises a compound selected
from the formulae
EN N+\)”_ HO E: N+\)”_ 02N E: NM Q_/ \) COZH Gd COZH 6Q COZH OH
COZH COZH
or a carboxylic acid salt or carboxamide derivative (CONHz) thereof, or a radical of any of
the ing, where n is an integer selected from 1, 2, 3, 4, 5, or 6; or a derivative thereof
comprising a chelated metal.
As used herein the term “radical” generally refers to an open valence
compound or chemical fragment that results after the removal of a hydrogen atom or a
yl group from a carboxylic acid. For example, the following radicals may be formed
from L-NETA
NAP“ *
* 02C—/
*OzC J NH *
where each (*) atom is an open e for attachment to a linker and/or targeting agent.
It is to be understood that the foregoing compounds and radicals thereof, may
be further functionalized to attach reactive groups for the uent attachment of linkers
and/or ing groups. Illustratively, the following reactive intermediates are described
herein
<C02H <COZH
HOZC—/ES:+\_LW2—>HOZC—/CE:+LLW
where n is 0 or 1, and NX is
O O O 0 O O O
N=C=S HNJJ\/SH HNJK/Ns HNJI\/ONH2 HNK b HNJJ\/\N
/ /
o O
and the like.
It is to be understood that the following compounds, and metal chelates
thereof, are not ates of the invention:
H020\|
COZH N
“1/deWMN\/\/\<(L;>VCOZH
fiJK/[Nj/\N COZH
H COzH O
HN N\ N
A l H
\ /
H2N N N
HOZC 0
NH HN NH 0 o /—\ COH
)/—NH M 2
NH HN4~<¥(\N/—
H020 o o HN N 1
H020 Ph
H020 H020 o o
HO2C\—)>NH >"‘”/—\—NH HN (\N/—C02H
NH HN n( N j
Where n is 1 or 3.
The compounds described herein may contain one or more chiral centers, or
may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in
one embodiment, the invention described herein is not limited to any particular sterochemical
requirement, and that the compounds, and compositions, methods, uses, and medicaments
that include them may be optically pure, or may be any of a variety of stereoisomeric
mixtures, including racemic and other mixtures of omers, other mixtures of
diastereomers, and the like. It is also to be understood that such es of stereoisomers
may include a single stereochemical configuration at one or more chiral s, while
ing mixtures of stereochemical configuration at one or more other chiral centers.
Similarly, the compounds described herein may include geometric centers,
such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment,
the invention bed herein is not limited to any particular geometric isomer ement,
and that the compounds, and compositions, methods, uses, and medicaments that include
them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be
understood that such mixtures of ric isomers may include a single configuration at one
or more double bonds, while including mixtures of geometry at one or more other double
bonds.
As used herein, the term “alkyl” includes a chain of carbon atoms, which is
optionally branched. As used herein, the terms “alkenyl” and “alkynyl” each include a chain
of carbon atoms, which is optionally branched, and include at least one double bond or triple
bond, respectively. It is to be understood that alkynyl may also include one or more double
bonds. It is to be further understood that in certain embodiments, alkyl is advantageously of
d length, including C1-Cz4, C1-C1z, C1-C8, C1-C6, and C1-C4. Illustratively, such
particularly limited length alkyl , including C1-C8, C1-C6, and C1-C4 may be referred to
as lower alkyl. It is to be further understood that in certain embodiments alkenyl and/or
l may each be advantageously of limited length, including C2—Cz4, C2—C12, C2—C8, C2—
C6, and C2-C4. Illustratively, such ularly limited length alkenyl and/or alkynyl groups,
including C2-C8, C2-C6, and C2-C4 may be referred to as lower alkenyl and/or alkynyl. It is
appreciated herein that r alkyl, alkenyl, and/or alkynyl groups may add less
ilicity to the compound and accordingly will have different pharmacokinetic behavior.
In embodiments of the invention described herein, it is to be understood, in each case, that the
tion of alkyl refers to alkyl as defined herein, and optionally lower alkyl. In
embodiments of the invention described herein, it is to be understood, in each case, that the
recitation of alkenyl refers to l as defined herein, and optionally lower alkenyl. In
WO 73678
embodiments of the invention described herein, it is to be understood, in each case, that the
tion of alkynyl refers to alkynyl as defined herein, and ally lower alkynyl.
Illustrative alkyl, alkenyl, and alkynyl groups are, but not limited to, methyl, ethyl, n-propyl,
isopropyl, n-butyl, yl, sec-butyl, tert—butyl, pentyl, yl, 3—pentyl, neopentyl, hexyl,
heptyl, octyl, and the like, and the corresponding groups containing one or more double
and/or triple bonds, or a combination thereof.
As used herein, the term ene” includes a divalent chain of carbon atoms,
which is optionally ed. As used herein, the term “alkenylene” and “alkynylene”
includes a divalent chain of carbon atoms, which is optionally branched, and includes at least
one double bond or triple bond, respectively. It is to be understood that alkynylene may also
include one or more double bonds. It is to be further understood that in certain embodiments,
alkylene is ageously of limited length, including C1—C24, C1—C12, C1—C8, C1—C6, and C1-
C4. Illustratively, such particularly limited length alkylene groups, ing C1-C8, C1-C6,
and C1-C4 may be referred to as lower alkylene. It is to be further understood that in certain
embodiments alkenylene and/or alkynylene may each be advantageously of limited length,
including C2—Cz4, C2-C12, C2-C8, C2-C6, and C2-C4. Illustratively, such particularly d
length alkenylene and/or lene groups, including C2-C8, C2—C6, and C2—C4 may be
referred to as lower alkenylene and/or alkynylene. It is appreciated herein that shorter
alkylene, alkenylene, and/or lene groups may add less lipophilicity to the compound
and accordingly will have different pharmacokinetic behavior. In embodiments of the
invention described herein, it is to be understood, in each case, that the recitation of alkylene,
alkenylene, and alkynylene refers to alkylene, alkenylene, and alkynylene as defined herein,
and optionally lower alkylene, alkenylene, and alkynylene. Illustrative alkyl groups are, but
not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-
butylene, pentylene, 1,2—penty1ene, 1,3-penty1ene, hexylene, heptylene, octylene, and the like.
As used herein, the term “linker” includes is a chain of atoms that connects
two or more functional parts of a molecule to form a conjugate. Illustratively, the chain of
atoms is selected from C, N, O, S, Si, and P, or C, N, O, S, and P, or C, N, O, and S. The
chain of atoms ntly ts different functional capabilities of the conjugate, such as
targeting agents, drugs, diagnostic agents, imaging agents, and the like. The linker may have
a wide variety of lengths, such as in the range from about 2 to about 100 atoms in the
contiguous backbone. The atoms used in forming the linker may be combined in all
chemically relevant ways, such as chains of carbon atoms forming alkylene, alkenylene, and
alkynylene groups, and the like; chains of carbon and oxygen atoms forming ethers,
polyoxyalkylene groups, or when combined with yl groups forming esters and
carbonates, and the like; chains of carbon and nitrogen atoms forming amines, imines,
polyamines, hydrazines, hydrazones, or when combined with carbonyl groups forming
amides, ureas, semicarbazides, carbazides, and the like; chains of carbon, nitrogen, and
oxygen atoms forming alkoxyamines, lamines, or when combined with yl
groups forming urethanes, amino acids, acyloxylamines, hydroxamic acids, and the like; and
many others. In addition, it is to be understood that the atoms forming the chain in each of
the foregoing illustrative embodiments may be either saturated or unsaturated, thus forming
single, double, or triple bonds, such that for example, s, s, alkynes, imines, and
the like may be radicals that are included in the linker. In addition, it is to be understood that
the atoms forming the linker may also be cyclized upon each other or be part of cyclic
structure to form divalent cyclic structures that form the linker, including cyclo alkanes,
cyclic , cyclic amines, and other heterocycles, arylenes, arylenes, and the like in
the linker. In this latter arrangement, it is to be tood that the linker length may be
defined by any pathway through the one or more cyclic ures. Illustratively, the linker
length is defined by the shortest pathway through the each one of the cyclic structures. It is
to be understood that the linkers may be optionally substituted at any one or more of the open
valences along the chain of atoms, such as optional substituents on any of the carbon,
nitrogen, silicon, or phosphorus atoms. It is also to be tood that the linker may connect
the two or more functional parts of a le to form a conjugate at any open valence, and it
is not necessary that any of the two or more functional parts of a molecule forming the
conjugate are attached at any apparent end of the linker.
As used herein, the term “cycloalkyl” includes a chain of carbon atoms, which
is ally branched, where at least a portion of the chain in cyclic. It is to be understood
that lkylalkyl is a subset of cycloalkyl. It is to be understood that cycloalkyl may be
polycyclic. Illustrative cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl,
cyclohexyl, 2-methylcyclopropyl, cyclopentyleth—2—yl, tyl, and the like. As used
herein, the term “cycloalkenyl” includes a chain of carbon atoms, which is optionally
branched, and includes at least one double bond, where at least a portion of the chain in
cyclic. It is to be understood that the one or more double bonds may be in the cyclic portion
of cycloalkenyl and/or the non-cyclic portion of cycloalkenyl. It is to be understood that
cycloalkenylalkyl and cycloalkylalkenyl are each subsets of cycloalkenyl. It is to be
understood that cycloalkyl may be polycyclic. Illustrative cycloalkenyl include, but are not
limited to, cyclopentenyl, exylethen—Z-yl, cycloheptenylpropenyl, and the like. It is to
be further understood that chain forming cycloalkyl and/or cycloalkenyl is advantageously of
limited , including C3-C24, , C3—C8, C3—C6, and C5-C6. It is appreciated herein
that shorter alkyl and/or alkenyl chains forming cycloalkyl and/or cycloalkenyl, tively,
may add less ilicity to the compound and accordingly will have different
cokinetic behavior.
As used herein, the term “heteroalkyl” includes a chain of atoms that includes
both carbon and at least one heteroatom, and is optionally branched. Illustrative heteroatoms
include nitrogen, oxygen, and sulfur. In certain variations, illustrative heteroatoms also
include phosphorus, and selenium. As used herein, the term “cycloheteroalkyl” including
cyclyl and heterocycle, includes a chain of atoms that includes both carbon and at least
one atom, such as heteroalkyl, and is optionally branched, where at least a portion of
the chain is cyclic. Illustrative heteroatoms include nitrogen, , and sulfur. In certain
variations, illustrative heteroatoms also include phosphorus, and um. Illustrative
cycloheteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl,
tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and
the like.
As used herein, the term “aryl” includes monocyclic and polycyclic aromatic
carbocyclic groups, each of which may be optionally substituted. Illustrative aromatic
carbocyclic groups described herein e, but are not d to, phenyl, naphthyl, and the
like. As used , the term “heteroaryl” includes aromatic heterocyclic groups, each of
which may be optionally substituted. Illustrative aromatic heterocyclic groups include, but
are not limited to, pyridinyl, dinyl, pyrazinyl, triazinyl, tetrazinyl, inyl,
quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,
benzisoxazolyl, benzisothiazolyl, and the like.
The term "optionally substituted" as used herein includes the replacement of
hydrogen atoms with other onal groups on the radical that is optionally substituted.
Such other functional groups illustratively include, but are not limited to, amino, hydroxyl,
halo, thiol, alkyl, kyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and derivatives thereof,
carboxylic acids and derivatives thereof, and the like. Illustratively, any of amino, hydroxyl,
thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl,
heteroarylheteroalkyl, andfor sulfonic acid is optionally substituted.
As used herein, the terms nally tuted aryl" and "optionally
substituted heteroaryl" include the replacement of hydrogen atoms with other functional
groups on the aryl or heteroaryl that is optionally substituted. Such other functional groups,
also referred to herein as aryl subsituents, illustratively include, but are not limited to, amino,
hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl, heteroarylheteroalkyl, nitro, ic acids and derivatives thereof,
carboxylic acids and derivatives thereof, and the like. ratively, any of amino, hydroxy,
thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl,
heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.
Illustrative substituents include, but are not limited to, a radical -(CH2)XZX,
where X is an integer from 0-6 and ZX is selected from halogen, hydroxy, yloxy,
including C1-C6 alkanoyloxy, ally substituted aroyloxy, alkyl, including C1—C6 alkyl,
alkoxy, including C1-C6 alkoxy, cycloalkyl, including C3-C3 cycloalkyl, cycloalkoxy,
including C3-C8 cycloalkoxy, alkenyl, including C2-C6 alkenyl, alkynyl, including C2-C6
l, haloalkyl, including C1-C6 haloalkyl, haloalkoxy, including C1-C6 haloalkoxy,
halocycloalkyl, including C3-C8 halocycloalkyl, halocycloalkoxy, including C3-C8
halocycloalkoxy, amino, C1—C6 alkylamino, (C1—C6 alkyl)(C1-C6 alkyl)amino,
alkylcarbonylamino, N—(C1—C6 alkyl)alkylcarbonylamino, aminoalkyl, C1—C6
alkylaminoalkyl, (C1-C6 alkyl)(C1—C6 alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N—(C1-C6
alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or ZX is selected from -C02R4 and
-CONR5R6, where R4, R5, and R6 are each independently selected in each occurrence from
hydrogen, C1-C6 alkyl, aryl-C1-C6 alkyl, and heteroaryl-Cl—Cg alkyl.
It is to be tood that in every instance disclosed herein, the recitation of a
range of integers for any le bes the d range, every individual member in the
range, and every possible subrange for that variable. For example, the recitation that n is an
integer from 0 to 8, describes that range, the individual and selectable values of 0, 1, 2, 3, 4,
, 6, 7, and 8, such as n is 0, or n is l, or n is 2, etc. In addition, the recitation that n is an
integer from 0 to 8 also describes each and every subrange, each of which may for the basis
of a further embodiment, such as n is an integer from 1 to 8, from 1 to 7, from 1 to 6, from 2
to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc.
As used herein, the term “composition” lly refers to any product
comprising the specified ingredients in the specified s, as well as any product which
results, directly or indirectly, from combinations of the specified ingredients in the specified
s. It is to be understood that the compositions bed herein may be prepared from
isolated compounds described herein or from salts, solutions, hydrates, solvates, and other
forms of the compounds described herein. It is appreciated that n functional groups,
such as the y, amino, and like groups form complexes and/or coordination compounds
with water and/or various solvents, in the various physical forms of the compounds. It is also
to be understood that the itions may be prepared from various amorphous, non-
amorphous, lly lline, crystalline, and/or other morphological forms of the
compounds bed herein. It is also to be understood that the compositions may be
prepared from s hydrates and/or solvates of the compounds described herein.
Accordingly, such pharmaceutical compositions that recite compounds described herein are
to be tood to e each of, or any ation of, the various morphological forms
and/or solvate or hydrate forms of the compounds described herein.
Illustratively, compositions may include one or more carriers, diluents, and/or
excipients. The compounds described herein, or compositions containing them, may be
formulated in a diagnostically or therapeutically effective amount in any conventional dosage
forms appropriate for the methods described herein. The compounds described herein, or
compositions containing them, including such ations, may be administered by a wide
variety of conventional routes for the methods described herein, and in a wide variety of
dosage formats, utilizing known procedures (see generally, Remington: The e and
Practice of Pharmacy, (21St ed., 2005)).
The term “diagnostically effective amount” as used herein, refers to that
amount of active compound or ceutical agent that elicits the biological or medicinal
response in a tissue system, animal or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes diagnosis and/or monitoring of
the symptoms of the disease or disorder being treated. Illustrative diagnostically effective
amounts of the conjugate to be administered to the host animal include about 1 pg/kg to about
mg/kg, 1 ng/kg to about 10 mg/kg, or from about 10 pig/kg to about 1 mg/kg, or from
about 100 ug/kg to about 500 ug/kg.
The term “therapeutically effective amount” as used herein, refers to that
amount of active compound or pharmaceutical agent that s the biological or medicinal
response in a tissue system, animal or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of
the disease or disorder being treated. In one aspect, the therapeutically effective amount is
that which may treat or alleviate the e or symptoms of the disease at a reasonable
t/risk ratio applicable to any medical treatment. However, it is to be understood that
the total daily usage of the compounds and compositions bed herein may be decided by
the attending physician within the scope of sound medical judgment. The specific
therapeutically-effective dose level for any particular patient will depend upon a variety of
factors, including the disorder being treated and the severity of the disorder; activity of the
specific compound employed; the specific composition employed; the age, body weight,
general health, gender and diet of the patient: the time of administration, route of
administration, and rate of ion of the ic compound employed; the duration of the
ent; drugs used in combination or coincidentally with the specific compound
ed; and like factors well known to the researcher, veterinarian, medical doctor or other
ian of ordinary skill. Illustrative therapeutically effective amounts of the conjugate to
be stered to the host animal include about 1 pg/kg to about 10 mg/kg, 1 ng/kg to about
mg/kg, or from about 10 pig/kg to about 1 mg/kg, or from about 100 ug/kg to about 500
rig/kg.
The term “administering” as used herein includes all means of introducing the
compounds and compositions described herein to the host animal, including, but are not
d to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal,
inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The compounds and
compositions described herein may be administered in unit dosage forms and/or formulations
containing conventional nontoxic pharmaceutically—acceptable carriers, nts, and/or
vehicles.
As used herein, the term “amino acid” refers generally to beta, gamma, and
longer amino acids, such as amino acids of the a:
-N(R)-(CR’R")q-C(O)-
where R is hydrogen, alkyl, acyl, or a suitable nitrogen protecting group, R’ and R" are
hydrogen or a substituent, each of which is independently selected in each occurrence, and q
is an integer such as l, 2, 3, 4, or 5. Illustratively, R’ and/or R" independently correspond to,
but are not limited to, hydrogen or the side chains t on naturally occurring amino acids,
such as methyl, benzyl, ymethyl, thiomethyl, carboxyl, carboxylmethyl,
guanidinopropyl, and the like, and derivatives and protected derivatives thereof. The above
described a includes all stereoisomeric variations. For example, the amino acid may
be ed from alanine, aspartic acid, asparagine, cysteine, glutamic acid, phenylalanine,
histidine, isoleucine, lysine, leucine, methionine, proline, glutamine, arginine, ,
threonine, valine, tryptophan, tyrosine, and ornithine, and the like.
It is to be understood that in every instance disclosed herein, the recitation of a
range of integers for any variable describes the recited range, every individual member in the
range, and every possible subrange for that variable. For example, the recitation that n is an
integer from 0 to 8, describes that range, the individual and selectable values of 0, 1, 2, 3, 4,
, 6, 7, and 8, such as n is 0, or n is 1, or n is 2, etc. In addition, the recitation that n is an
r from 0 to 8 also describes each and every subrange, each of which may for the basis
of a further embodiment, such as n is an integer from 1 to 8, from 1 to 7, from 1 to 6, from 2
to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc.
In another embodiment, the linkers described herein include a polyether, such
as the linkers of the following formulae:
O]/\/O\/Y N'eO‘PAofVOVYmono]/\/o
0 H02HZnCt.)O p:
aer/H“”3?"o erwvw\
'8 )”
H020 HOZC H020
,//N\/”\O/\\/O\//\O/\\/O\/”\O/\~/O+//\oi;\/O\//\n/N\r'\S/”
where m is an integer independently selected in each instance from 1 to about 8; p is an
integer selected from 1 to about 10; and n is an integer independently selected in each
instance from 1 to about 3. In one aspect, In is independently in each instance 1 to about 3.
In another aspect, n is 1 in each instance. In r aspect, p is independently in each
instance about 4 to about 6. ratively, the corresponding polypropylene polyethers
corresponding to the foregoing are described herein and may be ed in the conjugates as
linkers. In addition, it is appreciated that mixed polyethylene and polypropylene polyethers
may be included in the conjugates as linkers. Further, cyclic variations of the ing
polyether compounds, such as those that include tetrahydrofuranyl, 1,3-dioxanes, 1,4-
dioxanes, and the like are bed herein.
In another embodiment, the linkers described herein include a plurality of
hydroxyl functional groups, such as linkers that incorporate ccharides,
oligosaccharides, polysaccharides, and the like. It is to be understood that the polyhydroxyl
containing linkers comprise a plurality of —(CROH)- groups, where R is hydrogen or alkyl.
In another ment, the s include one or more of the ing
diradicals:
wherein R is H, alkyl, cycloalkyl, or kyl; m is an integer from 1 to about 3; n1 is an
integer from 1 to about 5, or n1 is an integer from 2 to about 5, p is an r from 1 to about
, and r is an integer selected from 1 to about 3. In one aspect, the r n is 3 or 4. In
another aspect, the integer p is 3 or 4. In another aspect, the integer r is 1.
In r embodiment, the linkers include one or more of the following
diradicals:
O 902H
/ * H 3 H020
S\ * o QOZH
* N N H ?
H mm N
* N NAC/Irs\ *
H H
(HOCIJH)n O
(Hoc|:H)n (HOCI3H)n
R R P
wherein R is H, alkyl, cycloalkyl, or arylalkyl; m is an integer from 1 to about 3; n is an
integer from 1 to about 5, or from 2 to about 5, p is an integer from 1 to about 5, and r is an
integer selected from 1 to about 3. In one , the integer n is 3 or 4. In another aspect,
the integer p is 3 or 4. In another aspect, the integer r is 1.
In another embodiment, the linker includes one or more of the following
cyclic polyhydroxyl groups:
O O
H / * a: Z]: / *
at u N
['0l4). HO
(OH)n HO OH
,3 p
wherein n is an integer from 2 to about 5, p is an integer from 1 to about 5, and each r is an
independently selected integer from 1 to about 4. In one aspect, the integer n is 3 or 4. In
another aspect, the integer p is 3 or 4. In another aspect, each r r is independently 2 or
3. It is understood that all stereochemical forms of such sections of the linkers are described
herein. For example, in the above formula, the n may be derived from ribose, xylose,
glucose, mannose, galactose, or other sugar and retain the stereochemical arrangements of
pendant hydroxyl and alkyl groups present on those molecules. In addition, it is to be
tood that in the foregoing formulae, various deoxy compounds are also described.
Illustratively, compounds of the ing ae are described:
wherein n is equal to or less than r, such as when r is 2 or 3, n is 1 or 2, or 1, 2, or 3,
respectively.
In r embodiment, the linker includes a polyhydroxyl compound of the
following formula:
wherein n and r are each an integer selected from 1 to about 3. In one aspect, the linker
includes one or more polyhydroxyl compounds of the following formulae:
0:3—TOH d/ D/OH H OA/OVOH
\o/*/\/O/\/LOH
HO /
N OH
HN/ ‘NH KKL / HO/kKLOH ‘
OH HN\ , OH
It is understood that all stereochemical forms of such sections of the linkers are described
herein. For example, in the above a, the section may be derived from ribose, xylose,
glucose, mannose, galactose, or other sugar and retain the stereochemical arrangements of
pendant hydroxyl and alkyl groups present on those molecules.
In another configuration, the linkers L described herein include polyhydroxyl
groups that are spaced away from the backbone of the linker. In one embodiment, such
carbohydrate groups or polyhydroxyl groups are connected to the back bone by a triazole
group, forming triazole-linked linkers. Illustratively, such linkers e diradicals of the
following formulae:
OH OH OH OH
HO HO
HO HO HO
“‘h‘rhfl”
COzHO HO 02 J]rm)
wherein n, m, and r are rs and are each independently selected in each ce from 1
to about 5. In one illustrative aspect, m is independently 2 or 3 in each instance. In another
aspect, r is l in each instance. In another aspect, n is l in each instance. In one variation, the
group connecting the polyhydroxyl group to the backbone of the linker is a different
heteroaryl group, including but not limited to, e, pyrazole, l,2,4-triazole, furan,
oxazole, isoxazole, thienyl, thiazole, azole, oxadiazole, and the like. Similarly, divalent
6—membered ring heteroaryl groups are described. Other variations of the foregoing
illustrative linkers include ylene groups, such as the following formulae:
OH OH OH OH
HO HO
(N?/* (N? N',.
COzHO HO 52 o
wherein n and r are integers and are each independently selected in each instance from 1 to
about 5; and p is an integer selected from 1 to about 4.
In another embodiment, such carbohydrate groups or droxyl groups are
connected to the back bone by an amide group, forming amide-linked linkers. Illustratively,
such linkers include diradicals of the following formulae:
HO HO OH
HO HO COZH Hofi
o 0
”‘(KFO "‘(KFO m ( O
NH NH \
*\s "(fifi/ * \S S
H A? H \(E)n H
n( bj/ \n/\H
N /* \n/\H/* N n(N]/N N “Lin/NV /*NH
COZHO COzHO COZHO
wherein each n is an independently selected r from 1 to about 3, and m is an
independently selected integer from 1 to about 22. In one illustrative aspect, each n is
independently l or 2. In another illustrative aspect, m is selected from about 6 to about 10,
illustratively 8. In one variation, the group connecting the polyhydroxyl group to the
backbone of the linker is a different functional group, including but not limited to, esters,
ureas, carbamates, drazones, and the like. Similarly, cyclic variations are bed.
Other variations of the foregoing illustrative linkers include oxyalkylene groups, such as the
following formulae:
HO\%HO 1&0COZH 140%:HO H0 HO
NH [le
* \s nH’ "(j/NH [HIif
MY1m” MW” "erW”
COZH O C02H O COZHO
wherein n is in each instance an independently selected integer from 1 to about 5; and p is an
integer selected from 1 to about 4.
In another embodiment, the linkers include one or more of the ing
diradicals:
wherein R is H, alkyl, cycloalkyl, or arylalkyl; each m is an ndently selected integer
from 1 to about 3; each n is an independently selected integer from 1 to about 6, p is an
integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variation,
each n is independently 3 or 4. In another variation, the integer p is 3 or 4. In another
variation, the integer r is 1.
In another embodiment, the linkers include one or more of the following
diradicals:
wherein R is H, alkyl, lkyl, or arylalkyl; each m is an independently selected r
from 1 to about 3; each n is an independently selected integer from 2 to about 6, p is an
integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variation,
each n is independently 3 or 4. In another variation, the integer p is 3 or 4. In another
ion, the integer r is 1.
In another embodiment, the linkers include one or more of the following
diradicals:
H P N,,
N\rj\ N/ * H
(H20)m m
HN 0
kb HO"
OH 'IOH
‘/)/n I‘OH
COZHp
H 002H NM(‘10ng
N H
. N r\*
(H2C)m
A p
HN o
HMOH H
(£0sz H
HOC k 0 $OZH
72 EH *
of 002H H EMS"
N \
*——N N *
H )m
(Hz/Zr" p
HN O
kfi/YnOH OH
COZHp ,
wherein each m is an independently selected integer from 1 to about 3; each n is an
ndently selected integer from 1 to about 6, p is an integer from 1 to about 5, and r is an
integer selected from 1 to about 3. In one variation, each n is independently 3 or 4. In
another ion, the integer p is 3 or 4. In another variation, the integer r is 1.
In another embodiment, the s e one or more of the following
diradicals:
O asco H 2
H _ )m
H 002H
* N
l r N
* ifN
H NW3“r
H H
(H C) o
HN O
HN o
m gm“
cozH P cozflp
_
wherein each m is an independently selected integer from 1 to about 3; each n is an
independently selected integer from 2 to about 6, p is an integer from 1 to about 5, and r is an
integer selected from 1 to about 3. In one variation, each n is independently 3 or 4. In
another variation, the integer p is 3 or 4. In another variation, the integer r is 1.
In another embodiment, the linkers include one or more of the following
diradicals:
wherein each m is an independently selected integer from 1 to about 3, p is an integer from 1
to about 5, and r is an integer selected from 1 to about 3. In another variation, the integer p is
3 or 4. In another variation, the integer r is 1.
In another ment, the linker is a ation of backbone and ing
side motifs such as is rated by the following formulae
H H H
N HO H0 HO 902 H
>x</ */N */N
) 0 ) o o
“0 ) ”O
* ) HM“ fir“N/‘jlhl
0 0 n 0
Ho Ho Ho
wherein n is an integer independently selected in each instance from 0 to about 3. The above
formula are intended to represent 4, 5, 6, and even larger membered cyclic sugars. In
addition, it is to be understood that the above formula may be ed to represent deoxy
sugars, where one or more of the hydroxy groups present on the formulae are replaced by
hydrogen, alkyl, or amino. In addition, it is to be tood that the corresponding carbonyl
compounds are described by the above formulae, where one or more of the hydroxyl groups
is oxidized to the corresponding carbonyl. In addition, in this illustrative embodiment, the
pyranose includes both carboxyl and amino functional groups and (a) can be inserted into the
ne and (b) can provide synthetic handles for branching side chains in variations of this
embodiment. Any of the pendant hydroxyl groups may be used to attach other al
radicals, including additional sugars to prepare the corresponding oligosaccharides. Other
variations of this embodiment are also described, including inserting the pyranose or other
sugar into the backbone at a single carbon, i.e. a spiro arrangement, at a geminal pair of
carbons, and like arrangements. For example, one or two ends of the linker, or the agent P, or
the ligand B may be ted to the sugar to be inserted into the backbone in a 1,1; 1,2; 1,3;
1,4; 2,3, or other arrangement.
In another embodiment, the linkers include one or more amino groups of the
ing formulae:
(EDOZHO
NW, co H NW 90 H
, 2 *
0 NWTWN : '
\NAMENd o * Nd \N *\ NJ 0 0 O
n NAM’n N n NAM? COZH
H H H H H
H H H H H
co H co H
2° * 20 “
’\ NdNWNTW”O O *\
m o NdNWNTW”O O O
n ”M COZH COZH m/\[,,Hkn ”M COZH COZH COQH
where each n is an integer independently selected in each instance from 1 to about 3. In one
aspect, the each n is independently l or 2 in each instance. In another aspect, the integer n is
l in each instance.
In r embodiment, the linker is a ic acid ester, such as an alkyl ester
of sulfuric acid. Illustratively, the linker is of the following formula:
\/0 HO
x/s’ \//o HO\ 0
o \o 0¢s\ /S//
g o o/ \o
>n M ()n
O O
HOQC 0 H020 HO n
HO\ /0 HO
és’ \éo HO\ 0
o \o O¢s\ /s/’
o o/ ‘o
>n N ()n
I ‘ N‘ ‘
//N | ,/N I o”
*\ (— N
“(K/“YR”n n( WHWN “Tl/k /*
H025 H H220 )n H
0 O
o HOQC
where each n is an integer independently selected in each instance from 1 to about 3.
Illustratively, each n is independently l or 2 in each ce.
It is understood, that in such polyhydroxyl, polyamino, carboxylic acid,
sulfuric acid, and like s that include free hydrogens bound to heteroatoms, one or more
of those free hydrogen atoms may be protected with the appropriate hydroxyl, amino, or acid
protecting group, respectively, or alternatively may be blocked as the corresponding pro-
drugs, the latter of which are selected for the particular use, such as pro-drugs that release the
parent drug under general or specific logical conditions.
It is to be understood that in each of the foregoing illustrative examples, the
stereochemical configurations shown herein are merely illustrative, and other stereochemical
configurations are described. For example in one variation, the corresponding unnatural
amino acid urations may be included in the conjugated described herein as follows:
H O CO2H
AVIS\ T'IOZC
N\ o
H COZH
* N *
‘ r N
H ”7N \ /rs\ *r
*‘O H H
7\ )r Fol4)r
(OH)n
p (OH)n
, , p
7 _HO C
Hozc\E 2 \: o
o H
H COZH 90sz
, ”AWN N rs“ ,,7N/\WN\ NM \,
H H H H
o 0
qo F0
)r I”
(OH): p (OH): p ,
wherein each n is an ndently ed integer from 2 to about 5, p is an integer from 1
to about 5, and r is an integer from 1 to about 4, as described above.
It is to be further understood that in the foregoing embodiments, open
positions, such as (*) atoms are locations for attachment of the targeting agent B or the agent
(P). In addition, it is to be understood that such attachment of either or both of B and A may
be direct or through an intervening linker. Illustrative additional linkers are described in US.
7,601,332, the disclosure of which is incorporated herein by reference.
Illustrative bivalent radicals forming part of the linker.
H2N NH
CO2H HN
HOZC O COZH
*V*I * K/\>x<
| *K/S\N*
COZH | f)
* OR
O gigN *g >z< |
| >I< O O
O R=H, alkyl, acyl
Hozo/jv/Yo I
/o o * o o
N/Y VN 00 H >x<
HO2C 2
>x< OR >I<
* OR o |::N’\ *
t 8* o
R=H, alkyl, acyl
NH2 0
COZH COZH * S
«k N *
‘ >k * 4‘ l\/S *
I >1:
0 O
H COZH
HO CAN/YO2 HO fO2
J NH J NVCOZH
NH N
H020 QI/ H020 g H
N * * o
*N * s *
| l * N
O O I
* O
O I
I CI)
/0 o O O
* * o
o H
* N N co H
OR N OR N
* N H
OR OR o I*|
O S >x< O
R=H, alkyl» acyl * N R=H, alkyl, acyl
COzH COzH
H020 O HO:L‘k20 N*
I *
>l< K/“\N* * >1< N
* N Ma:I
| COZH
H020 H020 o
O N as
>k N
* égN OR
* N * N
* *
O O >x< O
R=H, alkyl, acyl O
H2NYNH HZNYNH
HN HN
* N
>l< N>l< O
* N |
o O
NH2 NH2
ee >z<
N >l< >I< N *
* I *N 1I
o o O
SH SH /0 o
N * COZH
N >1: * * OR *NX/8* N *
>x< | OR
o O
R=H, alkyl, acyl
o o o o o o
, * *
S S “
N% * N% * N3*n NJn
O O O O
n=O-3 n= -3 n=1-3 n=1-3
O O 0
9: /\/O it
* S Nit *S o :1: N *
It is to be understood that the bivalent linkers may be combined in any
chemically relevant way, either directly or via an intervening heteroatom to construct the
linkers described herein.
In another embodiment, the polyvalent linkers described herein comprise a
linker selected from the group consisting of carbonyl, carbonyl, ne,
cycloalkylene, necycloalkyl, alkylenecarbonyl, cycloalkylenecarbonyl,
carbonylalkylcarbonyl, l alkylenesuccinimidyl, 1 (carbonylalkyl)succinimidy1,
alkylenesulfoxyl, sulfonylalkyl, alkylenesulfoxylalkyl, alkylenesulfonylalkyl,
carbonyltetrahydro—ZH—pyranyl, yltetrahydrofuranyl, 1—(carbonyltetrahydro-2H—
l)succinimidyl, and l-(carbonyltetrahydrofuranyl)succinimidyl.
In r embodiment, the nds described herein comprise one or
more amino acids.
The compounds described herein can be used for both human clinical
medicine and veterinary applications. Thus, the host animal harboring the population of
pathogenic cells and administered the compounds described herein can be human or, in the
case of veterinary applications, can be a laboratory, agricultural, domestic, or Wild animal.
The present ion can be applied to host animals including, but not d to, humans,
laboratory animals such rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys,
chimpanzees, ic animals such as dogs, cats, and rabbits, agricultural animals such as
cows, horses, pigs, sheep, goats, and Wild animals in captivity such as bears, pandas, lions,
tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.
The compounds, compositions, s, and uses described herein are useful
for diagnosing and/or monitoring diseases caused at least in part by populations of pathogenic
cells, which may cause a variety of pathologies in host animals. As used herein, the term
“pathogenic cells” or “population of pathogenic cells” gemerally refers to cancer cells,
infectious agents such as bacteria and viruses, bacteria- or virus-infected cells, inflammatory
cells, activated macrophages capable of causing a disease state, and any other type of
pathogenic cells that uniquely express, preferentially express, or overexpress g sites for
the targeting agents described herein.
Illustratively, the population of pathogenic cells can be a cancer cell
population that is tumorigenic, ing benign tumors and malignant tumors, or it can be
non-tumorigenic. The cancer cell population can arise spontaneously or by such processes as
mutations present in the germline of the host animal or somatic mutations, or it can be
chemically-, virally-, or ion—induced. The invention can be utilized to diagnose,
monitor, and/or treat such cancers, ing carcinomas, sarcomas, lymphomas, Hodgekin’s
disease, melanomas, mesotheliomas, Burkitt’s lymphoma, nasopharyngeal carcinomas,
leukemias, and myelomas. The cancer cell population can include, but is not limited to, oral,
d, endocrine, skin, gastric, esophageal, laryngeal, pancreatic, colon, bladder, bone,
ovarian, cervical, uterine, breast, testicular, prostate, rectal, kidney, liver, and lung cancers.
Illustratively, the population of pathogenic cells can also be activated
monocytes or macrophages associated with disease states such as fibromyalgia, rheumatoid
arthritis, osteoarthritis, ulcerative colitis, Crohn’s disease, psoriasis, osteomyelitis, multiple
sclerosis, atherosclerosis, pulmonary fibrosis, dosis, systemic sclerosis, organ lant
rejection (GVHD), lupus erythematosus, SjOgren’s syndrome, glomerulonephritis,
inflammations of the skin, such as psoriasis, and the like, chronic inflammations, and
inflammations due to injury, such as head or spinal cord injury, embolisms, and the like.
The conjugates described herein can be formed from, for example, a wide
variety of vitamins or receptor-binding n analogs/derivatives, linkers, and g and
radiotherapy agents. The conjugates described herein are capable of selectively targeting a
tion of pathogenic cells in the host animal due to preferential expression of a receptor
for the targeting agent, such as a n, accessible for binding, on the pathogenic cells.
Illustrative vitamin moieties that can be used as the ing agent (B) include carnitine,
inositol, lipoic acid, xal, ascorbic acid, niacin, henic acid, folic acid, riboflavin,
thiamine, biotin, n B12, and the lipid soluble vitamins A, D, E and K. These vitamins,
and their receptor—binding analogs and derivatives, constitute an illustrative targeting entity
that can be coupled with the imaging or radiotherapy agent by a bivalent linker (L) to form a
targeting agent (B) imaging or radiotherapy agent ate as described herein. The term
vitamin is understood to include vitamin s and/or derivatives, unless otherwise
indicated. Illustratively, pteroic acid which is a derivative of , biotin analogs such as
biocytin, biotin sulfoxide, tin and other biotin receptor-binding compounds, and the
like, are considered to be vitamins, n analogs, and vitamin derivatives. It should be
appreciated that n analogs or derivatives as described herein refer to vitamins that
incorporates an heteroatom through which the vitamin analog or derivative is covalently
bound to the bivalent linker (L).
Illustrative vitamin moieties include folic acid, biotin, riboflavin, thiamine,
vitamin B12, and receptor—binding analogs and derivatives of these vitamin molecules, and
other related vitamin receptor binding molecules.
In one embodiment, the targeting group B is a folate, an analog of folate, or a
derivative of folate. It is to be understood as used herein, that the term folate is used both
individually and collectively to refer to folic acid itself, and/or to such analogs and
derivatives of folic acid that are capable of binding to folate receptors.
Illustrative embodiments of vitamin analogs and/or derivatives include folate
and analogs and derivatives of folate such as folinic acid, pteropolyglutamic acid, and folate
receptor-binding pteridines such as tetrahydropterins, ofolates, tetrahydrofolates, and
their deaza and a analogs. The terms “deaza” and “dideaza” analogs refer to the art-
recognized analogs having a carbon atom tuted for one or two nitrogen atoms in the
naturally occurring folic acid structure, or analog or derivative thereof. For example, the
deaza s include the a, 3-deaza, 5-deaza, 8-deaza, and za analogs of folate,
folinic acid, pteropolyglutamic acid, and folate receptor-binding ines such as
tetrahydropterins, dihydrofolates, and tetrahydrofolates. The dideaza analogs include, for
example, 1,5-dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs of folate, folinic
acid, pteropolyglutamic acid, and folate receptor-binding pteridines such as tetrahydropterins,
dihydrofolates, and tetrahydrofolates. Other folates useful as complex forming s for
this invention are the folate receptor-binding analogs aminopterin, pterin (also known
as methotrexate), NIO-methylfolate, 2-deamino-hydroxyfolate, deaza analogs such as l-
deazamethopterin or 3-deazamethopterin, and 3’,5’—dichloroaminodeoxy-N10-
methylpteroylglutamic acid (dichloromethotrexate). The foregoing folic acid analogs and/or
derivatives are tionally termed es,” reflecting their ability to bind with folate-
receptors, and such ligands when conjugated with exogenous molecules are effective to
enhance transmembrane transport, such as via folate—mediated endocytosis as described
herein.
Additional analogs of folic acid that bind to folic acid receptors are described
in US Patent Application ation Serial Nos. 2005/0227985 and 2004/0242582, the
disclosures of which are incorporated herein by reference. Illustratively, radicals of such
folate analogs have the general formula:
R6 R7 R6 R7
(A2>‘r‘”n\,
AW‘16
wherein
X and Y are each—independently selected from the group consisting of halo,
R2, 0R2, SR3, and NR4R5;
U, V, and W represent divalent moieties each independently selected from the
group consisting of (R6a)C=, N=, (R6a)C(R7a), and N(R4a);
Q is selected from the group consisting of C and CH;
T is selected from the group consisting of S, O, N, NH, and —C=C-;
A1 and A2 are each independently selected from the group consisting of
oxygen, sulfur, C(Z), C(Z)O, OC(Z), N(R4"), C(Z)N(R4b), N(R4b)C(Z), OC(Z)N(R4"),
C(Z)O, N(R4b)C(Z)N(R5b), S(O), S(O)2, N(R4a)S(O)2, C(R6b)(R7b), N(CECH),
N(CH2CECH), C1—C12 alkylene, and C1—C12 alkyeneoxy, where Z is oxygen or sulfur;
R1 is ed-from the group consisting of hydrogen, halo, C1-C12 alkyl, and
C1—C12 alkoxy; R2, R3, R4, R4a, R4b, R5, RS", R6b, and R7b are each independently selected
from the group consisting of en, halo, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 yl,
C1-C1; l, C1-C12 alkynyl, ; alkoxy)carbonyl, and (C1-C12 alkylamino)carbony1;
R6 and R7 are each independently selected from the group ting of
hydrogen, halo, C1-C12 alkyl, and C1-C12 alkoxy; or, R6 and R7 are taken together to form a
carbonyl group; R621 and R721 are each independently selected from the group consisting of
hydrogen, halo, C1-C12 alkyl, and C1-C12 alkoxy; or R621 and R721 are taken together to form a
carbonyl group;
L is one or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, amino acids; and
n, p, r, s and t are each independently either 0 or 1.
As used herein, it is to be understood that the term folate refers both
individually to folic acid used in forming a conjugate, or alternatively to a folate analog or
derivative thereof that is capable of binding to folate or folic acid receptors.
In r embodiment, the targeting group is a PSMA ligand or inhibitor,
such as a derivative of pentanedioic acid of the formula:
H020 X
n X is RP(O)(OH)CH2— (US. 5,968,915); RP(O)(OH)N(R1)— (US. 5,863,536);
RP(O)(OH)O— (US. 877); RN(OH)C(O)Y— or RC(O)NH(OH)Y, wherein Y is
—CR1R2—, —NR3— or —0— (US. 5,962,521); RS(O)Y, RSOzY, or RS(O)(NH)Y, wherein Y is
—CR1R2—, —NR3— or —0- (US. 5,902,817); and RS-alkyl, wherein R is for example hydrogen,
alkyl, aryl, or arylalkyl, each of which may be optionally substituted (J. Med. Chem.
46:1989—1996 (2003)).
In each of the foregoing formulae, R, R1, R2, and R3 are each independently
selected from hydrogen, C1-C9 straight or branched chain alkyl, C2—C9 straight or branched
chain alkenyl, C3-C8 cycloalkyl, C5—C7 lkenyl, and aryl. In addition, in each case, each
of R, R1, R2, and R3 may be optionally substituted, such as with one or more groups selected
from C3-C8 cycloalkyl, C5—C7 lkenyl, halo, hydroxy, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, C2—C6 straight or branched chain alkenyl, C1-C4 alkoxy,
C2—C4 alkenyloxy, phenoxy, benzyloxy, amino, aryl. In one , aryl is selected from
1—naphthyl, 2-naphthyl, lyl, 3—indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2—pyridyl,
3—pyridyl, 4-pyridyl, benzyl, and phenyl, and in each case aryl may be optionally substituted
with one or more, illustratively with one to three, groups selected from halo, hydroxy, nitro,
trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 ht or branched chain
alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino. In one ion
of each of the above formulae, R is not hydrogen.
Illustrative PSMA ligands (US. 5,968,915) include
2—[[methylhydroxyphosphinyl]methyl]pentanedioic acid;
2—[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;
2—[[propylhydroxyphosphinyl]methyl]pentanedioic acid;
2—[[butylhydroxyphosphinyl]methyl]pentanedioic acid;
2—[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;
2—[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;
2—[[2-(tetrahydrofuranyl)hydroxyphosphinyl]methyl] pentanedioic acid;
2—[[(2-tetrahydropyranyl)hydroxyphosphinyl]methyl] edioic acid;
2—[[((4-pyridyl)methyl)hydroxyphosphinyl]methyl] pentanedioic acid;
2—[[((2-pyridyl)methyl)hydroxyphosphinyl]methyl] pentanedioic acid;
2—[[(phenylmethy1)hydroxyphosphinyl]methyl] pentanedioic acid;
2—[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl] pentanedioic acid;
3-phenylpropyl)methyl)hydroxyphosphinyl]methyl] pentanedioic acid;
2-[[((3-phenylbutyl)methy1)hydroxyphosphinyl]methyl] pentanedioic acid;
2-phenylbutyl)methyl)hydroxyphosphinyl]methyl] pentanedioic acid;
2-[[(4-phenylbuty1)hydroxyphosphinyl]methyl]pentanedioic acid; and
2—[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid.
Illustrative PSMA ligands (U.S. 5,863,536) include
N-[methylhydroxyphosphinyl]glutamic acid; N-[ethylhydroxyphosphinyl]glutamic acid;
N—[propylhydroxyphosphinyl]glutamic acid; N-[butylhydroxyphosphinyl]glutamic acid;
N-[phenylhydroxyphosphinyl]glutamic acid; N-[(phenylmethyl)hydroxyphosphinyl]glutarnic
acid; N-[((2-phenylethyl)methyl)hydroxyphosphinyl]glutamic acid; and
N-methyl—N-[phenylhydroxyphosphinyl]glutamic acid.
Illustrative PSMA ligands (US. 5,795,877) include
2—[[methylhydroxyphosphinyl]0xy]pentanedi0ic acid;
2—[[ethylhydroxyphosphinyl]oxy]pentanedioic acid;
2—[[propylhydroxyphosphinyl]0xy]pentanedi0ic acid;
2—[[butylhydroxyphosphinyl]oxy]pentanedi0ic acid;
2—[[phenylhydroxyphosphinyl]oxy]pentanedi0ic acid;
2—[[((4-pyridyl)methyl)hydr0xyph0sphinyl]oxy]pentanedi0ic acid;
2-[[((2-pyridyl)methyl)hydr0xyph0sphinyl]oxy]pentanedi0ic acid;
2-[[(phenylmethyl)hydr0xyph0sphinyl]oxy]pentanedi0ic acid; and
2[[((2—pheny1ethyl)methyl)hydr0xyph0sphinyl]oxy] pentanedioic acid.
Illustrative PSMA ligands (US. 5,962,521) include
2—[[(N—hydroxy)carbam0yl]methyl]pentanedi0ic acid;
—hydroxy-N—methyl)carbamoyl]methyl]pentanedi0ic acid; 2-[[(N-butyl-N-hydr0xy)
carbamoyl]methyl]pentanedioic acid;
2—[[(N—benzyl-N-hydroxy)carbanioyl]methyl]pentanedi0ic acid;
2—[[(N—hydroxy-N-phenyl)carbamoyl]methyl]pentanedi0ic acid;
2—[[(N—hydroxy-N—2-phenylethyl)carbanioyl]methyl]pentanedi0ic acid;
2—[[(N—ethyl-N-hydr0xy) carbamoyl]methyl]pentanedi0ic acid;
2—[[(N—hydroxy-N—propyl)carbamoyl]methyl]pentanedi0ic acid;
2—[[(N—hydroxy-N-S-phenylpr0pyl)carbam0yl]methyl]pentanedi0ic acid;
2—[[(N—hydroxy-N—4—pyridyl) carbamoyl]methyl]pentanedi0ic acid;
2—[[(N—hydroxy)carb0xamid0]methyl]pentanedi0ic acid; 2-[[N-hydr0xy (methyl)
carboxamido]methyl]pentanedioic acid; 2-[[N-hydr0xy (benzyl)
carboxamido]methyl]pentanedi0ic acid;
hydroxy(pheny1)carboxamido]methyl]pentanedioic acid;
hydroxy(2-phenylethyl)carboxamido]methyl]pentanedi0ic acid;
2—[[N—hydroxy(ethyl)carboxamido]methyl]pentanedi0ic acid; 2-[[N-hydr0xy(propyl)
amido]methyl]pentanedi0ic acid; 2-[[N-hydr0xy (3-phenylpr0pyl)
carboxamido]methyl]pentanedioic acid; and
2—[[N-hydroxy(4-pyridyl)carboxamido]n1ethyl]pentanedi0ic acid.
Illustrative PSMA s (US. 5,902,817) include
2—[(sulfinyl)methyl]pentanedioic acid; 2-[(methylsulfinyl)methyl]pentanedi0ic acid;
2—[(ethylsulfinyl)methyl]pentanedi0ic acid; 2-[(propylsulfinyl)methyl]pentanedi0ic acid;
2—[(butylsulfinyl)methyl]pentanedi0ic acid; 2-[(phenylsulfinyl]methyl]pentanedi0ic acid;
2—[[(2-phenylethyl)sulfinyl]methyl]pentanedioic acid;
2—[[(3 -phenylpropyl)sulfinyl]methyl]pentanedioic acid;
2—[[(4-pyridyl)sulfinyl]methyl]pentanedioic acid; 2-[(benzylsulfinyl)methyl]pentanedioic
acid; 2-[(sulfonyl)methyl]pentanedioic acid; 2-[(methylsulfonyl)methyl]pentanedioic acid;
hylsulfonyl)methyl]pentanedioic acid; 2-[(propylsulfonyl)methyl]pentanedioic acid;
2—[(butylsulfonyl)methyl]pentanedioic acid; 2-[(phenylsulfonyl]methyl]pentanedioic acid;
-phenylethyl)sulfonyl]methyl]pentanedioic acid;
2-[[(3-pheny1propyl)sulfonyl]methyl]pentanedioic acid; 2-[[(4-pyridyl)
sulfonyl]methyl]pentanedioic acid; nzylsulfonyl)methyl]pentanedioic acid;
2—[(sulfoximiny1)methyl]pentanedioic acid; 2-[(methylsulfoximinyl)methyl]pentanedioic
acid; 2-[(ethylsulfoximinyl)methyl]pentanedioic acid;
opylsulfoximinyl)methyl]pentanedioic acid; 2-[(butylsulfoximinyl)methyl]pentanedioic
acid; 2-[(phenylsulfoximinyl]methyl]pentanedioic acid;
2—[[(2-phenylethyl)sulfoximinyl]methyl]pentanedioic acid; 2-[[(3—phenylpropyl)
sulfoximinyl]methyl]pentanedioic acid; 2-[[(4-pyridyl)sulfoximinyl]methyl]pentanedioic
acid; and 2-[(benzylsulfoximinyl)methyl]pentanedioic acid.
Illustrative PSMA ligands include
O HOZC
H020 ('DHOH HOZC |\OH P\
OH HOZC I OH
H02C CO2H CO2H
E O
HCO H020 I\/\ HOZC |\/\COZH
2 OH OH
c02H OOH2 COZH COZH
HOZC COZH HOZC COZH H02C
In another embodiment, the PSMAHligand1s a urea of two amino acids. In one
aspect, the amino acids include one or more additional carboxylic acids. In another
ment, the amino acids include one or more additional phosphoric, phosphonic,
phosphinic, sulfinic, sulfonic, or boronic acids. In another aspect, the amino acids include
one or more thiol groups or derivatives thereof. In another aspect, the amino acids include
one or more carboxylic acid bioisosteres, such as tetrazoles and the like.
In another embodiment, the PSMA ligand is a compound of the formula:
AJL/Fv
HOZC N N
H H
where R1 is
/ \
RSI N\R
Bu COzH COZH
R=H, CHzCHzCN
* N
COZH / \N
COZH I;
R—H, OH_
R=H, OH
In another illustrative embodiment, the binding agent is a urea of an amino
dicarboxylic acid, such as aspartic acid, glutamic acid, and the like, and another amino
dicarboxylic acid, or an analog thereof, such as a binding agent of the formulae
~k *
HOOCHim HOOC
O ( ”\O O f0 NJLN)m 0 ( n\0
QJLN COOH HOOC NJLN COOH 5 COOH
H H H H H H H
n Q is a an amino dicarboxylic acid, such as aspartic acid, glutamic acid, or an analog
thereof, n and m are each independently selected from an integer between 1 and about 6, and
(*) represents the point of attachment for the linker L.
Illustratively, the PSMA ligand is a compound of the formulae:
g COOH
0 9
”0’38” 3J
HOPbH9f ”0Pal/V300” OOH COOH HOPbH COOH
00°” C00”
COOH COOH COOH
... C00” HOOCN 5... C00” EVEL/fl (PK/6
Hooc P\0H COOH HOOC PbH COOH
COOH COOH COOH COOH HNN,NN
HJLN fiCOOH HS
° f ° :
Hoocrinjku fiCOOHHOOC1H\NfiCHHOoci 8}Ni”: HuirmNfiC
DUPA MUPA
In another embodiment, the PSMA ligand is 2-[3-(1-Carboxymercapto-
ethy1)—ureido]—pentanedioic acid (MUPA) or 2—[3—(1,3—Dicarboxy—propyl)—ureido]—
pentanedioic acid .
Other illustrative examples of PSMA ligands include peptide analogs such as
quisqualic acid, aspartate glutamate (Asp-Glu), Glu-Glu, Gly-Glu, y-Glu-Glu, beta-N-acetyl—
L—aspartate-L—glutamate (B-NAAG), and the like.
In another embodiment, the PSMA ligand comprises a urea or thiourea of
lysine and an amino acid, or one or more carboxylic acid tives thereof, including, but
not limited to ureas or eas of lysine and aspartic acid, or glutamic acid, or
homoglutamic acid.
In another embodiment, the PSMA ligand comprises a urea or thiourea of L-
lysine and L-glutamate.
In another embodiment, the PSMA ligand comprises a compound selected
from the following
COZH COZH
K: K
o 902H 002H
HOZCANJLNWNHZ JOL
HOZCAN NWNHZ
H H H H
COZH COzH
In another embodiment, the PSMA ligand comprises the following
K o COZH
The compounds, s, ediates, and conjugates described herein may
be prepared using conventional processes, including the described in ational Patent
Publication Nos. WO 02993,
2006/012527, and US. Patent Appl. No. 13/837539 (filed March 15, 2013). The disclosures
of each of the foregoing are herein incorporated by reference in their entirety.
Each publication cited herein is incorporated herein by reference.
In another embodiment, a method is described for diagnosing and/or
monitoring a e or disease state Where the method comprises the steps of administering
to a patient being evaluated for the disease state an effective amount of a conjugate of the
general formula B-L-P. The method includes allowing sufficient time for the conjugate to
bind to the target tissue, and diagnosing and/or monitoring the disease or disease state extra-
corporeally, such as by using on on tomography.
The radionuclide may include a positron-emitting isotope having a suitable
half-life and toxicity profile. In various embodiments, the radioisotope has a half-life of more
than 30 minutes, more than 70 minutes, more than 80 minutes, more than 90 minutes, more
than 100 minutes, less than 8 hours, less than 6 hours, less than 4 hours, or less than 3 hours.
In other embodiments, the radioisotope has a half-life of about 30 minutes to about 4 hours,
about 70 minutes to about 4 hours, about 80 minutes to about 4 hours, about 90 minutes to
about 4 hours, about 100 minutes to about 4 hours, about 30 minutes to about 6 hours, about
70 s to about 6 hours, about 80 minutes to about 6 hours, about 90 minutes to about 6
hours, about 100 minutes to about 6 hours, about 30 minutes to about 8 hours, about 70
minutes to about 8 hours, about 80 minutes to about 8 hours, about 90 minutes to about 8
hours, or about 100 minutes to about 8 hours.
The uclide may include one or more positron-emitting isotopes, such as
but not limited to isotopes selected from 89Zr, 45Ti, 51Mn, 64Cu, 61Cu, 63Zn, 82Rb, 68Ga, 66Ga,
11C, ”N, 15O, 12“I, 34C1, and 18F. In another embodiment, the radionuclide is a halide, such as
a positron-emitting halide. In another ment, the radionuclide is a metal ion, such as a
positron-emitting metal ion. In another embodiment, the radionuclide is a gallium ion, such
as a positron-emitting gallium ion. In another embodiment, the radionuclide is ed from
89Zr, 64Cu, 68Ga, 66Ga, 1241, and 18F. In another illustrative embodiment, the radioisotope is
selected from 89Zr, 64Cu, 68Ga, 12“I, and 18F. In another embodiment, the radioisotope is 68Ga,
or 89Zr, or 18F. In another embodiment in each of the foregoing and following embodiments
described herein, the radioisotope is 68Ga. In another embodiment in each of the foregoing
and following embodiments described herein, the sotope is 18F. In another embodiment
in each of the foregoing and following embodiments described herein, the radioisotope is
89Zr. In another embodiment in each of the foregoing and ing embodiments described
herein, the radioisotope is 64Cu. It is also to be understood that the fluorine isotopes
described herein may be selected from various isotopic ations of 18F and 19F. It is
understood that factors that may be included during selection of a suitable isotope include
sufficient half-life of the positron-emitting isotope to permit ation of a stic
composition in a pharmaceutically acceptable carrier prior to administration to the patient,
and sufficient remaining half-life to yield sufficient activity to permit extra-corporeal
measurement by a PET scan. Further, a suitable e should have a sufficiently short half-
life to limit patient exposure to unnecessary radiation. In an illustrative embodiment, 18F,
having a ife of 110 minutes, es adequate time for preparation of the diagnostic
composition, as well as an acceptable deterioration rate. r, on decay 18F is converted to
Illustrative positron—decaying isotopes having suitable half-lives include 34Cl,
half-life about 32 s; 45Ti, half-life about 3 hours; 51Mn, ife about 45 minutes;
61Cu, half—life about 3.4 hours; 63Zn, half-life about 38 minutes; 82Rb, half-life about 2
minutes; 68Ga, half-life about 68 minutes, 66Ga, half-life about 9.5 hours, 11C, half-life about
minutes, 150, half-life about 2 minutes, 13N, half—life about 10 minutes, or 18F, half-life
about 110 minutes.
In another embodiment, the radionuclide is a radiotherapy agent. Illustrative
radionuclides for radiotherapy include isotopes of lutetium such as 177Lu, isotopes of yttrium,
such as 90Y, isotopes of copper, such as 67Cu and 64Cu, and the like.
The uclide may be covalently attached to the conjugate, such as to an
aryl or heteroaryl ic group, ing benzamidyl, benzylic, phenyl, pyridinyl,
pyrimidinyl, pyridazinyl, naphthyl, benzothiazolyl, benzimizolyl, azolyl, and like
groups. In one illustrative embodiment, the radioisotope is 18F and the radionuclide includes
an aryl group to which the radioisotope is covalently attached.
The radionuclide may be non-covalently attached to the conjugate, such as
within a chelate.
The methods may also be used in combination with any other methods of
cancer diagnosis already developed and known in the art, including methods using other
already developed diagnostic agents and utilizing x—ray computed tomography (CT),
magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI),
ultrasound, and single photon emission ed tomography (SPECT).
It is understood that in certain applications of the methods described ,
each of the processes and synthetic s described herein either substantially complete
fluorination, or alternatively only partial fluorination may be desired. Accordingly, the
processes and synthetic methods described herein may be performed in various alternative
ments. It is therefore understood that in those aspects where only partial fluorination
is desired, the processes and syntheses described herein may be performed with less than
stoichiometric s of ating agent. Similarly, it is understood that in certain
applications of the s described herein, each of the processes and synthetic methods
described herein either substantially complete radiofluorination, or alternatively only partial
uorination may be desired. Accordingly, the processes and synthetic methods
described herein may be performed in various ative embodiments. It is therefore
tood that in those aspects where only l radiofluorination is desired, the processes
and syntheses described herein may be performed with less than stoichiometric amounts of
radiofluorination agent, where the balance is optionally 19F.
The following examples r illustrate specific embodiments of the
invention; however, the following illustrative examples should not be interpreted in any way
to limit the invention.
EXAMPLES
WO 73678
General. Water was distilled and then deionized (18 MQ/cm2) by passing
through a Milli-Q water filtration system (Millipore Corp., Milford, MA). All chemicals and
solvents, unless specified, were purchased from Sigma (St. Louis, MO) and were used
without further purification. Amino acids were purchased from Chem-Impex Int (Chicago,
IL). 2,2'—(7-(2-((2,5-dioxopyrrolidinyl)oxy)oxoethyl)—1,4,7-triazonane—1,4-diyl)diacetic
acid (NOTA-NHS) was purchased from CheMatech (France). NlO—TFA-Pteroic Acid was
provided by Endocyte, Inc. erformance liquid tography (HPLC) analysis and
purification of the OTA precursor were performed on an Agilent G6130B
instrument. The radioactive HPLC was performed with a y-counter using a Xselect CSH C18
(250x10 mm) column and MeCN and 0.1% Formic Acid as mobile phases.
OZN O NaBH4 OZN BOC-ONO N2
_> —>
HZN OMe MeOH H2N OH CHsCN
BocHN OH
0004010 0004011
CIH—I:'\\N>_,BOOONCH3CN >—\ 3°C[TEE—$57M
ONaBH(OAc)3
60-90% Bil—NE? 02N4< BOCHN CICHZCHZCI
2 800 3
0004001 01B”
0 O
4MHC| ’ ‘WLQNO. O'Bu
Br’Y tBuO NJ H;
o _.
_. y m
dioxane </HN N MGOH
DIPEA,DMF O N N02
0004014 </N
S40 Qc 4o 0 51
O‘Bu O‘Bu
i50.1. on 0A 0
13” NAO’BU
gmNWNW[Buoh 0
9&0 0004016 06:)WNWNMOH0004018
‘Buo ‘Buo
EXAMPLE. C—NETA. tert—Butyl [2—Hydroxy—1—(4—
nitrobenzyl)ethyl]carbamate (QC04011) was prepared from the commercially available
methyl 2-amino(4-nitrophenyl)propanoate through NaBH4 reduction and Boc- protection.
Successive artin oxidation and reductive amination with QC04001 afforded tris-Boc
protected nd QC04013, which was transformed to QC04014 after Boc- deprotection
in 4 M HCl in dioxane. Treatment of QC04014 with tert—butyl bromoacetate, ed by
hydrogenolysis of the N02 group provided QC04016. Further reaction of QC04016 with
succinic anhydride provided the bifunctional C—NETA (QC04018) as the corresponding tert—
butyl ester.
QC04001
EXAMPLE. Di-tert—butyl [1,4,7]Triazanonane-1,4-dicarboxylate (QC04001).
QC04001 was prepared according to a modification of a synthetic procedure reported
previously.[19-21] To a solution of 1,4,7-triazonane trihydrogenchloride (TACN'3HCl, 1.85
g, 7.7 mmol, M.W.:238.6) in CHCl3 (25 mL) was added DIPEA (4.0 mL, 3.0 g, 23.1 mmol,
M.W.: 129.24, d: 0.742) and BOC-ON (3.77 g, 15.3 mmol, M.W.: ) in portions. The
resulting mixture was stirred for 5 days and the t evaporated under vacuum. The
residue was partitioned between 10% NaOH solution (10 mL) and diethyl ether (30 mL). The
ether layer was separated and washed with 10% NaOH solution (10 mL) and water (10 mL)
several times. The ether layer was dried (MgSO4), filtered, and concentrated under vacuum to
provide QC04001 (2.53 g, quantitative), which was used without furher purification. 1H
NMR (400 MHz, CDC13) 5 = 3.47—3.50 (m, 2 H), 3.42—3.45 (m, 2 H), 3.38 (br, s, 1 H), 3.28—
3.34 (m, 2 H), 3.16—3.28 (m, 2 H), 2.86—2.99 (m, 4 H), 1.48 (s, 18 H); 13C NMR (101 MHz,
CDCl3) 8 = , 155.85 (C = O), 79.80, 79.70 ("Bu), 53.20, 52.62, 52.52, 51.78, 50.50,
49.91, 49.63, 48.39, 48.23, 47.83, 47.46 (TACN ring from 5320—4746), 28.60 (t'Bu).
>_(O OZN4©—>_\_> 02N4©—>_\
HZN OMe "‘2N OH BocHN OH
0004010 Qco4o11
EXAMPLE. tert-Butyl [2-Hydroxy—1-(4-nitrobenzyl)ethyl]carbamate
(QC04011)[19]. With minor revision to the reported procedure,[19] where the HCl salt of
methyl 2-amino-3—(4-nitrophenyl)propanoate was used directly without neutralization with
Et3N, to a solution of the methyl 2-amino—3 -(4-nitrophenyl)propanoate hydrochloride salt
(6.22 g, 23.9 mmol) in MeOH (70 mL) at 23 0C was added NaBH4 (2.86 g, 71.4 mmol) in
multiple ns. The reaction was monitored by TLC and LC-MS. The mixture was heated
to reflux (with water bath at ~ 70 0 C), and NaBH4 was added portion-wise as needed until
most of the starting al eared, requiring about 6 grams of NaBH4 in total. After
evaporation of the solvent, the residue was treated with H20 (70 mL) and extracted with
DCM/IPA (3/ 1). The combined organic layer was dried, filtered, and concentrated under
vacuum to provide white solid QC04010 (4.4 g, 94), which was used t r
cation.
EXAMPLE. QC04010 (4.4 g, 22.7 mmol) was dissolved in CH3CN (30 mL)
at ambient temperature, to which was added BOC-ON (11.2 g, 27.2 mmol, 12 eq.)
portionwise. To the above mixture was added DIPEA (5.24 mL, 3.76 g, 29.2 mmol, M.W.:
129.24, d: 0.742), the resulting e was stirred for 4 h and evaporated. The residue was
partitioned between ether (50 mL) and 10% NaOH solution (20 mL). The ether layer was
separated and washed with 10% NaOH solution (10 mL) and water (10 mL) sequentially. The
ether layer was dried, ed, and concentrated under vacuum. The residue was washed with
ether (20 mL) to e QC04011 (5.31 g, 75%), which was used without further
purification. To prepare an analytical sample, the residue is purified via column
chromatography on $102 g with Hexane/Ethyl e (3/1 to 1/1 with 1% of MeOH) to
afford pure QC04011 as a white solid. 1H NMR (400 MHZ, CDCl3) 6 = 8.15 (d, J = 8.8 MHZ,
2 H), 7.40 (d, J=8.8 MHZ, 2 H), 4.84 (d, J: 6.8 MHZ, 1 H), 3.90 (s, 1 H), 3.68 (dd, J: 3.1
MHZ, 1 H), 3.57 (dd, J: 3.1 MHZ, 1 H), 2.98 (d, J = 6.0 MHZ, 2 H), 1.39 (s, 9 H); 13C NMR
(101 MHZ, CDCl3) 5 = 156.0, 146.4, 146.2, 130.1, 123.5, 79.8, 63.3, 53.1, 37.3, 28.0.
OZN —> 02N
BocHN 0H BocHN \o
Qco4o11 QC04012
EXAMPLE. tert-Butyl (1-(4-nitropheny1)oxopropanyl)carbamate.
QC04011 (1.27 g, 4.3 mmol) was dissolved in CH2Clz (40 mL), and cooled to 0 °C, to which
Dess—Martin periodinane (1.70 g, 5.16 mmol, 1.2 equiv) was added in one portion. After
stirring for 15 min at 0 0C, the reaction was warmed to 23 0C and stirred for 45 min. The
reaction was quenched by addition of a basic aq Na2S203 solution (50/50, v/v of aq NazszO3
and aq NazHCO3), and the ing mixture was vigorously stirred for 15 min. After
extraction with CH2C12 (3 x), the organic phases were washed successively with water and
brine, dried overNast4, filtered and concentrated in vacuo to provide QC04012, which was
used without further purification.
BOON mm aCJioBocl—\N N02
</Boc BocHN
QCMM2
QC04001 0604013
EXAMPLE. Reductive amination of QC04012 and QC04001 to prepare
QC04013 :4. 1 ,4-Di-tert-buty1 7-(2- { [(tert-Butoxy)carbonyl]amino} 3-(4-nitrophenyl)
propyl)-1,4,7-triaZ0nane-1,4-dicarboxylate (QC04013): nd QC04012 (4.3 mmol in
theory) was added to a solution of QC04001 (1.40 g, 4.3 mmol) in DCE (100 mL) at 0 °C .
The ing solution was stirred for 10 min and sodium toxyborohydride (1.28 g, 6.02
mmol, 1.4 eq.) was added portionwise to the solution over 30 min. The mixture was stirred at
ambient temperature ght. The reaction mixture was concentrated, treated with a
WO 73678
saturated aqueous solution of NaHCO3 (50 mL), and extracted with ethyl acetate (3 x 50 mL).
The combined organic layers were dried with NazSO4, ed, and trated in vacuo.
The residue was purified via flash chromatography (SiOz, Hex/EA = 3/1) to provide
QC04013 (2.31 g, 88.5 % for 2 steps, based on 2.61 g in theory) as a pale yellow semi-solid.
1H NMR (400 MHz, CDC13) 5 = 8.11 (2 H, d, J = 7.6 Hz), 7.35 (2 H, d, J = 7.6 Hz), 5.28 (1
H, s, br), 3.54—3.88 (2 H, m), 3.39—3.54 (2 H, m), 3.32—3.40 (1 H, m), 3.15-3.32 (2 H, m),
2.79—3.15 (4 H, m), 2.37—2.73 (6 H, m), 1.43 (9 H, s), 1.42 (9 H, s), 1.38 (9 H, s); 13C NMR
(101 MHz, CDC13) 5 = 156.15, , 155.70, 155.56, 147.00, 146.95, 146.81, 146.76,
130.36, 123.73, 123.65, 123.60, 80.07, 79.99, 79.92, 79.81, 79.57, 79.46, 60.79, 60.47,
55.52, 54.33, 54.06, 53.64, 53.15, 53.28, 51.54, 50.80, 50.71, 50.42, 49.87, 49.07, 48.12,
39.67, 39.45, 28.74, 28.61. MS m/z: MS—API: Calcd. for C30H50N508 ([M+H]+): 608.4,
Found: 608.3;
NHBoc
Bee 1 \ HCI/Dioxane
N02—>NHH
</BOC QC04013 4HC|
QC04014
EXAMPLE. 1-(4—Nitrophenyl)-3 -(1,4,7-triazonanyl)propanamine.
3 (2.31 g, 3.8 mmol) was dispersed in 30 mL of 4 M HCl/Dioxane, the resulting
mixture was stirred at room temperature for 20 hours. The reaction e was rapidly
added to cold EtzO to precipitate a white solid. The solid was collected and dried in air to
afford the pure product QC04014 (1.71 g, in quantitative yield) as a pale-white solid. MS
m/z: MS-API: Calcd. for C15H26N502 ([M+H]+): 3082, Found: 308.2;
o O
tB 1:BUO )LOtBu
.,01BBr/Nr u “2H ‘Wo W J4HCI <N/NJ >—<\/[—\
KPo QCO4015
Qco4o14 </KFO
‘BuO ‘BuO QCO4015
EXAMPLE. Introduction of the tri-tert-butyl ethylacetatelb. To a solution of
QC04014 (78 mg, 0.19 mmol) and DIPEA (0.272 mL, 202 mg, 1.56 mmol, 8.2 eq. M.W.:
129.24, d: 0.742) in DMF (2 mL) was added NaI (233.8 mg, 1.56 mmol, 8.2 eq. M.W.:
149.89) and tert-Butyl bromoacetate (0.126 mL, 168 mg, 0.86 mmol, 4.5 eq. M.W.: 195.05,
d: 1.321) slowly at room temperature. The resulting mixture was warmed to 60-70 °C and
stirred for 20 hs. After completion, monitored by TLC and LC-MS, the reaction was
ed by water and extracted with EtzO. The combined organic solvent was washed
successively with water and brine, and dried over Nast4. After filtration, the solvent was
evaporated under , and ing deep-colored oil residue was purified by flash
chromatography on SiOz (DCM/MeOH = 100/1-100/4) to provide QC04015 (14 mg, 10 %)
as a yellow oil and QC04015’ (61 mg, 49.4 %). MS m/z: MS—API: Calcd. for C39H66N5010
([M+H]+): 764.5, Found: 764.4;
O‘Bu otBu
OX O>‘OtBu Ojg jOtBu0
‘Buoh&WN%1atmOCNmWWZpd/C H2 ‘Bu0>_\ N
L L
tBUO QC04016
EXAMPLE. To a solution of 5 (20 mg, 0.039 mmol) in MeOH (2
mL) was added 10% Pd/C catalyst (5 mg). The resulting mixture was subjected to
hydrogenolysis by agitation with H2 (g) at 1 atm (~ 15 psi) at ambient temperature for 14 h.
The reaction e was diluted with excess DCM and filtered through celite, and the filtrate
was concentrated in vacuo to provide QC04016 (13 mg, 67.5 %). MS m/z: MS-API: Calcd.
for C39H63N508 ([M+H]+): 734.5, Found: 734.4;
FOLATE TARGETED EXAMPLES
o o 002Me
PyBOP DIPEA 0'3“
c W013“ DMSO 24°C_:2NHNJ/VL:f”
OCF3 (:OCF3
QC02023
N‘o-TFA-Pteroic Acid
EXAMPLE. (S)tert-butyl l-methyl 2-(4-(N-((2-aminooxo-3,4-
dihydropteridinyl)methyl)-2,2,2-trifluoroacetamido)benzamido)pentanedioate 23).
HCl-HzN-Glu(OtBu)-0Me (350 mg, 1.38 mmol) was added to a solution of A-Pteroic
Acid (560 mg, 1.37 mmol) and DIPEA (1.2 mL, 6.85 mmol) in DMSO (6.0 mL) at 23 0C
under N2. After stirring for 15 min at 23 °C, PyBOP (720 mg, 1.0 mmol) was added, and the
reaction mixture was stirred for 24 h at 23 OC. Volatile material was removed under reduced
vacuum to afford the crude product as a semi-solid, which was further purified via solid
extraction with Hex/EA (l/1) 3 times to provide QC02023 as a pale—yellow solid in
quantitative yield, which was used without further purification. Xmax = 280 nm; LC—MS
(Agilent G6130B Quadrupole : Mobile phase: Buffer (pH 7)-CH3CN; Column:
Analytic C18 column; Method: 0—100 CH3CN—15 min, U; = 5.62 min. MS m/z: :
Calcd. for C26H29F3N7O7 ([M+H]+): 608.2, Found: 608.1;
o 902Me 902Me
Poll—iN’VYOtB”O TFA/DCMCOCF3 —>HZNJ\HNJE ijiNWOHfCOCF3
Qcozozs 1/3, RT
QC02024
EXAMPLE. (S)-4—(4-(N-((2-amino—4-oxo—3,4-dihydropteridiny1)methy1)—
2,2,2-trifluoroacetamido)benzamido)methoxy-5—oxopentanoic acid (QC02024). 224 mg
of QC02023 was treated with TFA/DCM (15 mL, 1/3) at 23 OC. The reaction was stirred at
23 OC and monitored by TLC. After 1.5 hours, starting material was not observed by TLC.
The volatile material was removed under reduced pressure resulting in a semi-solid residue,
which was d with cold EtzO, to provide a pale white solid precipitate, which was
collected by filtration and dried in air to provide (S)(4-(N-((2-aminooxo-3,4-
dihydropteridinyl)methyl)-2,2,2-tn'fluoroacetamido)benzamido)-5 -methoxy
oxopentanoic acid QC02024 (169 mg, 83 % for 2 steps). 7mm = 280 nm; LC—MS (Agilent
G6130B Quadrupole : Mobile phase: Buffer (pH 7)-CH3CN; Column: Analytic C18
column; Method: 0—100 15 min, U; = 3.40 min. MS m/z: MS-API: Calcd. for
F3N7O7 ([M+H]+): 552.1, Found: 552.1; 1H NMR (400 MHz, DMSO) 5 = 12.16 (s, br,
1 H), 8.88 (d, J: 7.2 Hz, 1 H), 8.65 (s, 1 H), 7.92 (d, J: 8.0 Hz, 2 H), 7.64 (d, J: 8.0 Hz, 2
H), 7.16 (s, br, 1 H), 5.14 (s, 2 H), 4.38—4.55 (m, 1 H), 3.64 (s, 3 H), 2.28—2.40 (m, 2 H), 2.00-
2.12 (m, 1 H), 1.87—2.00 (m, 1 H); 13C NMR (101 MHz, DMSO) 5 = 173.91, 172.36, 165.93,
161.03, 156.11, 155.76 (d, J: 35.8 Hz), 154.19, 149.40, , 141.80, 134.30, 128.89,
128.62, 128.29, 117.91 (d, J = 48.5 Hz), 5390, 52.23, 52.06, 30.26, 25.81; 19F NMR (377
MHz, CDCl3) 5 = -62.87.
H2N N N EC 1777
C25H31N907
Exact Mass: 569.23
MOI. Wt.: 569.57
EXAMPLE. lu—Lys—OH (EC1777). EC1777 was prepared using solid
phase peptide synthesis as follows.
nd mmol Equivalent Molecular ty
Weight (grams)
Fmoc-Lys—Resin 0.5 1 1.00
(Loading
~0.5mmol/g)
FmOC-Glu-O‘Bu 425-5 0426
NIO-TFA-Pteroic 0.65 1.3 408 0.265
PyBOP 520.31
DIPEA 1.5 3 129.24 0.168
(d=0.742)
In a peptide synthesis vessel, Fmoc-Lys-resin (1.0g, 0.5mmol) was placed and
washed with DMF (3 X 10 ml). Initial Fmoc deprotection was performed using 20%
piperidine in DMF (3 x 10 ml) solution for 10 mins per cycle. Subsequent washes of DMF (3
X 10 ml) and i-PrOH (3 X 10 ml), a Kaiser test was done to determine reaction completion.
Following another DMF wash (3 x 10 ml); an amino acid solution (2.0 eq.) in DMF, PyBOP
(2.0 eq.) and DIPEA (3.0 eq.) were added to the vessel and the solution bubbled with Argon
for 1 hour. The coupling solution was filtered, the resin was washed with DMF (3 x 10 ml)
and i-PrOH (3 X 10 ml) and a Kaiser test was done to assess reaction completion. The above
process was performed successively for the additional coupling. Resin cleavage was
performed with a cocktail consisting of 95% CF3CO2H, 2.5% H20 and 2.5%
triisopropylsilane. The cleavage il (10 ml) was poured onto the resin and bubbled with
Argon for 30 mins, followed by filtration into a clean flask. Further ge was performed
twice successively with fresh cleavage cocktail for 10 mins of bubbling. The combined
filtrate was poured onto cold diethyl ether, the precipitate formed was collected by
centrifugation at 4000 rpm for 5 mins (3X). The itate was obtained following decanting
and drying of the solid under vacuum. Deprotection of the trifluoro-acetyl group was
ed by dissolving the crude itate in H20 (15 ml), which was basified with
Na2CO3 to pH 9 with Argon ng. Upon completion of the reaction, confirmed by
LCMS, the solution was acidified to pH 3 using 2 M HCl and the desired linker was purified
by preparative HPLC (mobile phase A = 10mM Ammonium acetate, pH = 5; Organic phase
B = Acetonitrile; Method; 10% B to 100%B in 30 mins) to yield EC 1777 (112 mg, 39%); 1H
NMR (500 MHz DMSO—d6) Pivotal s: 5 8.60 (s, 1H), 7.58 (d, 2H), 6.60 (d, 2H), 4.45
(s, 2H). [M+H]+ = Calculated 570.23, found 570.582
0 QOZH H H H
' N N N
HNJK/[NjAN o cogH 8 NJ
H2NJ\\N H
N/ H020J
E01778
C45H57N13O138
Exact Mass: 9
Mol. Wl.: 1020.08
EXAMPLE. Pte-yGlu-Lys—NOTA. In a dry flask, EC 1777 (30.5 mg, 0.054
mmol, 1.0 eq.), 1,1,3,3-tetramethy1guanidine (13.45 ul, 0.107 mmol, 2.0 eq.) and DMSO (2.5
ml) under Argon were sonicated for 1 hour. DIPEA (0.19 ml, 1.07 mmol, 20 eq.) was added
to the on, followed by sonication for an addition hour. To the transparent solution was
added p—SCN—Bn—NOTA.3HCl (33 mg, 0.059 mmol, 1.1 eq.) and the on was moitored
until completion by LCMS and purified using ative HPLC (mobile phase A = 10mM
Ammonium acetate, pH = 5; Organic phase B = Acetonitrile; Method; 10% B to 100%B in
mins) to yield EC 1778 (16 mg, 29%). 1H NMR (500 MHz DMSO-d6) Pivotal s: 8
8.60 (s, 1H), 7.58 (d, 2H), 7.29 (d, 2H), 7.07 (d, 2H), 6.61 (d,2H), 4.45 (s, 2H), 4.20 (t, 1H).
[M+H]+ = Calculated 1020.39, found 1020.63.
EXAMPLE. Pte-yGlu-Lys-NOTA -Al-18F is prepared by reaction of Pte-
yGlu-Lys—NOTA with A118F3-3H20 (1 step method) or with 3H20 followed by
reaction with NalSF (2 step method) using published processes.
0 _
TENT” H
O 1 O
H2N \N N/ OJNCF3
be\ &
N NH
EXAMPLE. N10-TFA-Pte—yGlu-OtBu-Arg(be)-Arg(be)-Lys(Mtt)—resin 3.
The general procedure described for the synthesis of resin bound folate-peptide resin 1 was
followed for the coupling of 2X Fmoc-L—Arg(be)—OH, Fmoc-Glu-OtBu, and N10-TFA-Pte—
OH to —Lys(Mtt)—Wang resin.
HZN NH
o J::j)Lm/\¢Ajy ; H
N O ;If\/A\/ jS],N\[::L\/<é{_\NACOZF
HQN N N NH H020
HZN/L3NH
E02217
C571-181N21O15S
Exact Mass: 1331 .59
Mol. Wt: 1332.45
EXAMPLE. Pte-yGlu-Arg—Arg-Lys-Bn-NOTA 4 (EC2217). In a peptide
synthesis vessel, A—Pte-yGlu-OtBu—Arg(be)-Arg(be)-Lys(Mtt)-resin (0.28g,
0.07mmol) was placed and washed with DCM (3 x 10 m1). Selective Mtt deprotection was
performed by adding a 2% CF3C02H/ DCM solution to the vessel and bubbling with Argon
for 10 min. After filtering, the resin was washed with dichloromethane followed by a fresh
solution of 2% H/ DCM. This process was repeated until there was no more yellow
solution being yielded and a Kaiser test was done. Following a DMF wash (3 X 10 ml); p-
SCN-Bn-NOTA.3HC1 (50 mg, 0.09 mmol, 1.2 eq.) in DMF, and DIPEA (80 ul, 0.45 mmol,
6.0 eq.) were added to the vessel and the solution bubbled with Argon for 2 hour. The
coupling solution was filtered, the resin was washed with DMF (3 x 10 m1) and i-PrOH (3 x
ml) and a Kaiser test was done to assess reaction completion. Resin cleavage/global tert-
butyl ester ection was performed with a cocktail consisting of 95% CF3COzH, 2.5%
H20 and 2.5% triisopropylsilane. The cleavage cocktail (10 ml) was poured onto the resin
and bubbled with Argon for 60 mins, followed by filtration into a clean flask. Further
cleavage was performed twice successively with fresh ge cocktail for 20 mins of
bubbling. The combined filtrate was poured onto cold diethyl ether, the precipitate formed
was ted by centrifugation at 4000 rpm for 5 mins (3x). The precipitate was obtained
following decanting and drying of the solid under vacuum. Deprotection of the ro-
acetyl group was achieved by dissolving the crude precipitate in H20 (15 ml), which was
basified with NazCO3 to pH 9 with Argon bubbling. Upon completion of the reaction,
confirmed by LCMS, the solution was acidified to pH 5 using 2 M HCl and the desired linker
was purified by preparative HPLC (mobile phase A = 10mM Ammonium acetate, pH = 5;
Organic phase B = itrile; Method; 10% B to 100%B in 30 mins) to yield EC2217
(35mg, 35%). 1H NMR (500 MHz DMSO—d6) Pivotal signals: 5 8.61 (s, 1H), 7.54 (d, J =
8.4 Hz, 2H), 7.17 - 7.03 (m, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 8.5 Hz, 2H), 4.52 -
4.45 (m, 1H), 4.17 (dt, J = 8.9, 4.6 Hz, 2H), 4.12 (s, 1H), 4.07 — 3.97 (m, 1H). [M+H]+ =
Calculated 1332.59, found 1332.87
be’NYNH
+ NH
0V0 o o
: NJ H
o IW NHMtt
N H’Vfig i g: H
HM ‘W Y o 1
HZN \N N/ OJ\CF3 >ro NH
Mann/km
EXAMPLE. N10-TFA-Pte-yGlu-OtBu-Asp(OtBu)-Arg(be)-Arg(be)-
Lys(Mtt)-resin 5. The general ure bed for the synthesis of resin bound folate-
e resin 1 was followed for the coupling of 2X Fmoc—L-Arg(be)-OH, Fmoc-L—
Bu)-OH, Fmoc-Glu—OtBu, and N10—TFA-Pte-OH to —Lys(Mtt)-Wang resin.
HZNYNH
HO cxl2 \
Oo§_/0H OVOH N
o NAcogH
: N
N N WJL
0 NHW N h] N N
: B _ H H HOZCJ
)\\ If” OH 1
H2N N N NH
HgN/kNH
EC2218
CG1H86N2201BS
Exact Mass: 1446.62
Mol. Wt: 1447.54
EXAMPLE. Pte-yGlu-Asp-Arg-Arg-Lys-Bn-NOTA 6 (EC2218). Pte-yGlu-
Asp-Arg-Arg-Lys-Bn-NOTA, EC2218 was prepared in 18% yield according to the process
described for folate-peptide-NOTA, 4. 1H NMR (500 MHz DMSO-d6) Pivotal signals: 5
8.58 (s, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.14 — 7.08 (m, 4H), 6.61 (d, J = 9.0 Hz, 2H), 4.16 —
4.09 (m, 2H), 4.06 (dd, J = 10.0, 4.3 Hz, 1H), 3.90 (dd, J = 7.8, 4.7 Hz, 1H). [M+H]+ =
Calculated 1449.64, found 1449.76
HNjfiNfN O
H2N)\\N N/ 0%CF3 \L
Pka/KNH
H
EXAMPLE. N10—TFA-Pte—yGlu-OtBu-Arg(be)-Lys(Mtt)—resin 7. The
general procedure described for the synthesis of resin bound folate-peptide resin 1 was
followed for the coupling of -Arg(be)-OH, Fmoc—Glu-OtBu, and N10-TFA-Pte-OH
to Fmoc-L—Lys(Mtt)-Wang resin.
Ho 02 I—\
o OVOH o OVOH NAcogH
UW imm
o u H N H028
N 1%
HgN/KN”“51 3”” N/ 1
HZN’l§NH
E02219
CS1H69N17O14S
Exact Mass: 1175.49
Mel. W1.: 1176.27
WO 73678
EXAMPLE. Pte-yGlu-Arg—Lys-Bn—NOTA 8 (EC2219). Pte-yGlu-Arg-Lys—
Bn-NOTA, EC2219 was preapred in 20% yield ing to the process described for folate—
peptide-NOTA, 4. 1H NMR (500 MHz DMSO-d6) l signals: 5 8.68 (s, 1H), 7.60 (d, J
= 8.4 Hz, 3H), 7.27 — 6.97 (m, 4H), 6.77 - 6.69 (m, 2H), 4.28 —f 4.19 (m, 2H), 4.08 (dd, J =
9.0, 5.4 Hz, 1H), 4.01 (dd, J = 8.5, 5.4 Hz, 1H). [M+H]+ = Calculated 1, found 1178.7
H/£:::I/H\H NQKH H
N /—\
0 NW N IW \n/\N N’\
lN o <\1\H; o 0
0 OH <tjf‘i> COZH
EC2222
C49H74N20014
Exact Mass: 1166.57
Mol. Wt.: 1167.24
EXAMPLE. Pte-yGlu—Arg—Arg—Lys—NOTA 9 (EC2222). In a peptide
synthesis vessel, N10-TFA-Pte-yGlu-OtBu-Arg(be)-Arg(be)-Lys(Mtt)-resin (0.5g,
0.12mmol) was placed and washed with DCM (3 x 10 m1). ive Mtt deprotection was
performed by adding a 2% CF3C02H / DCM solution to the vessel and bubbling with Argon
for 10 min. After filtering, the resin was washed with dichloromethane ed by a fresh
solution of 2% CF3COzH/ DCM. This process was repeated until there was no more yellow
solution being d and a Kaiser test was done. Following a DMF wash (3 X 10 ml);
NOTA-Bis(tBu)ester (0.10 g, 0.24 mmol, 20 eq.) in DMF, PyBOP (0.14 g, 0.26 mmol, 2.2
eq) and DIPEA (64 ul, 0.36 mmol, 3.0 eq.) were added to the vessel and the solution bubbled
with Argon for 2 hour. The coupling solution was filtered, the resin was washed with DMF (3
x 10 ml) and i-PrOH (3 x 10 ml) and a Kaiser test was done to assess reaction completion.
Resin cleavage/global tert—butyl ester deprotection was performed with a cocktail consisting
of 95% CF3COzH, 2.5% H20 and 2.5% triisopropylsilane. The cleavage cocktail (10 ml) was
poured onto the resin and bubbled with Argon for 1hr, followed by filtration into a clean
flask. Further cleavage was performed twice successively with fresh cleavage cocktail for 10
mins of bubbling. The combined filtrate was poured onto cold diethyl ether, the itate
formed was collected by centrifugation at 4000 rpm for 5 mins (3X). The precipitate was
obtained following decanting and drying of the solid under vacuum. Deprotection of the
trifluoro-acetyl group was achieved by dissolving the crude precipitate in H20 (15 ml), which
was basified with Na2CO3 to pH 9 with Argon bubbling. Upon completion of the reaction,
confirmed by LCMS, the solution was acidified to pH 5 using 2 M HCl and the desired linker
was purified by preparative HPLC (mobile phase A = 10mM Ammonium acetate, pH = 5;
Organic phase B = itrile; Method; 10% B to 100%B in 30 mins) to yield EC2222
(28mg, 20%). 1H NMR (500 MHz DMSO—d6) Pivotal s: 8 8.60 (s, 1H), 7.51 (d, J =
8.1 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 4.21 — 4.09 (m, 2H), 4.09 — 4.03 (m, 1H), 3.98 — 3.88
(m, 1H), 3.50 (s, 1H). [M+H]+ = Calculated 1167.57, found 1167.8
0 902Me
O NHW PyBOP, DIPEA
WailNfem,N O H2N\/\O/\/o\/\NHBOC —>
HN \ N + o
0002024 DMSO,23 C
902Me
ngkNNWNwO/VowNHBOCQC07010rooms
EXAMPLE. thyl 18-(4-(N-((2-aminooxo—3,4-dihydropteridin
y1)methyl)—2,2,2-trifluoroacetamido)benzamido)-2,2—dimethyl-4,15—dioxo-3 ,8,1 1-trioxa-5,14—
diazanonadecanoate (QC07010). QC02024 (100 mg, 0.181 mmol) is added to a solution
of Mono-Boc-PEG-NHZ (45 mg, 0.181 mmol) and DIPEA (0.158 mL, 0.905 mmol) in
DMSO (2 mL) at 23 0C under N2. After being d for 15 min at 23 OC, PyBOP (94.2 mg,
0.181 mmol) was added, and the reaction mixture was stirred for 24 h at 23 OC. Volatile
material was removed under reduced vacuum, the crude material was further ed by SPE
cation: extract successively with ACN (2 X), EA (1 X) and EtzO (1 x) to afford pure
product QC07010 (127mg, 90%). Xmax = 280 nm; LC-MS (Agilent G6130B Quadrupole
LC/MS): Mobile phase: Buffer (pH CN; : Analytic C18 column; Method: 0—
100 CH3CN—15 min, tR = 5.06 min. MS m/z: MS-API: Calcd. for C33H43F3N9010
([M+H]+): 782.3, Found: 782.2; 1H NMR (400 MHz, DMSO) 5 = 11.59 (s, br, 1 H), 8.92 (d,
J = 7.2 Hz, 1 H), 8.64 (s, 1 H), 7.85—8.02 (m, 3 H), 7.64 (d, J = 8.0 Hz, 2 H), 6.75 (t, J = 5.2
Hz, 1 H), 5.13 (s, 2 H), 4.33—4.48 (m, 1 H), 3.64 (s, 3 H), 3.46 (s, 4 H), 3.30—3.41 (s, 4 H),
3.14—3.23 (m, 2 H), 3.01-3.08 (m, 2 H), 2.19—2.30 (m, 2 H), 2.02-2.12 (m, 1 H), 1.89—2.00
(m, 1 H), 1.35 (s, 9 H); 13C NMR (101 MHz, DMSO) 8 = 172.43, 171.46, 165.73, 160.87,
156.80, 15570 (d, J = 35.5 Hz), 155.67, 154.17, 149.49, 144.20, 141.73, 134.30, ,
128.55, 128.23, 116.20 (d, J = 290.0 Hz), 77.65, 69.58, 69.50, 69.193, 69.192, 53.88, 52.52,
51.96, 38.89, 38.62, 31.65, 28.23, 26.32; 19F NMR (377 MHZ, CDC13) 6 = -62.87.
O EOZMe H o TFA/DCM
0 0*N/V\n/ \/\O/\/ \/\NHBOC—>
HNJENjA'll o 1l3
QC0701O
N)\\N N/ COCF3
O gone H
NfifiNfEOCFg,N duwwvmQCO7011
E. (S)-methyl 2-(4-(N-((2-aminooxo-3,4-dihydropteridin
y1)methyl)-2,2,2—trifluoroacetamido)benzamido)-5—((2-(2—(2—
aminoethoxy)ethoxy)ethy1)amino)—5-oxopentanoate (QC07011). QC07010 (274 mg, 0.35
mmol) was treated with TFA/DCM (4 mL, 1/3) at 23 oC. The reaction was stirred at 23 OC
and monitored by LC-MS. After 1.5 h, TLC showed that all starting material eared.
The mixture was diluted with CH3CN and evaporated to dry via ap. Residue TFA (b.p.
72.4 0C) was d through azeotropic distillation with ACN to afford the product
QC07011 in quantitative yield, which was used without further purification. kmax = 280 nm;
LC—MS (Agilent G6130B Quadrupole LC/MS): Mobile phase: Buffer (pH 7)—ACN; :
Analytic C18 column; : 0-100 ACN 15 min, tR = 3.84 min. MS m/z: MS-API: Calcd.
for C28H35F3N903 ([M+H]+): 682.2, Found: 682.2.
0 902Me
I«(j/k” =
“WNV\O/\/o\/\NH2—>NOTA-NHS o
HNJj:N\ o DIPEA,DMSO
NkN | rCOCFs QC07011 COZH
:NOiNW N002Me N
if!“/>N\_/¥002H
EXAMPLE. (S)-2,2'—(7-(4-(4—(N-((2—amino—4—oxo-3,4—dihydropteridin—6-
hyl)-2,2,2-tn'fluoroacetamido)benzamido)-3 ,7,18-trioxo-2,11,14-trioxa-8,17-
diazanonadecany1)-1,4,7-t1iazonane-1,4-diy1)diacetic acid (QC07013). QC07011 (15.7
mg, 0.023 mmol) in DMSO (0.5 ml) was added NOTA-NHS (18.2 mg, 0.028 mmol)
followed by DIPEA (15 uL, 0.084 mmol). The reaction was stirred at 23 °C, monitored by
LC—MS, and most of the starting material was converted to QC07013 in 5 hours. The product
was purified by RP-Clg HPLC to afford the pure product QC07013 (13.0 mg, 58.5 %). Xmax =
280 nm; LC—MS (Agilent G6130B Quadrupole LC/MS): Mobile phase: Buffer (pH 7)-
CH3CN; Method: 0—100 CH3CN—15 min, tR = 3.74 min. MS m/z: MS—API: Calcd. for
WO 73678
C40H54F3N12013 ([M+H]+): 967.4, Found: 967.2; HPLC (Agilent ative C18 Column):
Mobile phase: Buffer (pH 7)-CH3CN; Method: 0-100 30 min, tR = 10.75 min
c0211
O COZMQ O<N\N/N>
O /\/\n/N\/\O/\/O\/\NJJ\/N\—/LCO2H
HN N\ NQXH
J\\ I COCF3
/ QC07013
N N N
1 M NaOH (aq) C02H
23 °C 15 min
60 % afterOHPLC ON/V\n/ \/\O/\/0\/\NCOZH OFN/>
N /U\/N
1¥C02H
QC07017
EXAMPLE. (S)—2,2'—(7—(1-(4—(((2-amino—4—oxo—3,4—dihydropteridin—6—
yl)methyl)amino)phenyl)-3 -carboxy-1,6,17-trioxo-10, 13 -dioxa-2,7,16-triazaoctadecan
y1)—1,4,7-triazonane—1,4-diyl)diacetic acid (FA—PEGl—NOTA, QC07017). QC07013 (20.8
mg, 0.022 mmol ) was stirred in 1.2 mL of 1 M NaOH (aq.) at 23 OC and the reaction was
monitored by LC-MS. After 15 min, all ng material was transformed to product, the
crude material was purified by RP-C18 HPLC to afford QC07017 (11.3 mg, 60%). kmax =
280 nm; HPLC (Agilent Preparative C18 Column): Mobile phase: Buffer (pH 7)—CH3CN;
Method: 0-30 CH3CN-30 min, tR = 11.49 min. LC-MS (Agilent G6130B Quadrupole
LC/MS): Mobile phase: Buffer (pH CN; Method: 0—100 CH3CN 15 min, tR = 2.72
min. MS m/z: MS-API: Calcd. for C37H53N120l2 ([M+H]+): 857.4, Found: 857.2. 1H
NMR (400 MHz, DMSO) 5 = 8.62 (s, 1 H), 8.28 (t, J = 5.6 Hz, 1 H), 7.99 (t, J = 5.6 Hz, 1 H),
7.85 (d, J = 7.2 Hz, 1 H), 776—780 (S, br, 2 H), 7.58 (d, J = 8.8 Hz, 2 H), 7.00 (t, J = 6.0 Hz,
1 H), 6.62 (d, J = 8.8 Hz, 2 H), 4.47 (d, J = 5.2 Hz, 2 H), 4.13—4.18 (m, 1 H), 3.43 (s, 4 H),
3.31—3.41 (m, 4 H), 3.29—3.32 (m, 2 H), 3.10—3.24 (m, 4 H), 3.03—3.10(s,br, 2 H), 2.90—3.03
(3, br, 2 H), 2.10—2.14 (m, 2 H), .05 (m, 1 H), 1.84—1.91 (m, 1 H); 13C NMR (101
MHz, DMSO) 6 = 174.33, 172.21, 171.17, 170.35, 165.70, 161.85, , 154.95, 150.56,
148.45, 148.32, 128.62, 127.87, 121.84, 111.38, 69.44, 69.30, 69.08, 68.70, 60.95, 57.48,
53.11, 50.85, 49.41, 48.91, 45.88, 38.60, 38.18, 32.04, 27.52.
Q 00N’\/ 2 1)Swe||DCM2h DMF2h ® 000W0WOVEONNHFWC
2) Fmoc—NH—(PEG)5——COOH
HATU/DIPEA/DMF
Trt-EDA Resin
1) 20% Piperidine/DMF, 1) 20% PiperidinelDMF,
H 00213”
H 30 mln;
min; N
Q 00”N WCk/igoA/NWNHFmoc—>
0 0
2) Fmoc—GIu-O‘Bu 2) N‘O-(TFA)pteroic acid
HATU/DIPEA/DMF, 2 h; 0 HATU/DIPEA/DMF, 2h
1) TFA/HQO/TIPS (95:25:25);
tBUOZC o
H H
@ O ”wNwoflo/VNWN 2) Sat Na2C03, HPLC purification
O o o ACFgN/\::fLNHNHZ
o 902H H H
o N\/\or»:OWN\/\
N o o
\ Nofiw HZNJNjK/[NfH Qc03019
EXAMPLE. Solid Phase Synthesis (SPS) of FA-PEGa-EDA-NHZ Precursor
(QC03019). 1,2-Diaminoethane trityl resin (1.2 mmol/g, 100 mg, 0.12 mmol) was swollen
with dichloromethane (DCM, 3mL) followed by dimethyl formamide (DMF, 3 mL). After
swelling the resin in DMF, a solution of fluorenylmethoxycarbonyl -PEG6-OH (1.5
equiv), HATU (1.5 , and DIPEA (2.0 equiv) in DMF was added. Argon was bubbled
for 2 h, and resin was washed with DMF (3 x 3 mL) and i-PrOH (3 x 3 mL). The above
sequence was repeated for two more coupling steps for conjugation of Fmoc-Glu-(OtBu)-OH
and Nlo-TFA-Ptc-OH. The final product was cleaved from the resin using a trifluoroacetic
acid HzOztriisopropylsilane cocktail (95:2.5:2.5) and concentrated under vacuum. The
concentrated product was precipitated in l ether and dried under vacuum, which was
then incubated in Sat. Na2C03 and monitored by LC-MS. 1 hour later, the mixture was
neutralized to pH = 7 with 2 M HCl (aq.) which was purified by preparative with preparative
RP-CIS HPLC [solvent nt: 0% B to 50% B in 30 min; A = 10 mM NH4OAC, pH = 7; B
= CH3CN]. Acetonitrile was removed under vacuum, and the residue was freeze-dried to
yield QC03019 as a yellow solid (59 mg, 60%). Analytical RP—C18 HPLC: tR = 4.22 min (A
= 10 mM , pH = 7.0; B = CH3CN, solvent gradient: 0% B to 50% B in 15 min);
ative RP-C18 HPLC: tR = 11.7 min (A = 10 mM NH4OAC, pH = 7.0; B = CH3CN,
t gradient: 0% B to 50% B in 30 min); kmx = 280 nm; HPLC (Agilent Preparative C18
): Mobile phase: Buffer (pH 7)-CH3CN; Method: 0-30 CH3CN-30 min, tR = 11.7 min.
LC-MS (Agilent G6130B Quadrupole LC/MS): Mobile phase: Buffer (pH 7)-CH3CN;
Method: 0—50 CH3CN-15 min, tR = 4.22 min. MS m/z: : Calcd. for C36H55N10012
([M+H]+): 819.4, found, 819.2. 1H NMR (DMSO—ds/DzO) 5 = 8.63 (s, 1H), 7.64 (d, J = 8.8
Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 4.48 (s, 2H), 4.12—4.21 (m, 1 H), 3.58 (t, J: 6.4 Hz, 2 H),
3.41—3.53 (m, 24 H), 3.18—3.25 (m, 2 H), 3.11—3.18 (m, 2 H), 2.28 (t, J: 6.4, 2H), 2.15 (t, J:
7.4, 2H), 2.03 (m, 1H), 1.88 (m, 1H) ppm.
NWNwO’(\/OWN\/\NH2 —>NOTA—NHS
2)qu o DIPEA, DMSO
0003019
NWNwoNOWNWNkflNFCO2H
FwtfiEL/[NNjANN/(j)kN 0
ocovozs {:ch
EXAMPLE. FA—PEGs—NOTA. To QC03019 (9.5 mg, 0.011 mmol) in DMSO
(0.40 ml, with a tration at 0.029 M) was added NOTA-NHS (8.6 mg, 0.013 mmol)
ed by DIPEA (7.0 uL, 0.039 mmol). The reaction was stirred at 23 OC, monitored by
LC-MS, and most of the starting material was ormed to the corresponding product in 5
hours. The crude material was ed by RP-C1g HPLC to afford the pure product QC07029
(5.5 mg, 45 %). Analytical RP-Cls HPLC: tR = 3.91 min (A = 10 mM NH4OAc, pH = 7.0; B
= CH3CN, solvent gradient: 0% B to 50% B in 15 min); Preparative RP-C18 HPLC: tR =
10.51 min (A = 10 mM NH4OAc, pH = 7.0; B = CH3CN, solvent gradient: 0% B to 50% B in
min); max = 280 nm; HPLC (Agilent Preparative C18 Column): Mobile phase: Buffer (pH
7)—CH3CN; Method: 0—30 CH3CN—30 min, 61 = 10.51 min. LC-MS (Agilent G6130B
pole LC/MS): Mobile phase: Buffer (pH 7)—ACN; Method: 0-50 ACN-15 min, tR =
3.91 min MS m/z: MS-API: Calcd. for C48H74N13017 ([M+H]+): 1104.5, Found: 1104.4
1'1sz wmuoNWNHMVOPNFCZJla)AIFa; pH4. orpH 4.5-5
b) AICI3; then NaF,
n=1-20
H N NACOZH
N o m31a HN n N
J\\ H
N N <
n: 1-20
E. FA-NOTA-Al—lSF Radiotracer[2]. Two s for the
formation of FANOTA-Al-lSF are described herein. Conditions including the pH value,
concentration of the ates and temperature for the chelating reaction with 18F-Al can be
varied. The general methods for FA-NOTA-Al-lSF are described as followed:
Method a). FA-NOTA Precursor was dissolved in 2 mM NaOAc (pH 4.5) and
0.5 mL of ethanol, which was treated with A118F3-3H20 (1.5 eq.) which was freshly prepared
before ation. The pH was adjusted to 4.5-5.0, and the reaction mixture was refluxed for
-30 min with pH kept at 45-50. After being cooled down to room temperature, the crude
material was loaded to a cartridge, and the radiotracer was eluted into vial. After sterile
filtration and being diluted to appropriate radioactivity (5-10 mCi) and specific activity (> 1
Ci/umol), the radiotracer was ready for in vivo PET imaging study.
Method b). A Precursor was dissolved in 2 mM NaOAc (pH 4.5),
and treated with 3HzO (1.5 eq.). The pH was adjusted to 4.5—5.0, and the reaction
mixture was refluxed for 15-30 min with pH kept at 45-50. The crude material was purified
by RP-HPLC to afford the A-Al-OH intermediate ready for 18F— labeling.
Appropriate amount of FA—NOTA—Al-OH was treated with NalSF saline solution and ethanol
(1/ 1, v/v), and the whole mixture was heated at 100-110OC for 15 min. After being cooled
down to room temperature, the crude material was loaded to a cartridge, and the radiotracer
was eluted into vial. After e filtration and being diluted to appropriate radioactivity (5-10
mCi) and specific activity (> 1 l), the radiotracer was ready for in viva PET imaging
study.
O COZH O<N\N/>
O 'LCOZH
HN N\ NdHWN\/\O/\/O\/\Nj)J\/N folate-NOTA (1)
Ax I H
N N N iAI‘BFa rcozH
o OCH2 0 {N3
: H 0
o mmN \/\ /\/ \/\. k/NAFBFN
u uL
HzNifiNjflNN -NOTA-AI13F (2)
EXAMPLE. Standard Protocol for the Formulation of Folate-NOTA-AllSF
Radiotracer. The resin containing 18F was first washed with 1.5 mL of ultrapure water, and
then 18F was eluted out from resin by using 1.0 mL of 0.4 M KHC03 solution. 100 uL of the
eluting solution containing 18F was added to a stem vial charged with 10 uL acetic acid, 25
uL AlC13 (2 mM in 0.1 M NaOAc pH 4 ) and 125 ”L 0.1 M NaOAc pH 4 buffer. The
whole mixture was incubated for 2 min before 0.25 mg folate-NOTA precursor (1) in 125 uL
of 0.1 M NaOAc pH 4 buffer was transferred to the same stem via]. The reaction was
immediately heated to 100 0C for 15 min.
After cooling to room temperature, the crude material was mixed with 0.7 mL
0.1% formic acid and purified by radioactive HPLC on a Xselect CSH C18 (250 x 10 mm)
column using MeCN and 0.1% formic acid as the mobile phase. The fraction at 11.5 min was
collected to afford pure radiotracer in ~ 40-50% hemical yield (RCY) with ~ 98%
radiochemical purity (RCP). The total radiochemical synthesis of folate-NOTA-APSF (2,
AllSF-QC07017) was accomplished in ~37 min with a specific activity (SA) of 70 i 18.4
ol. After sterile filtration and appropriate dilution in isotonic saline to the desired
radioactivity, the folate-NOTA-AllSF (2) racer was ready for PET imaging study.
Using same strategy, radiochemcial synthesis of FA—PEG1z—NOTA—Al-18F
radiotracer (QC07043) was accomplished in ~35 min with a specific activity (SA) of 49 i
17.1 GBq/umol. Although the radiochemical purity is excellent, 100% after radioactive
HPLC purification, the total hemical yield (RCY) is relatively low, ~ 25-30%. After
sterile filtration and appropriate dilution in isotonic saline to the desired ctivity, the FA-
PEGiz—NOTA-Al—lsF radiotracer was ready for PET imaging study.
NH «s 00NM1) Swell DCM 2 h DMF 2 h Q5 00 ~“WV)?W0 ~NHFmoc
2) FmocNH(PEG)5COOH
HATU/DIPEA/DMF 0”
Trt-EDA Resin
1) 20% Piperidine/DMF, 1) 20% PiperidinelDMF,
H COZ‘Bu
min;
min; N
Q 00”N WOWONNWNHFFHOC—p
0 0
2) Fmoc—GIu-O‘Bu 2) N‘O-(TFA)pteroic acid
HATU/DIPEA/DMF, 2 h; 0 HATU/DIPEA/DMF, 2h
1) TFA/HQO/TIPS (95:25:25);
H tBUOZC
@ O 2) Sat Na2C03 HPLC purification
HNNNWOwO/VNWNN/‘KQjL/T
0 ° %CF3\N
wrjfiwiwwwwQC07041
EXAMPLE. Solid Phase Synthesis (SPS) of FA-PEGiz-EDA-NHZ
(QC07042)[11]. 1,2-Diamin0ethane trityl resin (1.2 mmol/g, 50 mg, 0.06 mmol) was swollen
with dichloromethane (DCM, 3mL) followed by dimethyl formamide (DMF, 3 mL). After
swelling the resin in DMF, a solution of fluorenylmethoxycarbonyl (Fmoc)-PEG12-OH (1.5
equiv), HATU (1.5 equiv), and DIPEA (2.0 equiv) in DMF was added. Argon was d
for 2 h, and resin was washed with DMF (3 x 3 mL) and i-PrOH (3 x 3 mL). The above
sequence was repeated for two more coupling steps for conjugation of Fmoc-Glu-(OtBu)-OH
and N10-TFA-Ptc-OH. The final product was cleaved from the resin using a roacetic
acid (TFA):HzOztriisopropylsilane cocktail :25) and concentrated under vacuum. The
concentrated product was precipitated in diethyl ether and dried under vacuum, which was
then ted in Sat. Na2C03 and monitored by LC-MS. 1 hour later, the mixture was
neutralized to pH = 7 with 2 M HCl (aq.) which was ed by preparative with preparative
RP-CIS HPLC [solvent gradient: 0% B to 50% B in 30 min; A = 10 mM NH4OAC, pH = 7; B
= CH3CN]. Acetonitrile was removed under vacuum, and the residue was freeze-dried to
yield pure QC07042 as a yellow solid (32.5 mg, 50 %). Analytical RP—C18 HPLC: tR = 4.76
min (A = 10 mM NH4OAC, pH = 7.0; B = CH3CN, t gradient: 0% B to 50% B in 15
min); ative RP-Cig HPLC: tR = 13.75 min (A = 10 mM NH4OAC, pH = 7.0; B =
CH3CN, solvent gradient: 0% B to 50% B in 30 min); UV-Vis: max = 280 nm; Preparative
RP—C18 HPLC: HPLC (Agilent Preparative C18 Column): Mobile phase: Buffer (pH 7)-
CH3CN; Method: 0—50 CH3CN, 30 min, tR = 13.75 min. LC-MS: LC—MS (Agilent G6130B
Quadrupole LC/MS) of t Mobile phase: Buffer (pH CN; Method: 0-50 CH3CN,
min, tR = 4.76 min. MS m/z: MS-API: Calcd. for C48H79N10018 ([M+H]+): 1083.6, Found:
1083.4;
o 902H
_ H H
_ HS
HNWNth/OWNwNHZ —>11
N o o DIPEA,DMSO
HN \ N
A ' JAH QC7042
\ /
N N
O ”WHwOA/OWHWNJLPSQOZH 0 co H2
O O
Qco7o43 N
HzNXNHNfiNjflNH K
N/ COzH
EXAMPLE. FA—PEG12—EDA—NH2—NOTA (QCO7043). To FA—PEG12—
EDA—NHz (QCO7042, 4.78 mg, 0.004 mmol, M.W.:1082.5) in DMSO (0.25 ml, with a
concentration at 0.025 M) was added NOTA-NHS (3.5 mg, 0.005 mmol, 1.2 eq.) ed by
DIPEA (2.7 ”L, 0.039 mmol). The whole mixture was stirred at 23 OC and red by LC-
MS. 4 hours later, LC—MS showed that almost all of the starting material was transformed to
the product. The crude material was then purified by preparative RP-HPLC to afford the pure
FA—PEG12—EDA-NH2—NOTA (QCO7043, 4.09 mg, 68 %). Analytical RP-C18 HPLC: tR =
6.21 min (A = 10 mM NH4OAc, pH = 7.0; B = CH3CN, solvent gradient: 0% B to 30% B in
min); Preparative RP-Clg HPLC: tR = 15.60 min (A = 10 mM NH4OAC, pH = 7.0; B =
CH3CN, solvent gradient: 0% B to 30% B in 30 min); UV-Vis: kmax = 280 nm; LC—MS: LC—
MS (Agilent G6130B Quadrupole LC/MS) of t Mobile phase: Buffer (pH 7)—CH3CN;
Method: 0——8.00 (1n, 1 H), 7.55 (d, J: 6.4 Hz, 1 H), 7.54 (3, br, 2 H), 6.81—6.93 (m, 1 H),
6.62 (d, J = 8.0 Hz, 2 H), 4.45 (d, J = 4.4 Hz, 2 H), 3.95—4.03 (m, 1 H), 3.64-3.70 (m, 2 H),
3.56—3.63 (m, 6 H), 3.38—3.50 (m, 28 H), 3.33—3.36 (m, 6 H), 3.20—3.24 (m, 4 H), 3.09—3.18
(m, 10 H), 3.04-3.09 (m, 4 H), 2.50 (s, 12 H, overlapping with the residue peak of DMSO),
2.27—2.34 (m, 2 H), 2.02—2.12 (m, 2 H), 1.99—2.01 (m, 2 H).
N o
O gozH H
\/\O/\/ \/\O O N NM“_< >‘ N/—l\\l/—<OH
N @HW O </N\7
+5: folate--C-NETA
I jflu
H2N \N N/ Oi)
E. C-NETA and folate-C—NETA. A PyBOP promoted coupling
between QC04018 and compound 6, followed by deprotection of tert-butyl ester with TFA,
provided folate-C-NETA. The folate-C-NETA is used to evaluate the labeling efficiency with
A118F and 68Ga and evaluate the in vivo PET imaging.
0 O
OMe OMe
F MeZN
CM CM
QC07002
EXAMPLE. Methyl 3-cyano(dimethylamino)benzoate 02)[1]. To
a stirred solution of methyl 3-cyanofluorobenzoate (5 g, 27.9 mmol) in DMSO (6 ml) was
added dimethylamine hydrochloride (2.75 g, 33.7 mmol) ed by potassium carbonate
(8.1 g, 58.6 mmol). The reaction mixture was stirred at room temperature ght and
trated. The residue was dissolved in dichloromethane (50 ml) and washed with water
(2 X 25 m1), brine, dried over NazSO4 and concentrated in vacuo to give the methyl 3—cyano—
4—(dimethylamino)benzoate (QC07002) in quantitative yield and was used without further
purification.
0 o
’ (B
MeZN Me3N
CN CF 860 ON
QC07002 3 3
0607003
EXAMPLE. 2-Cyano(methoxycarbonyl)—N,N,N—trimethylbenzenaminium
trifluoromethanesulfonate (QC07003). To a stirred solution of methyl 3-cyano
(dimethylamino)benzoate (3.4 g, 16.7 mmol) in anhydrous dichloromethane (17 ml) was
added methyl trifluoromethanesulfonate (10 g, 60.9 mmol, M.W. 164.1) dropwise. The
reaction was stirred at RT for 16 h and another portion of methyl trifluoromethanesulfonate
(10 g, 60.9 mmol, M.W.: 164.1) was added. The reaction was stirred for another 16 hours and
tert-butylmethylether (20 ml) was added slowly. The suspension was filtered and the
collected solid was washed with tert-butylmethylether. The crude product was purified by
RP—C18 HPLC: (acetonitrile/water-gradient 1:99 to 80:20) to afford product QC07003 (3.69
g) in 60 % yield. Analytical RP-Clg HPLC: tR = 0.49 min (A = 10 mM NH4OAc, pH = 7.0; B
= CH3CN, solvent gradient: 0% B to 100% B in 15 min); kmax = 275 nm; LC-MS (Agilent
G6130B Quadrupole LC/MS): Mobile phase: Buffer (pH 7)-CH3CN; Column: ic C13
column;Method: 0-100 CH3CN-15 min, tR = 0.49 min. MS m/z: MS-API: Calcd. for
C12H15N202 ([M]+): 219.1, Found: 219.0; 1H NMR (400 MHz, D20) 5 = 8.67 (d, J=2.1 Hz, 1
H), 8.44 (dd, J=9.1, 2.1 Hz, 1 H), 8.15 (d, J=9.1 Hz, 1 H), 3.93 (s, 3 H), 3.87 (s, 9 H) ppm.
0 0
OMG OH
(+) —> 9
MegN MegN
e 9
C" CN
CF3SO3 CF3803
QC07003 QC07004
EXAMPLE. 4-Carboxycyano-N,N,N-trimethylbenzenaminium
oromethanesulfonate (QC07004). A solution of QC07003 (3.6 g, 9.8 mmol) in water
(83 ml) and TFA (83 ml) was heated at 120°C for 48 h. The reaction e was
concentrated in vacuo, the light green oil was treated with diethylether to result a suspension.
This solid was collected by filtration, washed with diethylether and dried in vacuo to give 4—
carboxycyano-N,N,Ntrimethy1benzenaminium oromethanesulfonate 4 (2.8 g,
82%). Analytical RP-CIS HPLC: U; = 0.61 min (A = 10 mM NH4OAc, pH = 7.0; B =
CH3CN, solvent gradient: 0% B to 100% B1n 15 min); Mm: 240 nm. LC-MS (Agilent
G6130B Quadrupole LC/MS): Mobile phase: Buffer (pH 7)-CH3CN; : Analytic C18
column; Method: 0-100 CH3CN 15 min, tR = 0.61 min. MS m/z: MS-API: Calcd. for
C11H13N202 ([M]+): 205.1, Found: 205.1; 1H NMR (400 MHZ, DMSO) 5 = 8.58 (d, J = 2.07
Hz, 1 H), 8.39 — 8.49 (m, 1H), 8.23 - 8.35 (m, 1 H) 3.85 (s, 9 H).
COZMG
@010 0.00wN\/\ /\/O\/\o e
Me3N BACOCFS Qco7o11
CF3803 4
o gone o
H e
:qu N/\/\n/N\/\o/\/O\/\N CF3803
o @
COCF3 CN
Qco7oos
EXAMPLE. FA—PEGi-TMA Precursor (QC07005). QC07004 (62 mg, 0.17
mmol) was added to the solution of QC07011 (0.14 mmol) and DIPEA (87 “L, 1.75 mmol) in
DMSO (2.0 mL) at 23 0C under N2. After being stirred for 15 min at 23 OC, PyBOP (91 mg,
0.17 mmol) was added, and the reaction mixture was stirred for 24 h at 23 0C. Volatile
material was removed under reduced vacuum to afford the crude product which was r
purified by RP-HPLC (C13) to afford the pure compound QC07005 as pale yellow colored
solid (125.1 mg, 72 %). Analytical RP-Clg HPLC: tR = 4.17 min (A = 10 mM NH4OAc, pH
= 7.0; B = CH3CN, solvent gradient: 0% B to 100% B in 15 min); Max: 280 nm; LC-MS
(Agilent G6130B Quadrupole LC/MS): Mobile phase: Buffer (pH CN; Column:
ic C18 column; Method: 0—100 CH3CN—15 min, ti: = 4.17 min. MS m/z: MS—API:
Calcd. for C28H35F3N908 ([M]+): 868.3, Found: 868.2.
oN/"\/\n/N\/\o/\/O\/\No902Me 6
CF3303
”N 0|:j/\N
QC07005 NMes
COCF3 CN
)iNN/\/”1(N\/\o/\/O\/\HJkI;:LF0007006 CN
LE. General procedure for the one—pot 19F— introduction and
deprotection. 8.3 pL of freshly prepared KF—Kryptofix (1/ 1.5) (0.0012 mmol, 0.144 M)
solution was azeotropically dried with CH3CN at 90-100 0C, to which 1.2 mg (0.0012 mmol,
1.0 equiv.) QC07005 in 50 ul of anhydrous DMSO was added with a concentration of
precursor at 0.024 M. The resulting mixture was immediately immersed into an oil bath
ted to 70-75 0C and kept at 70-75 0C for 10 min. After being cooled down to room
temperature, 200 111 of 1M NaOH (aq.) was added with a concentration of NaOH (aq.) at 0.8
M. The on was monitored by LC—MS and found complete after 5 min, which was
neutralized with 1 M HCl (aq.) and ed by LC—MS (QC07006). And the total labeling
efficiency was about 30 % based on the analysis of LC—MS. Analytical RP-C18 HPLC: A =
mM NH4OAc, pH = 7.0; B = CH3CN, solvent gradient: 0% B to 100% B in 15 min; km“:
280 nm; LC—MS: Method: 0—100 CH3CN—15 min, tR = 5.13 min. MS m/z: MS-API: Calcd.
for C36H37F4N1009 ([M+H]+): 829.3, Found: 829.1.
0 002m COZH
Wow:@WFA-Tris
0002024
3 :flOiN/\/\n/N“1460‘0/80/ HZNA HFolate—Tris-Borate
KF/ Kryptofix 222 oim{..002H
—> Hle-fiLJENNj/\NFolate-Tris— Borate-18F PET Agent
EXAMPLE. Folate—lSF-Boronate PET Imaging Agent
PSMA TARGETED EXAMPLES
HCI o
H H
NH2 #0 YNJOJ<i
1) rophenyl chloroformate, o
2) H-Lys(Z)-OtBu, DIPEA, O O I
1)Pd/CH2 MeOH
2) 4--Nitropheny|
chloroformate,
DIPEA, DCM
C31H48N4011EC1380HN\©\ NO2
Exact Mass: 652.33
Mol. Wt.: 652.73
EXAMPLE. EC1380, 10. In a dry flask, H—Glu(OtBu)—OtBu.HCl (2.48g ,
8.41 mmol) and 4—nitrophenyl formate (1.86 g, 9.25 mmol, 1.1 eq) were added,
dissolved in CH2Clz (30ml) under Argon atmosphere. The stirring solution was chilled to 0
°C, followed by the dropwise addition of DIPEA (4.50 ml, 25.2 mmol, 3 eq). The reaction
mixture was allowed to warm to room temperature and stirred for 1 hr. To the stirring
solution was added H-Lys—(Z)-O‘Bu (4.39 g, 11.8 mmol, 1.4 eq), DIPEA (4.50 ml, 25.2
mmol, 3 eq) and stirred for 1 hr. Upon completion, the reaction was quenched with saturated
NaHCOs and extracted with CH2C12 three times. The organic extracts were combined, dried
over NazSO4, filtered and the solvent was removed via reduced pressure. The product was
purified using silica gel tography with petroleum ether and ethyl acetate. The Cbz
protected amine was erred to a round bottom flask with 10% Pd/C (10% wt eq),
dissolved in MeOH (30 ml) under Hydrogen atmosphere (latm) and stirred for 3 hr. Upon
completion, the reaction mixture was filtered through celite and the t was removed Via
reduced pressure to yield the crude amine. The amine was taken up in CH2C12 (30ml) under
Argon atmosphere and chilled to 0 °C. To the chilled on was added 4-nitropheny1
chloroformate (2.2 g, 10.9 mmol, 1.3 eq) and DIPEA (6.0 ml, 33.6 mmol, 4 eq) subsequently
and stirred for 2 hr at room temperature. The reaction mixture was quenched with saturated
NH4Cl and extract three times with ethyl acetate. The c extracts were combined, dried
over Na2804, filtered, and solvent was removed under vacuum and purified using silica gel
chromatography to yield the desired activated amine, EC1380 (2.54 g, 46%).
1‘0 Oyoj< 0k NHMtt
'JL JOL
Worm NW N 0 (:3 O
EXAMPLE. Glu(O‘Bu)—OtBu—Lys—O‘Bu—AMPAA—Asp(O‘Bu)—Asp(O’Bu)—
Lys(Mtt)-resin 11. The general procedure bed for the synthesis of resin bound folate-
peptide resin 1 was followed for the ng of 2 X Fmoc—L-Asp(O‘Bu)-OH, Fmoc-
AMPAA-OH, Fmoc-L-Lys(Z)-O‘Bu, and Fmoc-(L)—Glu(O‘Bu) to Fmoc-L—Lys(Mtt)—Wang
resin. The resin bound penta-peptide was subjected to rd Fmoc deprotection, washings
and Kaiser test. Following another DMF wash (3 x 10 m1); an EC1380 on (2.0 eq.) in
DMF, and DIPEA (3.0 eq.) were added to the vessel and the solution bubbled with Argon for
2 hour. The coupling solution was filtered, the resin was washed with DMF (3 x 10 m1) and i-
PrOH (3 x 10 ml) and a Kaiser test was done to assess reaction completion.
O 902H 0 H020“) \
/\:JLW JL COZH COZH
H020 N N N N O 902H
H H H H NEJiNHWHJL H00)2
0 '\
E02209
CS6H78N1ZOZSS
Exact Mass: 1318.50
MOI. Wt.: 1319.35
EXAMPLE. Glu-Lys-AMPAA-Asp-Asp-Lys-Bn-NOTA 12. Glu-Lys-
AMPAA—Asp-Asp-Lys-Bn-NOTA, EC2209 was prepared in 47% yield according to the
process bed for folate-peptide-NOTA, 4. 1H NMR (500 MHZ DMSO—dg) l
signals: 5 7.25 — 7.18 (m, 2H), 7.14 (d, J: 8.1 Hz, 1H), 7.12 — 7.06 (m, 5H), 4.47 (ddd, J:
17.8, 7.5, 5.6 Hz, 2H), 4.11 — 4.08 (m, 3H), 4.08 — 4.02 (m, 2H), 3.98 (dd, J: 8.2, 5.1 Hz,
1H). [M+H]+ = Calculated 1319.50, found 1319.70
beHNYNH beHNY
NWNJQENHE):\Og/éNH—{ENHfifg:NHMtt
COQtBUOE
\ngtBL?OIW
ButOZC\ N N COgtBu
EXAMPLE. Bu)—O‘Bu—Lys—OtBu—Aoc—Phe—Phe—Arg(be)—Asp(OtBu)—
Arg(be)—Lys(Mtt)—resin 13. The general procedure described for the sis of resin
bound folate-peptide resin 1 was followed for the coupling of —Arg(be)-OH, Fmoc-
L—Asp(O’Bu)-OH, Fmoc—L—Arg(be)-OH, 2 X Fmoc-Phe—OH, Fmoc-Aoc—OH, Fmoc-L-
Lys(Z)-O’Bu, Fmoc-(L)-Glu(OtBu) and ECl380 to Fmoc-L—Lys(Mtt)-Wang resin.
H2NYNH HZNVNH
NH NH
O O O
001.111;an “VLuJi'VLuH H H H l—\
“MNrN NAC02H
H0201. O \O O \COZHO 002” O <jNJ
HNYN H020
0 COZH
EC2390
C73H114N20023
Exact Mass: 4
Mol. Wt.: 1639.81
EXAMPLE. Glu—Lys-Aoc—Phe-Phe-Arg-Asp-Arg—Lys-NOTA 14. Glu-Lys—
Aoc-Phe-Phe-Arg—Asp-Arg-Lys-NOTA, EC2390 was prepared in 37% yield according to the
process described for folate-peptide-NOTA, 4. 1H NMR (500 MHZ DMSO-ds) Pivotal
signals: 6 7.25 — 7.14 (m, 6H), 7.16 — 7.08 (m, 3H), 4.47 (dd, J = 9.0, 4.7 Hz, 1H), 4.42 (t, J:
.9 Hz, 1H), 4.36 (dd, J: 10.4, 4.4 Hz, 1H), 4.27 (t, J: 6.9 Hz, 1H), 4.16 (t, J: 5.6 Hz, 1H),
3.97 — 3.88 (m, 2H). [M+H]+ = Calculated 1639.84, found 1640.22
000:3” COOBn COO’Bu COOH COOtBu
a i 6" i
HOOC NH2.HC| {BuOOC N N i COO’Bu tBuOOC i ’
H H H H H H H H H COO Bu
1 2 DUPA_1
Reagents and conditions:
(a) triphosgene, TEA/ DCM, -78 °C; (b) H-L-GIu(OBn)-OtBuHC|; (0) H2; Pd-C/DCM.
EXAMPLE. DUPA-EAOA—Phe-Arg-Lys-NHz, 2-[3—(3-Benzyloxycarbonyl-
1—tert—butoxycarbonyl-propyl)-ureido]pentanedioic acid di—tert-butyl ester (2). [1, 2] To a
solution of L-glutamate t-butyl ester hydrochloride 1 (1.0 g, 3.39 mmol) and
triphosgene (329.8 mg, 1.12 mmol) in DCM (25.0 mL) at —78 OC, tn'ethylamine (TEA, 1.0
mL, 8.19 mmol) was added. After stirring for 2 h at —78 0C under argon, a solution of L-
Glu(OBn)—OtBu (1.2 g, 3.72 mmol) and TEA (600 ,uL, 4.91 mmol) in DCM (5.0 mL) was
added. The reaction mixture was allowed to come to room temperature (rt) over a period of 1
h and stirred at ambient temperature overnight. The reaction was quenched with 1 M HCl,
and the organic layer was washed with brine and dried over NazSO4. The crude product was
purified using flash chromatography (hexane:EtOAc ) 1:1) to yield the ediate 2 (1.76 g,
90.2%) as a colorless oil and crystallized using hexane:DCM. Rf) 0.67 (hexane:EtOAc ) 1:1).
1H NMR (CDClg): 6 1.43 (s, 9H, CH3—tBu); 1.44 (s, 9H, CH3—tBu); 1.46 (s, 9H, CH3—tBu);
1.85 (m, 1H, Glu—H); 1.87 (m, 1H, Glu—H); 2.06 (m, 1H, Glu-H); 2.07 (m, 1H, Glu—H); 2.30
(m, 2H, ; 2.44 (m, 2H, Glu—H); 4.34 [s (broad), 1H, RH]; 4.38 [s (broad), 1H, R-H];
.10 (s, 2H, CH2—Ar); 5.22 [s (broad), 2H, Urea-H); 7.34 (m, 5H, Ar-H). EI-HRMS (m/z): (M
+ H)+ calcd for C30H47N209, 82; found, 89.
EXAMPLE. 2-[3-(1,3-Bis—tert-butoxycarbonyl-propyl)-ureido]pentanedioic
Acid 1-tert-Butyl Ester, DUPA_1. To a on of 2 (250 mg, 432 mmol) in DCM, 10%
Pd/C was added. The reaction mixture was enated at 1 atm for 24 h at rt. Pd/C was
filtered through a Celite pad and washed with DCM. The crude product was purified using
flash chromatography (hexane: EtOAc ) 40:60) to yield DUPA_1 (169 mg, 80.2%) as a
colorless oil, and crystallized using hexanezDCM. Rf: 0.58 (hexane: EtOAc = 40:60). 1H
NMR (CDCl3): 6 1.46 (m, 27H, CH3— tBu); 1.91 (m, 2H,Glu—H); 2.07 (m, 1H, Glu—H); 2.18
(m,1H, Glu-H); 2.33 (m, 2H, Glu-H); 2.46 (m, 2H, ; 4.31(s (broad), 1H, RH); 4.35 (s
(broad), 1H, R-H); 5.05 (t, 2H,Urea-H); EI-HRMS (m/z): (M + H)+ calcd for
C23H41N209,489.2812; found, 489.2808.
H2N NH
DUPA-EAOA-Phe-Arg-Lys-NH2
Reagents and conditions: (a) (i) 20 idine/DMF,room temperature,10min;(ii)Fmoc—
Arg(Boc)2-OH, HBTU, HOBt, DMF-DIPEA, 2h. (b) (i) 20%piperidine/DMF,room
temperature,10min; (ii) Fmoc-Phe—OH, HBTU, HOBt, DMF-DIPEA, 2h. (c) (i) 20%
piperidine/DMF, room temperature,10min; (ii) Fmocamino-
octanoic(EAO)acid,HBTU,HOBt,DMF/DIPEA,2h. (d) (i) 20% dine/DMF, room
temperature,10min; (ii) (tBuO)3-DUPA-OH, HBTU, HOBt, DIPEA, 2h. (e) TFA/H20/TIPS
(95:2.5:2.5),1h
EXAMPLE. DUPA—EAOA—Phe-Arg-Lys-NHz. Fmoc-Lys(Boc)-Wang resin
(0.43 mM) was swollen with DCM (3 mL) followed by yl formamide (DMF, 3 mL). A
solution of 20% piperidine in DMF (3 x 3 mL) was added to the resin, and argon was
bubbled for 5 min. The resin was washed with DMF (3 x 3 mL) and isopropyl alcohol (1'-
PrOH, 3 x 3 mL). Formation of free amine was ed by the Kaiser test. After swelling the
resin in DMF, a solution of Fmoc-Arg(Boc)2-OH (2.5 equiv), HBTU (2.5 equiv), HOBt (2.5
, and DIPEA (4.0 equiv) in DMF was added. Argon was bubbled for 2 h, and resin was
washed with DMF (3 x 3 mL) and i-PrOH (3 x 3 mL). The coupling efficiency was assessed
by the Kaiser Test. The above sequence was repeated for 3 more coupling steps to introduce
the phenylanaline (Phe), 8—amino-octanoic acid (EAO), and DUPA successively. Final
compound was cleaved from the resin using a trifluoroacetic acid
(TFA):HzO:triisopropylsilane cocktail (95:25:25) and trated under . The
concentrated product was precipitated in cold diethyl ether and dried under vacuum. The
crude product was purified using preparative RP-HPLC [(11) 210 nm; solvent gradient: 0% B
to 50% B in 30 min run; mobile phase: A) 0.1 % TFA, pH = 2; B) acetonitrile (ACN)]. ACN
was removed under vacuum, and pure fractions were —dried to yield DUPA-EAOA-
Phe-Arg-Lys—NHz as a white solid. UV/vis: lmax = 205 nm. Analytical C: tR = 6.2
min (A = 0.1 % TFA; B = CH3CN, solvent gradient: 0% B to 50% B in 15 min); ESI-MS
(m/z): (M + H)+ calcd for C40H65N10013, 893.5; found, 893.4.
co H2 n O
JL O—N
HOZC N N COZH N N
H H A +
J o H2N NH N O
DUPA-EAOA-Phe-Arg-Lys-NH2 (ocosoo1) HO 0)2
Chemical Formula: C40H64N1oo13
Exact Mass: 892.5
Molecular Weight: 893.0
H2N NH
QC08002
Chemical Formula: N13013
Exact Mass: 1177.6
Molecular Weight: 1178.3
EXAMPLE. DUPA-EAOA-Phe—Arg—Lys—NHz—NOTA. To DUPA—EAOA—
Phe—Arg-Lys—NHz (QC08001, 5.0 mg, 0.0056 mmol, M.W.:893.0) in DMSO (0.20 ml, with a
concentration at 0.028 M) was added NOTA-NHS (5.5 mg, 0.0084 mmol, 1.5 eq.) followed
by DIPEA (2.9 uL, 0.017 mmol). The on was stirred at 23 OC, monitored by LC—MS,
and most of the starting material was transformed to the corresponding product in 5 hours.
The crude material was purified by RP—C13 HPLC. ACN was removed under vacuum, and
pure fractions were freeze-dried to yield the pure AOA-Phe-Arg-Lys-NH2—NOTA
(QC08002, 3.3 mg, 50 %). ical RP-CIS HPLC: tR = 5.98 min (A = 0.1 % TFA; B =
CH3CN, solvent gradient: 0% B to 50% B in 15 min); Preparative RP—C18 HPLC: tR = 16.16
min (A = 0.1 % TFA; B = CH3CN, solvent gradient: 0% B to 50% B in 30 min); UV-Viszkmax
= 201 nm; HPLC (Agilent Preparative C18 Column): Mobile phase: A = 0.1 % TFA; B =
CH3CN; Method: 0-50 CH3CN-30 min, tR = 16.16 min LC—MS (Agilent G6130B Quadrupole
LC/MS): Mobile phase: A = 0.1 % TFA; B = CH3CN; Method: 0-50 30 min, tR =
5.98 min; MS m/z: MS-API: Calcd. for C52H84N13018 ([M+H]+): 1178.6, Found: 1178.4.
O s
COZH E
EL Jk0 f KCOZH
H020 N M COZH HN
HZN/kNH
EXAMPLE. DUPA-EAOA-Phe—Arg—Lys—NH2—NOTA—A118F. Method a):.
DUPA-EAOA-Phe-Arg-Lys-NH2—NOTA is dissolved in 2 mM NaOAc (pH 4.5) and 0.5 mL
of ethanol, and treated with A118F3-3H20 (1.5 eq.) which is y ed before
application. The pH is ed to 4.5-5.0, and the reaction mixture is refluxed for 15-30 min
with pH kept at 45-50. After cooling to room temperature, the crude material is loaded to a
cartridge, and the radiotracer eluted into vial. After sterile filtration and being diluted to
appropriate radioactivity (5-10 mCi) and specific activity (> 1 Ci/umol), the racer is
used in in vivo PET imaging.
Method b). DUPA—EAOA-Phe-Arg-Lys—NHz—NOTA is dissolved in 2 mM
NaOAc (pH 4.5), and treated with A1Cl3-3H20 (1.5 eq.). The pH is ed to 4.5-5.0, and
the reaction mixture is refluxed for 15-30 min with the pH kept at 45-50. The crude material
is purified by RP-HPLC to afford the DUPA-EAOA-Phe-Arg-Lys-NHz-NOTA-A1—OH
intermediate ready for 18F- labeling. riate amount of DUPA-EAOA-Phe-Arg-Lys-
NHz—NOTA—Al—OH is d with Na18F saline solution and ethanol (1/ 1, v/v), and the whole
mixture is heated at 100-110 0C for 15 min. After cooling to room temperature, the crude
material is loaded to a cartridge, and the racer eluted into vial. After e filtration
and being diluted to appropriate radioactivity (5-10 mCi) and specific activity (> 1 Ci/umol),
the radiotracer is ready for use in in vivo PET imaging.
0 (e)H02C c02H
DUPAEAOAPhePheEDA.NH2
Trt-EDA Resin
Reagents and conditions: (a) Fmoc-Phe-OH, HBTU, HOBt, DMF/DIPEA, 2h. (b) (i) 20
%piperidine/DMF,room temperature,10min; (ii) Fmoc-Phe—OH, HBTU, HOBt,
DMF/DIPEA, 2h. (c) (i) 20%piperidine/DMF,room temperature,10min; (ii) Fmoc-S—amino-
octanoic (EAO) acid, HBTU, HOBt, DMF/DIPEA, 2h. (d) (i) 20% piperidine/DMF, room
temperature,10min; (ii) (tBuO)3-DUPA-OH, HBTU, HOBt, DIPEA, 2h. (e) TFA/HzO/TIPS
(95:2.5:2.5),1h.
EXAMPLE. Solid Phase Peptide Synthesis (SPPS) of AOA—Phe-
A—NH2.[2, 3]. As described herein for AOA-Phe-Arg—Lys—NH2 01),
DUPA-EAOA-Phe—Phe-EDA-NH2 is preapred. The commercially available Trt-EDA resin
was swollen with DCM (3 mL) followed by dimethyl formamide (DMF, 3 mL), to which a
solution of Fmoc-Phe-OH (2.5 equiv), HBTU (2.5 equiv), HOBt (2.5 equiv), and DIPEA (4.0
equiv) in DMF was added. Argon was bubbled for 2 h, and resin was washed with DMF (3 x
3 mL) and i-PrOH (3 x 3 mL). The ng efficiency was assessed by the Kaiser Test. A
solution of 20% piperidine in DMF (3 x 3 mL) was added to the resin, and argon was
bubbled for 5 min. The resin was washed with DMF (3 x 3 mL) and isopropyl alcohol (1'-
PrOH, 3 x 3 mL). Formation of free amine was assessed by the Kaiser test. The above
sequence was repeated for 3 more coupling steps to introduce the second phenylanaline
(Phe), 8-amino-octanoic acid (EAO), and DUPA successively. Final compound was cleaved
from the resin using a trifluoroacetic acid (TFA):H20:triisopropylsilane cocktail (95:2.5:2.5)
and concentrated under vacuum. The concentrated product was precipitated in cold diethyl
ether and dried under vacuum. The crude product was ed using preparative RP-HPLC
[/1] 210 nm; solvent gradient: 0% B to 100% B in 30 min run; mobile phase: A) 10 mM
NH4OAc (pH = 7, buffer); B) acetonitrile (ACN)]. ACN was removed under vacuum, and
pure fractions were freeze—dried to yield AOA-Phe—Phe-EDA-NH2 as a white solid.
Analytical RP—C13 HPLC: tR = 3.99 min (A = 10 mM NH4OAc, pH = 7.0; B = CH3CN,
solvent gradient: 0% B to 100% B in 15 min); Preparative RP-C18 HPLC: tR = 16.05 min (A
= 10 mM NH4OAc, pH = 7.0; B = CH3CN, t gradient: 0% B to 100% B in 30 min);
UV-Vis: kmax = 209 nm; LC-MS: LC-MS (Agilent G6130B pole LC/MS) of Product
Mobile phase: Buffer (pH 7)-CH3CN; Method: 0-100 ACN-15 min, tR = 3.99 min. MS m/z:
MS-API: Calcd. for C39H56N7011([M+H]+): 7984, Found: 798.3; Calcd. for C39H55N7O11K
([M+K]+): 836.4, Found: 836.3. HPLC (Agilent Preparative C18 Column): Mobile phase:
Buffer (pH 7)-CH3CN; Method: 0—100 ACN-30 min, tR = 16.05 min.
o o Hozcfil \ o—N
O “W H2
N N/\g/
H I H + <1JO
0 J HPFe-TFA
JL U H020MoecuaI I rW'eig ht" 660 38. .
H020 m M COzH
DUPA-EAOA-Phe-Phe-EDA-NHZ QC08008
Chemical Formula: C39H55N7O11
Exact Mass: 797.4
Molecular Weight: 797.9
O O
H H
F”\/\/\/\)L
i/\NHKCOZ
DIPEA u
0 “MNHV” NNJ_
’ 0
DMSO JL \\cozH
HOZC COZH ocosooa U n u Chemical Formula: C51H74N1OO16
Exact Mass: 1082.5
Molecular Weight: 1083.2
EXAMPLE. To DUPA—EAOA—Phe-Phe—EDA—NH2 (QC08008, 5.9 mg,
0.0074 mmol, M.W.:797.4) in DMSO (0.25 ml, with a concentration at 0.025 M) was added
NOTA—NHS (7.3 mg, 0.011 mmol, 1.5 eq.) followed by 4 drops of DIPEA. The mixture was
stirred at 23 OC and monitored by LC-MS. 4 hours later, LC—MS showed that almost all of the
starting material was transformed to the product. The crude al was then purified by
preparative RP-HPLC to afford the pure DUPA-EAOA-Phe—Phe-NOTA (QC08009, 4.50 mg,
56 %, based on 8.02 mg in theory, 97 % purity by HPLC at 210 nm). Analytical RP-C18
HPLC: tR = 3.45 min (A = 10 mM NH4OAc, pH = 7.0; B = CH3CN, solvent gradient: 0% B
to 100% B in 15 min); Preparative RP-CIS HPLC: tR = 10.09 min (A = 10 mM NH4OAc, pH
= 7.0; B = CH3CN, solvent gradient: 0% B to 100% B in 30 min); UV-Vis: max = 211 nm;
LC-MS: LC-MS (Agilent G6130B Quadrupole LC/MS) of Product Mobile phase: Buffer (pH
CN; Method: 0-100 ACN—15 min, tR = 3.45 min. MS m/z: MS-API: Calcd. for
C51H75N10016 ([M+H]+): 1083.5, Found: 1083.3; HPLC (Agilent Preparative C18 ):
Mobile phase: Buffer (pH 7)-CH3CN; Method: 0—100 ACN-30 min, tR = 10.09 min. 1H NMR
(400 MHz, DMSO—d6) 5 = 10.13 (br, 1 H), 8.98 (br, 1 H), 8.43 (br, 1 H), 7.90 (br, 3 H), 7.30—
7.10 (m, 10 H), 6.37 (br, 1 H), 6.28 (br, 1 H), 4.60—4.52 (m, 1 H), 4.32—4.44 (m, 1 H), 4.24—
4.31 (m, 2 H), .03 (m, 2 H), 3.85—3.92 (m, 2 H), 3.28 (s, 4 H), 3.25 (s, 2 H), 3.09 (m, 1
H), 3.05 (m, 1 H), 2.92—3.02 (m, 4 H), 2.54-2.67 (m, 12 H), 2.31—2.38 (m, 2 H), 2.19-2.31 (m,
3 H), 2.11—2.18 (m, 2 H),2.02—2.10 (m, 3 H), 1.52-1.72 (m, 4 H), 1.25—1.37 (m, 4 H), 1.05—
1.13 (m, 2 H),
o o COZH 0 fl co H
F”H\/\/\/\)L
? r 2
COZH N N$NWNJLN
H ; H H
Of NNJ
\\COZH
A DUPA-EAOA-Phe-Arg-LyS-NOTA
N N H QC08004
64CuCIZ-NH4OAc
pH 5.5, 95 00
o o COZH 0 m 00 H
HM H ? r 2
COzH FN NJNWNJLN s
HOZC N N COZH HN
H H A DUPA-EAOA-Phe-Arg-Lys-NOTA-B‘Cu
H2N NH
EXAMPLE. Radiochemical Synthesis of DUPA-EAOA-Phe—Arg-Lys-
NOTA-“Cu Radiotracer. NOTA based chelators have also been ed and ed in
the formulation of NOTA—64/67Cu for nuclear ne/radiotherapy.[14-16] The
corresponding DUPA-NOTA-64Cu was prepare for the dual purpose of imaging and therapy,
also referred to as ostics. DUPA-EAOA-Phe—Arg-Lys—NOTA—64Cu was prepared
according a standard protocol with minor modifications. [4, 14-16] The 64Cu(OAc)2, in situ
ed from z with 0.1 M ammonium acetate (pH 5.5),was added to the reaction tube
containing the DUPA-NOTA precursor. The resulting mixture was then heated to 95 0C for
15 min. After cooling to room temperature, the crude material was purified by radioactive
HPLC on a C18 column using MeCN and 0.1% TFA as the mobile phase to afford the target
radiotracer with ~ 90% radiochemical purity (RCP). Sterile filtration and dilution in isotonic
saline to the desired radioactivity provided the radiotracer ready for PET imaging.
COZH i
H020 NJLN COzH DUPA-EAOA-Phe-Phe-NOTA
H H (Qcosoos) H
COZH E
H020EarN COZH
H M = 68Ga, 64Cu or Al-13F
DUPA-EAOA-Phe-Phe-NOTA-“CulAl-“F
EXAMPLE. Radiochemical sis of DUPA-EAOA-Phe-Phe-NOTA-
64Cu/Al—13F.
o N
COZH ;
o o
o \\
JP COZH
DU PA-EAOA-Phe-Phe-NOTA
H (0008009) U
COZH F
HOZC N N COZH
H H
DUPA-EAOA-Phe-Phe-NOTA-“Ga
EXAMPLE. Radiochemical synthesis of DUPA-EAOA-Phe-Phe-NOTA-
68Ga.
EXAMPLE. l procedure for 68Ga labeling: 68Ga was eluted from the
68Ge/68Ga generator with 0.1N HCl. A predetermined amount of 68'Ga in 0.1N HCl was added
to a DUPA-NOTA on in acetate buffer (pH 4.8). The labeling mixture was incubated at
room temperature, and labeling efficiencies were d by radioactive HPLC. The
radiolabeled product was purified by radioactive HPLC and the DUPA-NOTA-68Ga peak
sample was collected. After sterile filtration and being diluted to appropriate radioactivity (5-
10 mCi) and specific activity (> 1 l), the radiotracer was ready for in vivo PET
imaging study.
COZH E
H02C N N COzH
H H
DUPA-C-NETA
DUPA-C-NETA-M OH
M = AI-13F, 68Ga, 1”Lu or say
EXAMPLE. Radiochemical synthesis of DUPA-C-NETA based theranostics.
51) Qcosoos.
, DIPEA;
b) TFA
HgLfiNHNHQfdl—Lfio”o COZH FHW
° “
H020 ”k” COZH
DUPA-C-NETA 0?:
EXAMPLE. ation of the NOTA Derivatives. Bifunctional conjugates,
also referred to as theranotics, are described herein. Compounds described herein can tightly
chelate both radionuclides such as 18F and 68Ga for PET imaging, and radionuclides 177Lu and
90Y for radiotherapy. C—NETA, a NOTA derivative, has been reported to e AllSF with
about twice the efficiency (87%) of 17] Moreover, C-NETA also reportedly chelates
the commonly used radiotherapeutic es, such as 177Lu and 90Y, with high labeling
ency.[18] Thus, it is appreciated , that C—NETA is useful as a bifunctional
chelator that can be used for both PET imaging and radiotherapy, where the radionuclide is a
metal or metal halide, such as A118F, 68Ga, 177Lu or 90Y.
EXAMPLE. A PyBOP promoted coupling between QC04018 and QC08008,
followed by deprotection of tert-butyl ester with TFA provides DUPA-C-NETA. DUPA-C-
NETA is used to evaluate the labeling efficiency to AllSF, 68Ga, 177Lu and 90Y, and evaluate
the in viva PET imaging and radiotherapy.
METHOD EXAMPLES
EXAMPLE. The specificity of the radionuclide containing conjugates binding
to FR is evaluated against KB xenografts homogenates and Cal5l xenografts homogenates.
Concentration dependent binding was evaluated for F-QCO7017 and 18F—AIF-
QC07043, and separated into specific and non-specific binding. Significant non-specific
binding was not observed in KB homogenates. Minor non—specific binding was observed in
Cal5l homogenates, with a specific/non-specific g ratio of >3:l at all trations up
to about 30 nM for 18F—AIF—QCO7017, and a specific/non—specific binding ratio of >221 at all
concentrations up to about 20 nM for 18F—AIF-QC07043. Minor non-specific binding was
observed in A549 homogenates, with a specific/non-specific binding ratio of >2:l at all
trations up to about 10 nM for 18F—AIF-QC07043. Scatchard analyses were also
performed. Displaceable and saturable binding of 18F—AIF—QC07017 in human tumor
xenografts (KB and Ca151) by self competition was observed. Both 18F-AIF—QCO7017 and
F-QC07043 bound one site with high affinity in all cell xenografts. The high ratio of
Bmax/Kd indicated a high specific g affinity to KB xenografts. Moderate binding
affinity was observed for Ca151 afts, and the lowest binding affinity was observed for
A549 xenografts. Without being bound by , it is believed herein that the moderate
expression of FR in Ca151 xenografts accounts for the lower g affinity.
g affinities of 18F—AIF-QCO7017 (2) to FR in KB and Ca151 tumor crude homogenate.
Folate-NOTA-A118F (2) Bmax / Kd
Binding ties of 18F—AIF-QC07043 to FR in KB and Ca151 tumor crude homogenate.
FA-PEG12-NOTA-A118F Bmax/Kd
EXAMPLE. uPET imaging was performed on nude mice bearing KB tumor
xenografts under baseline and competed conditions to evaluate the in vivo binding specificity
of 18F-AIF—QCO7017 (2) to FR. Nude mice bearing KB tumor xenografts on their left
shoulder were injected with 0.30-0.40 mCi (2). The ed group received 100 pg of folic
acid 10 min before the iv. injection of (2), and the ent group was injected with a
corresponding volume of phosphate buffer. Time course inspection of PET images obtained
at various time points revealed that the data acquired in 60—90 min post tracer injection gave
the best visual PET imaging. The KB tumors were clearly visualized in the treated group,
whereus the uptake of (2) was completely inhibited by competing with folic acid, ting
a high specificity of (2) binding to FR in vivo. Without being bound by theory, it is believed
herein that the high ctivity found in kidneys was due to the uptake mediated by FR that
is expressed in the proximal tubule cells in kidneys and the potential accumulation of
radiotracer via renal excretion, which was further supported by the biodistribution studies
described herein. With the exception of the liver, significant uptake in other organs was not
observed. A significant blocking effect in liver uptake was observed in under competed
conditions.
E. Ex vivo tribution study of compounds described herein
under both baseline and competed conditions in nude mice g KB tumor xenografts on
their left shoulder demonstrates a high and specific uptake in FR(+) tumors. Radiotracer
levels of 18F—AIF-QC07017 and 18'F—AIF-QC07043 were determined in whole blood, plasma,
heart, kidney, liver, lung, muscle, spleen, KB xenograft tumor tissues and A549 xenograft
tumor s (, , and ). The highest signal was observed in the
kidneys. Accumulation was observed to a substantially less extent in the liver. Without
being bound by theory, it is believed herein that the highest accumulation of radioactivity in
kidneys, along with the relative low uptake of radiotracer in the hepatobiliary system i.e.
liver, bile and ine/feces supports that renal elimination is the predominant ion
pathway. Except for the kidneys, accumulation in KB xenograft tumor tissues was greatest,
and significantly greater than in the liver. lation in A549 xenograft tumor tissues
was comparable to the liver. Accumulation in both KB xenograft tumor tissues and A549
xenograft tumor tissues was blocked under competition conditions with folic acid (
and ). The FR specificity of 18F—AIF-QC07‘017 and 18F—AIF—QC07043 was
comparable to latide (EC20), a compound in clinical trials, in both KB xenograft tumor
tissues and A549 xenograft tumor tissues.
Uptake in KB xenografts
Example Uptake Uptake under competed
(SUV) conditions
(i SEM) (SUV)
(i SEM)
18F-AIF—QC07017 2.84 i 0.76 0.34 i 0.02
F—QC07043 2.33 i 0.13 0.41 i 0.06
99mTc—EC20 2.75 i 0.14 0.43 i 0.05
P values: 99mTc—EC20 vs 18F—AIF—QC07043, p=0.15; 18F—AIF-QC07017 vs 18F-AIF—
QC07043, p=0.48; EC20 VS 18F—AIF—QC07017, p=0.85.
Uptake in A549 xenografts
Example Uptake Uptake under competed
(SUV) ions
(i SEM) (SUV)
(i SEM)
18F-AIF-QC07017 0.64 i 0.16 0.03 i 0.01
18F—AIF—QC07043 0.53 i 0.06 0.04 i 0.01
99mTc-EC20 0.71 i 0.09 0.08 i 0.02
P : 99mTc-EC20 vs l8F—AIF—QC07043, p=0.l3; 18F-AIF-QC07017 vs F—
QC07043, p=0.50; 99mTc—EC20 vs 18F—AIF—QC07017, p=0.74
E. In vitro evaluation of DUPA-EAOA-Phe-Phe-NOTA-68Ga
radiotracer (68Ga-QC08009). 67Ga has a longer half life than 68Ga (about 3.3 days versus
about 68 minutes, respectively). Thus, 67Ga is used as a surrogate of 68Ga for in vitro
evaluation of Kd values and tissue imaging. It is to be understood that the in vitro evaluation
of Kd values and tissue imaging observed for 67Ga is predictive of 68Ga. DUPA-EAOA-Phe-
Phe-NOTA-67Ga (67Ga—NOTA—LC-PSMA2) was prepared in nearly tative
hemical yield. In vitro study in both the PSMA(-) cell line (PC3) and the PSMA(+)
cell lines (LnCaP and PIP—PC3) ed a PSMA mediated high and specific uptake with a
Kd = 8.45i2.l6 nM. PC3 is a PSMA (-) cell line; LnCap is a PSMA (+) cell line; and PIP-
PC3 is a transfect cell line with higher PSMA expression. Uptake of 68Ga—QC08009 by PC3
cells was minimal, and did not change when competed. Uptake of C08009 by LnCaP
and PIP-PC3 was substantial, with PIP-PC3 cells showing the highest uptake. In both cases,
Uptake of 68Ga-QC08009 by LnCaP and PIP-PC3 is blocked by competing ligand.
Compared to 67Ga-DKFZ—PSMAll, an imaging agent in clinical trials, 67Ga-NOTA-LC—
PSMA2 demonstrated superior binding to PSMA(+) prostate cancer tissues.
EXAMPLE. In Vivo PET imaging and BioD study of DUPA-EAOA-Phe-Phe-
NOTA-63Ga radiotracer (63Ga-QC08009). In vivo micro-PET/CT scan with 68Ga-NOTA-LC—
PSMA2 racer in mice carrying PSMA (+) LnCaP xenografts showed 4.29 %ID uptake
in PSMA(+) tumor. At 1 hour post-injection, most of the racer was found in bladder.
Without being bound by theory, it is ed herein that the data support that the y
elimination pathway is in urine. In addition, compared to other tissues, minor accumulation
of radiotracer was observed in the kidneys. Without being bound by theory, it is believed
herein that the relatively high PSMA expression in mouse kidneys, compared to other tissues,
accounts at least in part for the minor accumulation of 68Ga—NOTA—LC—PSMA2 radiotracer in
kidneys.
Claims (13)
1. A conjugate of the formula B-L-P or a pharmaceutically acceptable salt thereof, wherein B is a folic acid moiety, L is a divalent linker comprising a polyether, and P comprises a on-emitting isotope having a half-life of more than 80 minutes.
2. The conjugate of claim 1, comprising folate-Asp.
3. The conjugate of claim 1, comprising folate-Arg.
4. The conjugate of claim 1 wherein the linker ses a polypeptide comprising lysine, ne, or aspartic acid, or a combination thereof.
5. The conjugate of any one of claims 1 to 4, wherein the polyether is a polyethylene glycol (PEG).
6. The conjugate of any one of claims 1 to 5, wherein the positron-emitting e has a half-life of more than 90 minutes.
7. The conjugate of any one of claims 1 to 5, wherein the positron-emitting isotope has a half-life of more than 100 minutes.
8. The ate of any one of claims 1 to 5, wherein the positron-emitting isotope has a half-life of 80 minutes to 8 hours.
9. The conjugate of any one of claims 1 to 4, wherein the positron-emitting isotope is selected from the group consisting of 45Ti, 61Cu, 66Ga, and 18F.
10. The conjugate of claim 1 having the formula wherein n is from 1 to 20.
11. The conjugate of claim 1, comprising the formula
12. A composition comprising a ate according to any one of claims 1 to 11, and an acceptable carrier.
13. A dosage form comprising a conjugate according to any one of claims 1 to 11, in a solution. WO 73678 5E3.» :mmfim .63..
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Application Number | Priority Date | Filing Date | Title |
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US201361904387P | 2013-11-14 | 2013-11-14 | |
US201361904400P | 2013-11-14 | 2013-11-14 | |
US61/904,400 | 2013-11-14 | ||
US61/904,387 | 2013-11-14 | ||
US201361909822P | 2013-11-27 | 2013-11-27 | |
US61/909,822 | 2013-11-27 | ||
PCT/US2014/065467 WO2015073678A1 (en) | 2013-11-14 | 2014-11-13 | Compounds for positron emission tomography |
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NZ719939B2 true NZ719939B2 (en) | 2022-06-28 |
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