US20080193381A1 - Heterodimers of glutamic acid - Google Patents
Heterodimers of glutamic acid Download PDFInfo
- Publication number
- US20080193381A1 US20080193381A1 US11/936,659 US93665907A US2008193381A1 US 20080193381 A1 US20080193381 A1 US 20080193381A1 US 93665907 A US93665907 A US 93665907A US 2008193381 A1 US2008193381 A1 US 2008193381A1
- Authority
- US
- United States
- Prior art keywords
- compound
- substituted
- radionuclide
- alkyl
- chelate complex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 title description 5
- 235000013922 glutamic acid Nutrition 0.000 title description 5
- 239000004220 glutamic acid Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 31
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- -1 when substituted Chemical group 0.000 claims abstract description 23
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 18
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 17
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 13
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 9
- 230000005764 inhibitory process Effects 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 60
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 58
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 56
- 230000027455 binding Effects 0.000 claims description 36
- 210000001519 tissue Anatomy 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 239000004472 Lysine Substances 0.000 claims description 17
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims description 17
- 150000002367 halogens Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 238000003384 imaging method Methods 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001576 beta-amino acids Chemical class 0.000 claims description 9
- 239000000833 heterodimer Substances 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- ZZASEPMMGWJWOV-YUMQZZPRSA-N (2s)-2-[[(1s)-5-amino-1-carboxypentyl]carbamoylamino]pentanedioic acid Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCC(O)=O ZZASEPMMGWJWOV-YUMQZZPRSA-N 0.000 claims description 5
- KRBIFVSYVYPEFJ-UHFFFAOYSA-N 2-[[5-[(4-bromophenyl)carbamoylamino]-1-carboxypentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC(=O)NC(C(O)=O)CCCCNC(=O)NC1=CC=C(Br)C=C1 KRBIFVSYVYPEFJ-UHFFFAOYSA-N 0.000 claims description 5
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 210000002307 prostate Anatomy 0.000 claims description 5
- 229940056501 technetium 99m Drugs 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 4
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 4
- HDDBVNPCLXYMKS-GJZGRUSLSA-N (2s)-2-[[(1s)-1-carboxy-5-[(2-chlorophenyl)methylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCCCNCC1=CC=CC=C1Cl HDDBVNPCLXYMKS-GJZGRUSLSA-N 0.000 claims description 3
- HKCPAWLISGYKTE-GJZGRUSLSA-N (2s)-2-[[(1s)-1-carboxy-5-[(3-chlorophenyl)methylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCCCNCC1=CC=CC(Cl)=C1 HKCPAWLISGYKTE-GJZGRUSLSA-N 0.000 claims description 3
- WXQQOZABOOIEOS-GJZGRUSLSA-N (2s)-2-[[(1s)-1-carboxy-5-[(4-chlorophenyl)methylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCCCNCC1=CC=C(Cl)C=C1 WXQQOZABOOIEOS-GJZGRUSLSA-N 0.000 claims description 3
- JUBJIZWZJOLMOS-UHFFFAOYSA-N 2-[[1-carboxy-5-[(3-iodophenyl)methylcarbamoylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC(=O)NC(C(O)=O)CCCCNC(=O)NCC1=CC=CC(I)=C1 JUBJIZWZJOLMOS-UHFFFAOYSA-N 0.000 claims description 3
- VSJUFKLNBGXFBO-UHFFFAOYSA-N 2-[[1-carboxy-5-[(4-chlorophenyl)carbamoylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC(=O)NC(C(O)=O)CCCCNC(=O)NC1=CC=C(Cl)C=C1 VSJUFKLNBGXFBO-UHFFFAOYSA-N 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- DMTAKQVZLZCXBV-CABCVRRESA-N (2s)-2-[[(1r)-5-(benzylamino)-1-carboxypentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@@H](C(O)=O)CCCCNCC1=CC=CC=C1 DMTAKQVZLZCXBV-CABCVRRESA-N 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
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- 201000000980 schizophrenia Diseases 0.000 claims description 2
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- 150000004697 chelate complex Chemical class 0.000 claims 27
- 241000124008 Mammalia Species 0.000 claims 18
- 210000000056 organ Anatomy 0.000 claims 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 8
- WUAPFZMCVAUBPE-NJFSPNSNSA-N 188Re Chemical compound [188Re] WUAPFZMCVAUBPE-NJFSPNSNSA-N 0.000 claims 4
- 108091005804 Peptidases Proteins 0.000 claims 4
- 102000035195 Peptidases Human genes 0.000 claims 4
- 230000001575 pathological effect Effects 0.000 claims 4
- 235000019833 protease Nutrition 0.000 claims 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 4
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 claims 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 3
- 229910052802 copper Inorganic materials 0.000 claims 3
- 239000010949 copper Substances 0.000 claims 3
- 125000003107 substituted aryl group Chemical group 0.000 claims 2
- YHGIYVVZAPBHCX-UHFFFAOYSA-N 2-[[1-carboxy-5-(phenylcarbamoylamino)pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)NC(=O)NC(C(O)=O)CCCCNC(=O)NC1=CC=CC=C1 YHGIYVVZAPBHCX-UHFFFAOYSA-N 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 208000031229 Cardiomyopathies Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 208000019693 Lung disease Diseases 0.000 claims 1
- 208000001647 Renal Insufficiency Diseases 0.000 claims 1
- 206010062237 Renal impairment Diseases 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 230000033115 angiogenesis Effects 0.000 claims 1
- 210000005013 brain tissue Anatomy 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 208000035269 cancer or benign tumor Diseases 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 230000005977 kidney dysfunction Effects 0.000 claims 1
- 201000006370 kidney failure Diseases 0.000 claims 1
- 210000005084 renal tissue Anatomy 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
- 108090000369 Glutamate Carboxypeptidase II Proteins 0.000 abstract description 19
- 102000003958 Glutamate Carboxypeptidase II Human genes 0.000 abstract description 19
- 238000011282 treatment Methods 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 4
- 125000005842 heteroatom Chemical group 0.000 abstract description 4
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- 210000004027 cell Anatomy 0.000 description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- OXUUJYOSVPMNKP-ZANJDRPYSA-N (2s)-2-[[(1s)-1-carboxy-5-[(4-iodanylphenyl)methylamino]pentyl]carbamoylamino]pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)N[C@H](C(O)=O)CCCCNCC1=CC=C([123I])C=C1 OXUUJYOSVPMNKP-ZANJDRPYSA-N 0.000 description 51
- 239000000047 product Substances 0.000 description 43
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 38
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 36
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
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- ISEYJGQFXSTPMQ-UHFFFAOYSA-N 2-(phosphonomethyl)pentanedioic acid Chemical compound OC(=O)CCC(C(O)=O)CP(O)(O)=O ISEYJGQFXSTPMQ-UHFFFAOYSA-N 0.000 description 12
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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Definitions
- NAALADase N-acetylated alpha-linked acidic dipeptidase
- GCPII glutamate carboxypeptidase II
- NAAG N-acetylaspartyl-glutamate
- the enzyme is a type II protein of the co-catalytic class of metallopeptidases, containing two zinc atoms in the active site.
- NAALADase independent of its characterization in the nervous system, one form of NAALADase was shown to be expressed at high levels in human prostatic adenocarcinomas and was designated the prostate-specific membrane antigen (PSMA).
- PSMA prostate-specific membrane antigen
- the NAALADase/PSMA gene is known to produce multiple mRNA splice forms and based on previous immunohistochemical evidence, it has been assumed that the human brain and prostate expressed different isoforms of the enzyme.
- PSMA Human prostate-specific membrane antigen
- FOLH1 folate hydrolase I
- PSMA is a trans-membrane, 750 amino acid type II glycoprotein which is primarily expressed in normal human prostate epithelium but is upregulated in prostate cancer, including metastatic disease.
- PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates, capable of sequentially removing the poly-gamma-glutamyl termini. Since PSMA is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic and hormone-refractory carcinomas, it is a very attractive target for prostate imaging and therapy.
- Developing ligands that interact with PSMA and carry appropriate radionuclides may provide a promising and novel targeting option for the detection, treatment and management of prostate cancer.
- the radio-immunoconjugate form of the anti-PSMA monoclonal antibody (mAb) 7E11, known as the PROSTASCINT scan, is currently being used to diagnose prostate cancer metastasis and recurrence.
- mAb monoclonal antibody
- PROSTASCINT targets the intracellular domain of PSMA and is thought to bind mostly necrotic portions of prostate tumor. 14 More recently, monoclonal antibodies have been developed that bind to the extracellular domain of PSMA and have been radiolabeled and shown to accumulate in PSMA-positive prostate tumor models in animals.
- One aspect of the present invention relates to compounds of Formula (I)
- R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′,
- Q is C(O), O, NR′, S(O) 2 , C(O) 2 (CH2)p
- Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
- Z is H or C 1 -C 4 alkyl
- m is 0, 1, 2, 3, 4 or 5 n is 0, 1, 2, 3, 4, 5 or 6 p is 0, 1, 2, 3, 4, 5 or 6
- R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ further wherein (i) at least one of R or R′ is a C 6 -C 12 aryl or C 6 -C 12 heteroaryl substituted with a halogen or (ii) at least one of R or R′ is a C 6 -C 12 heteroaryl or a pharmaceutically acceptable salt
- Another aspect of the present invention relates to compounds of Formula (Ia)
- R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′,
- Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
- Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
- Z is H or C 1 -C 4 alkyl
- m is 0, 1, 2, 3, 4 or 5 n 0, 1, 2, 3, 4, 5 or 6 n′ 0, 1, 2, 3, 4, 5 or 6 p is 0, 1, 2, 3, 4, 5 or 6
- R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ further wherein (i) at least one of R or R′ is a C 6 -C 12 aryl or C 6 -C 12 heteroaryl substituted with at least a halogen or (ii) at least one of R or R′ is a substituted or un
- n is 0 or 1 and n′ is 0 or 1.
- the present invention also relates to glutamate-urea-lysine PSMA-binding moieties and their use in diagnostic and therapeutic treatment.
- the urea-based analogues described here are glutamate-urea- ⁇ or ⁇ -amino acid heterodimer coupled through the ⁇ -NH 2 or ⁇ -NH 2 groups.
- Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.
- the compounds of the present invention can find use as targeting agents and diagnostic and therapeutic agents for the treatment and management of prostate cancer and other diseases related to NAALADase inhibition.
- FIGS. 1A-1C are HPLC chromatograms respectively of the co-injection of the TC-99m-glu-urea-DpK (Tc-99m-MIP 1008), the rhenium analog, and the rhenium diester complexes.
- FIGS. 2A-2D show stability of the Tc-99m complex of Glu-urea-DpK (Tc-99m-MIP 1008) at 37° C. in respectively PBS pH 7.2, 0.1 M Cysteine in PBS, 0.1 M DTPA in PBS, and 5% mouse serum in PBS for 6 hours.
- FIGS. 3A-3B are respective HPLC chromatograms of N—[N—[(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-iodo-L-tyrosine (I-131 DCIT) crude reaction FIG. 3A , top, purified at 2 hours, FIG. 3B , middle and at 2 days FIG. 3C , bottom.
- FIG. 5 shows I-123 DCIT bound specifically to LnCap cells and not PC3 cells (left set) as is evident by the counts displaceable by nonradiolabeled compound (middle set) or PMPA (right set) in LnCap cells.
- the histograms show the mean ⁇ SEM, each experiment was performed in duplicate.
- FIG. 6 is Scatchard Analysis in PSMA Cellular Binding Assay with cold 2- ⁇ 3-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-ureido ⁇ -pentanedioic acid (DCT).
- DCT cold 2- ⁇ 3-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-ureido ⁇ -pentanedioic acid
- FIG. 7 shows biological assessments of selected compounds in the PSMA-positive LNCaP cells.
- FIG. 8 show biological assessments of lead compounds in the PSMA-positive LNCaP cells.
- FIG. 9 Shows Scatchard Analysis in PSMA Cellular Binding Assay with MIP1072.
- FIG. 10 shows internalization of I-131-MIP 1072.
- FIGS. 11A and 11B respectively show stability of I-131 MIP-1072 verses DCT and Phenacetin in rat microsomes for 60 minutes.
- FIG. 12 shows tissue biodistribution of the I-131 MIP1072 in xenograft tumored mice.
- FIG. 13 shows inhibition of NAALADase activity from LNCaP cellular lysates.
- FIG. 14 shows inhibition of NAALADase Activity from LNCaP Cellular lysates.
- FIG. 15 shows inhibition of NAALADase Activity from LNCaP Cellular lysates.
- FIG. 16 shows the ability of test compounds to inhibit the binding of a known NAALADase inhibitor, 131I-DCIT, to PSMA on LNCaP cells was examined. Cells were incubated with various concentrations of test compounds and 131I-DCIT for 1 hour then washed and counted to determine IC50 values.
- FIG. 17 is direct binding analysis of MIP-1072.
- 123 I-MIP-1072 (3 nM, >1,000 mCi/ ⁇ mole) was incubated with PSMA positive LNCaP cells or PSMA negative PC3 cells (300,000 cells/well), in both the absence and presence of either non-radioactive 10 ⁇ M MIP-1072 or 10 ⁇ M of a specific PSMA inhibitor (PMPA).
- PMPA specific PSMA inhibitor
- FIG. 18 shows saturation binding analysis of 123 I-MIP-1072 in LNCaP cells.
- FIG. 19 shows internalization of 123 I-MIP-1072.
- FIG. 20 shows uptake of 123 I-MIP-1072 in LNCaP xenograft bearing mice. Tissue biodistribution of 123 I-MIP-1072 (2 ⁇ Ci/mouse, >1,000 mCi/ ⁇ mole) was assessed in selected tissues from LNCaP (PSMA positive) tumor bearing nude mice. Results are expressed as the percent of the injected dose per gram of the selected tissues (% ID/g).
- FIG. 21 Uptake of 123 I-MIP-1072 in LNCaP and PC3 xenograft bearing mice. Tissue biodistribution of 123 I-MIP-1072 (2 ⁇ Ci/mouse, >1,000 mCi/ ⁇ mole) was assessed in selected tissues from LNCaP (PSMA positive) and PC3 (PSMA negative) tumor bearing nude mice with (Blocked) or without (Normal) pretreatment with 50 mg/kg PMPA.
- “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
- Alkyl refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
- the alkyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, or alkoxy.
- R′ substituent it is a lower alkyl of from 1 to 6 carbons, more preferably 1 to 4 carbons.
- Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
- the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
- substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
- Examples of aryl groups include phenyl, napthyl and anthracyl groups. Phenyl and substituted phenyl groups are preferred.
- Heteroaryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.
- the following compounds were all prepared in overall yields ranging from 20-40% following the route depicted in Scheme 1.
- the first step performed at 0° C. under inert conditions used the di-t-butyl ester of Glutamic acid with CDI in the presence of base to form the intermediate Glu-urea-imidazole derivative 2.
- This intermediate was activated with MeOTf under basic conditions to afford the methylated imidazole 3, which under inert conditions reacted readily with amines.
- the tert-butyl ester protecting groups were removed using 20% TFA in DCM for 1 to 4 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator or blown dry with nitrogen and purified on a silica column or recrystallized. The final products were tested in vitro and in vivo.
- the analogs can be prepared via the isocyanate generated in situ using triphosgene. This approach can be accomplished by either activation of the glutamate residue and coupling with a lysine residue (route A) or by activating the lysine residue and coupling it with the glutamate (route B) as shown in scheme 2 below.
- reaction is concentrated, diluted with 50 mL ethyl acetate, washed 2N NaHSO4 (2 ⁇ 50 mL), brine (50 mL) and dried over sodium sulfate to yield a yellow oil. Purification by column chromatography to afford the desired product as a clear oil which upon standing solidifies to a white solid (1.9 g, 54%).
- reaction was concentrated to dryness, diluted with 150 mL ethyl acetate, washed with 2N NaHSO 4 (2 ⁇ 200 mL), brine (150 mL) and dried over sodium sulfate to yield a yellow oil.
- This oil was purified by column chromatography (SiO 2 ) to afford the desired product as a clear oil which upon standing solidifies to a white solid (12.0 g, 72%).
- a tether is incorporated onto the side chain of glutamic acid or lysine prior to conjugation to form the urea dimer.
- the side chain carboxylic acid of one of the glutamic acids is modified into a tether to append a chelator, atom or functional group that is or contains a radionuclide (Scheme 4).
- the protected intermediate was prepared by reductive amination using pyridine-2-carboxaldehyde as previously described. Treatment with 2M LiOH in MeOH effected hydrolysis of the methyl ester. The methanol was removed and excess DCM:TFA (1:1) was added and the reaction stirred at room temperature overnight. The crude material was converted into the desired Rhenium conjugate following the procedure described above. Preparative HPLC afforded the desired molecule (9.5 mg, 16%).
- the following compounds were all prepared in overall yields ranging from 20-40% usin the route depicted in Scheme 3.
- the Z-deprotected Glu-urea-lysine was mixed with the appropriate aldehyde (0.9 equivalents) at room temperature for one hour to form the ⁇ chiff base intermediate.
- the ⁇ chiff base was reduced using 1 equivalent of sodium triacetoxyborohydride.
- the compounds were deprotected using 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator or were blown dry with nitrogen and extracted using methylene chloride and water. The water layer was evaporated to dryness to afford the deprotected product in 40-80% yield.
- the reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was purified by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam.
- phenyl isocyanate (100 mg, 0.84 mmol) was dissolved in DCM (10 mL) 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (409 mg, 0.84 mmol) was added and stirred for 3 hours.
- the reaction mixture was evaporated to dryness and the crude mixture was purified via flash column chromatography 2:1 hexanes/ethyl acetate to afford the tert-butyl ester as a white solid which was deprotected using TFA/CH 2 Cl 2 affording the desired product.
- the rhenium complexes of the SAAC-inhibitors are conveniently isolated from the reactions of the readily available precursor [Net 4 ] 2 [Re(CO) 3 Br 3 ] with the SAAC-inhibitor. Since the donor sets provided by the SAAC terminus are well documented as effective chelators for the ⁇ M(CO) 3 ⁇ +1 core and have been designed to adopt the required facial arrangement about the metal site, the preparations of the complexes were unexceptional.
- the PEG2 dipyridyl compound, (17R,21S)-11,19-dioxo-1-( yridine-2-yl)-2-( yridine-2-ylmethyl)-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme 1, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
- the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental.
- the PEG4 dipyridyl compound (23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14-tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
- the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product. (5.1 mg, 29.6%) as a white solid.
- the PEG8 dipyridyl compound, (35R,39S)-29,37-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahentetracontane-35,39,41-tricarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
- the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (8.0 mg, 30.4%) as a white solid. ESMS m/z: 1195 (M+H) + .
- the C11-PAMA compound, (19R,23S)-13,21-dioxo-2-( ⁇ yridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid was prepared employing the same general procedure as shown in Scheme A, using previously prepared and protected 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester.
- the rhenium ester complex was prepared employing the same procedure as described in the general rhenium experimental. The compound was deprotected using the previously described methods to yield the desired product (3.0 mg, 75%) as an off-white solid.
- Table 1 below is a summary of synthesized PSMA inhibitors investigated.
- the properties of the Group VII metals technetium and rhenium are very similar due to their periodic relationship. It was anticipated that the metals would demonstrate similar reaction chemistry, which is often the case for the tricarbonyl, nitrogen, and thiazole chemistry of these two metals. Likewise, due to their similar size that stabilizes the spin paired d 6 electron configuration of M(I), perrhenate and pertechnetate have very similar reaction behaviors. Synthesizing the rhenium-TECs allowed us a facile route to structurally characterize the products. The periodic relationship between Tc and Re indicates that Tc-99m radiopharmaceuticals can be designed by modeling analogous rhenium complexes.
- rhenium-TEC complexes were synthesized with macroscopic quantities of rhenium for characterization by conventional methods, including mass-spectrometry, 1 H and 13 C NMR spectrometry. Following purification, the synthesized rhenium complexes were run through a HPLC column for purification and identification of retention times to compare with Tc reaction products. The rhenium-TEC complexes were also crystallized.
- the rhenium complexes of the SAAC-inhibitors are conveniently isolated from the reactions of the readily available precursors ⁇ Re(CO) 3 (H 2 O) 3 ⁇ +1 and [Net 4 ] 2 [Re(CO) 3 Br 3 ] with the SAAC-inhibitor. Since the donor sets provided by the SAAC terminus are well documented as effective chelators for the ⁇ M(CO) 3 ⁇ +1 core and have been designed to adopt the required facial arrangement about the metal site, the preparations of the complexes were unexceptional.
- the compounds of the general structure 3 were prepared in overall yields ranging from 20-40% using the general route depicted in Scheme A.
- the key synthetic intermediate (1) was reacted with the appropriate aldehyde at room temperature in for one hour to form the ⁇ yridi base intermediate.
- the ⁇ yridi base was not isolated but was reduced in situ with sodium triacetoxyborohydride.
- the t-butyl ester protecting groups were removed using 50% TFA in DCM for 1 hour at room temperature. Upon completion of the deprotection, the reactions were concentrated on a rotary evaporator and purified by HPLC or flash chromatography to afford the desired products (3) in 40-80% yield.
- the following compounds of the general structure 8 were prepared in overall yields ranging from 20-60% by the route depicted in Scheme B.
- the key synthetic intermediate (4) was reacted with the appropriate phenylisocyanate at room temperature to afford the desired protected intermediates (5) in good yields.
- the t-butyl ester protecting groups were removed in the presence of 50% TFA in DCM for 1 hour at room temperature. Upon completion, the reactions were concentrated on a rotary evaporator purified by HPLC or recrystallization to afford the desired products (6) in 40-90% yield.
- the stability of the radiolabeled compounds in solution and in serum were determined as a function of time and solution conditions. Specifically, after radiolabeling and isolation, the product was stored at room temperature for 6 h after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of TcO 4 ⁇ and the presence of the reduced material TcO 2 was analyzed.
- ligand challenges were performed. Specifically, the stabilities of the 99m Tc complexes were investigated by incubating the HPLC purified complexes in 5% mouse serum at room temperature and 37° C. The ability of competing ligands, such as cysteine and DTPA, to extract Tc-99m from the complexes was studied by incubating the purified complexes with solutions (PBS pH 7.2) containing competing ligands at final concentrations of 0.1 M.
- solutions PBS pH 7.2
- the stability of the radiolabeled compound in solution was determined as a function of time. Specifically, after radiolabeling and isolation, the product was stored at room temperature for 48 h after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of NaI and the presence of the reduced iodates was analyzed. The results of the labeling stability study demonstrated no significant degradation of the I-131 DCIT out to 2 days at room temperature. The results of the study are shown in FIG. 3 .
- the stability of the radiolabeled compound in solution was determined as a function of time. Specifically, after radiolabeling and isolation, the product was stored at 37° C. for 3 days after which HPLC analysis was performed to check for degree of label retention, as well as potential product degradation. The reformation of NaI and the presence of the reduced iodates was analyzed. The results of the labeling stability study demonstrated no significant degradation of the I-13 11072 out to 3 days at room temperature in DMSO, 10% ethanol/saline, PBS pH 7.2, and 6% ascorbate/3% gentisic acid solution. The results of the study are shown in FIG. 4 .
- the newly prepared SAAC-urea-Glu conjugates were screened in a human prostate cancer cell binding assay using PSMA-positive, LnCap cells, and PSMA-negative, PC3 cells. Compounds demonstrating specific uptake or binding to PSMA-positive cells will be studied for tumor localization in vivo.
- LNCaP and PC3 human prostate cancer cells were obtained from American Type Culture Collection, Rockville, Md. LNCaP cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). PC3 cells were grown in F12K medium supplemented with 10% FBS. Binding of the radiolabeled compound and competition with cold derivatives to LNCaP and PC-3 cells was performed according to the methods of Tang et al. (Tang, H.; Brown, M.; Ye, Y.; Huang, G.; Zhang, Y.; Wang, Y.; Zhai, H.; Chen, X.; Shen, T.
- the resulting slurry was then centrifuged at 21,000 ⁇ G for 10 min and the supernatant was collected and injected onto an Agilent LCMS model MSD SL using a 95:5 water:acetonitrile (with 0.1% formic acid) to 40:60 water:acetonitrile (with 0.1% formic acid) gradient and monitoring for the parent ion only in single ion mode.
- the results, shown in FIGS. 11A and 11B are expressed as degradation of the parent ion with respect to the 0 min time point.
- MIP-1072 The stability of MIP-1072 was assessed using rat liver microsomes. MIP-1072 (50 ⁇ M) and Phenacetin (100 ⁇ M) were incubated with rat liver microsomes at 37° C. for the indicated time. Phenacetin was used as a control substance that is known to be metabolized. MIP-1072 was not degraded by the rat liver microsomes during the incubation period. However, phenacetin was degraded by 22% after a 60 min incubation.
- the lead compound, MIP 1072 was I-131-labeled for tissue distribution studies in mice with both LNCaP (PSMA positive) and PC3 (PSMA negative) tumors implanted.
- the compound was radiolabeled by the route shown below.
- NAALADase for therapeutic treatments.
- Diseases that could be receptive to NAALADase treatment include painful and sensory diabetic neuropathy, neuronal damage and prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral schlerosis, or diabetic neuropathy.
- the present compounds can also be used an analgesic.
- Guidance for the modeling of such therapeutic treatments can be found in Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw Hill, 10 edition, 2001, Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, CRC, 2001 and Handbook of Pharmaceutical Excipients, AphA Publications, 5 edition, 2005.
- LNCaP cells (300,000 cells/well) were incubated for 1 hour with 3 nM [ 131 I]-DCIT in the presence of 1-10,000 mM MIP-1072 in RPMI-1640 medium supplemented with 0.5% bovine serum albumin, then washed and counted in a gamma counter. All documents cited in this specification including patent applications are incorporated by reference in their entirety.
- LNCaP cells or the PSMA negative cell line, PC3 cells, were incubated in RPMI-1640 medium supplemented with 0.5% bovine serum albumin for 1 hour with 3 nM 123 I-MIP-1072 alone, or in the presence of 10 ⁇ M unlabeled MIP-1072, or 10 ⁇ M 2-(phosphonomethyl)-pentanedioic acid (PMPA), a structurally unrelated NAALADase inhibitor. Cells were washed and counted in a gamma counter.
- PMPA 2-(phosphonomethyl)-pentanedioic acid
- the affinity constant (K d ) of MIP-1072 was determined by saturation binding analysis ( FIG. 18 ).
- LNCaP cells were incubated for 1 hour with 30-100,000 pM 131 I-MIP-1072 in HBS (50 mM Hepes, pH 7.5, 0.9% sodium chloride) at either 4° C. or 37° C. in the absence or presence of 10 ⁇ M unlabeled MIP-1072 (to determine non-specific binding). Cells were then washed and the amount of radioactivity was measured on a gamma counter. Specific binding was calculated as the difference between total binding and nonspecific binding.
- the affinity constant (K d ) of the interaction of MIP-1072 with PSMA on LNCaP cells was determined by saturation binding analysis performed by titrating 123 I-MIP-1072 (3 pM-1,000 nM) in the presence and absence of an excess of non-radiolabeled MIP-1072 (10 ⁇ M).
- a K d of 4.8 nM, and Bmax of 1,490 fmoles/10 6 cells at 4° C. was determined by nonlinear regression analysis using Graph Pad Prism software ( FIG. 18 ).
- the K d was not significantly different at 37° C., 8.1 nM.
- the Bmax was greater at 37° C. than at 4° C.; 1,490 vs. 4,400 fmol/10 6 cells, respectively, indicating internalization of MIP-1072.
- the results below are representative of two independent analyses.
- LNCaP cells were incubated in HBS with 100 nM 123 I-MIP-1072 for 0-2 hours at 4 and 37° C. At the indicated time the media was removed and the cells were incubated in mild acid buffer (50 mM glycine, 150 mM NaCl, pH 3.0) at 4° C. for 5 minutes. After the brief incubation the cells were centrifuged at 20,000 ⁇ g for 5 minutes. The supernatant and cell pellet were counted in a gamma counter.
- mild acid buffer 50 mM glycine, 150 mM NaCl, pH 3.0
- a quantitative analysis of the tissue distribution of 123 I-MIP-1072 was performed in separate groups of male NCr Nude ⁇ / ⁇ mice bearing PSMA positive LNCaP xenografts (approximately 100-200 mm 3 ) administered via the tail vein as a bolus injection (approximately 2 ⁇ Ci/mouse) in a constant volume of 0.05 ml.
- Tissues blood, heart, lungs, liver, spleen, kidneys, adrenals, stomach, large and small intestines (with contents), testes, skeletal muscle, bone, brain, adipose, and tumor
- LLB Model 1282 Wallac Oy, Finland
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