title: Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer.
abstract: Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (K(i) = 4.6 +/- 1.6 nmol/L and 0.24 +/- 0.14 nmol/L, respectively) and, when radiolabeled with (123)I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (K(d) = 3.8 +/- 1.3 nmol/L and 0.81 +/- 0.39 nmol/L, respectively). The association of [(123)I]MIP-1072 and [(123)I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [(123)I]MIP-1072 and [(123)I]MIP-1095 internalized into LNCaP cells at 37 degrees C. Tissue distribution studies in mice showed 17.3 +/- 6.3% (at 1 hour) and 34.3 +/- 12.7% (at 4 hours) injected dose per gram of LNCaP xenograft tissue, for [(123)I]MIP-1072 and [(123)I]MIP-1095, respectively. [(123)I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [(123)I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [(123)I]MIP-1072 and [(123)I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.
authors.affiliation: Molecular Insight Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Femia
authors.forename: John C
authors.initials: JC
authors.lastname: Marquis
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Foss
authors.forename: Nghi
authors.initials: N
authors.lastname: Nguyen
authors.forename: Craig N
authors.initials: CN
authors.lastname: Zimmerman
authors.forename: John A
authors.initials: JA
authors.lastname: Barrett
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D043425:Glutamate Carboxypeptidase II / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005971:Glutamates / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014508:Urea / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: C544834:2-(3-(1-carboxy-5-(3-(4-iodobphenyl)ureido)pentyl)ureido)pentanedioic acid; C544833:2-(3-(1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid; D000954:Antigens, Surface; D005971:Glutamates; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D008239:Lysine
references.citation: Mamm Genome. 2001 Feb;12(2):117-23
references.pmid: 11210180
references.citation: Cancer Res. 1999 Jul 1;59(13):3192-8
references.pmid: 10397265
references.citation: Clin Cancer Res. 2005 Jun 1;11(11):4022-8
references.pmid: 15930336
references.citation: J Biol Chem. 1982 Nov 25;257(22):13306-11
references.pmid: 6292185
references.citation: J Clin Oncol. 2007 Feb 10;25(5):540-7
references.pmid: 17290063
references.citation: Urology. 1998 Oct;52(4):637-40
references.pmid: 9763084
references.citation: Clin Cancer Res. 2008 May 15;14(10):3036-43
references.pmid: 18483369
references.citation: Urology. 1996 Aug;48(2):326-34
references.pmid: 8753752
references.citation: Cancer Res. 2008 Nov 1;68(21):9070-7
references.pmid: 18974153
references.citation: Neurosci Lett. 2005 Oct 28;387(3):141-4
references.pmid: 16006038
references.citation: Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3943-53
references.pmid: 15217924
references.citation: Biochem Biophys Res Commun. 1990 Jul 16;170(1):223-30
references.pmid: 2372287
references.citation: N Engl J Med. 2009 Mar 26;360(13):1310-9
references.pmid: 19297565
references.citation: Clin Cancer Res. 1996 Sep;2(9):1445-51
references.pmid: 9816319
references.citation: J Med Chem. 2008 Dec 25;51(24):7737-43
references.pmid: 19053759
references.citation: J Med Chem. 2008 Aug 14;51(15):4504-17
references.pmid: 18637669
references.citation: Cancer Res. 1993 Jan 15;53(2):227-30
references.pmid: 8417812
references.citation: Anticancer Res. 1987 Sep-Oct;7(5B):927-35
references.pmid: 2449118
references.citation: Mol Pharm. 2009 May-Jun;6(3):780-9
references.pmid: 19361233
references.citation: Cancer Res. 2000 Sep 15;60(18):5237-43
references.pmid: 11016653
references.citation: Cancer Res. 1990 Oct 1;50(19):6423-9
references.pmid: 1698122
references.citation: Prostate. 1997 Mar 1;30(4):232-42
references.pmid: 9111600
references.citation: Hum Pathol. 2007 May;38(5):696-701
references.pmid: 17320151
references.citation: J Nucl Med. 2003 Apr;44(4):610-7
references.pmid: 12679407
references.citation: Prostate. 2006 Jun 15;66(9):903-10
references.pmid: 16496413
references.citation: Histol Histopathol. 2004 Jul;19(3):715-8
references.pmid: 15168332
references.citation: Radiology. 2007 Apr;243(1):28-53
references.pmid: 17392247
references.citation: N Engl J Med. 2004 May 27;350(22):2239-46
references.pmid: 15163773
references.citation: BJU Int. 2003 Jul;92(2):159-64
references.pmid: 12823366
references.citation: Clin Cancer Res. 2005 Oct 1;11(19 Pt 2):7195s-7200s
references.pmid: 16203821
references.citation: Prostate. 1999 Apr 1;39(1):28-35
references.pmid: 10221263
references.citation: J Nucl Med. 1999 Oct;40(10):1706-15
references.pmid: 10520713
references.citation: J Clin Oncol. 2005 Jul 20;23(21):4591-601
references.pmid: 15837970
references.citation: J Natl Cancer Inst. 1999 Jun 16;91(12):1017-24
references.pmid: 10379964
references.citation: J Urol. 2002 Jan;167(1):103-11
references.pmid: 11743285
references.citation: Clin Cancer Res. 1999 Oct;5(10):2674-81
references.pmid: 10537328
references.citation: Urol Oncol. 1995 Jan-Feb;1(1):18-28
references.pmid: 21224086
references.citation: Clin Cancer Res. 1997 Jan;3(1):81-5
references.pmid: 9815541
references.citation: Biochem Biophys Res Commun. 2003 Jul 18;307(1):8-14
references.pmid: 12849974
references.citation: J Med Chem. 2008 Dec 25;51(24):7933-43
references.pmid: 19053825
references.citation: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references.pmid: 4202581
references.citation: Mol Pharm. 2009 May-Jun;6(3):790-800
references.pmid: 19361232
references.citation: Urol Oncol. 1995 Jan-Feb;1(1):29-37
references.pmid: 21224087
references.citation: Prostate. 2008 Jun 15;68(9):955-64
references.pmid: 18361407
references.citation: Int J Cancer. 2005 Sep 1;116(3):415-21
references.pmid: 15800947
references.citation: J Med Chem. 2009 Jan 22;52(2):347-57
references.pmid: 19111054
references.citation: N Engl J Med. 1991 Apr 25;324(17):1156-61
references.pmid: 1707140
references.citation: Cancer Control. 2002 Jul-Aug;9(4):335-42
references.pmid: 12228759
references.citation: J Nucl Med. 2000 Jan;41(1):85-92
references.pmid: 10647609