title: 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer.
abstract: Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and small-molecule radiopharmaceuticals targeting PSMA rapidly detect the location and extent of disease. Here we evaluated preclinically 4 novel (99m)Tc-labeled small-molecule inhibitors of PSMA with the potential for clinical translation for molecular imaging of prostate cancer in humans.
  
  
  METHODS
  Four PSMA inhibitors derived from the glutamate-urea-glutamate or glutamate-urea-lysine pharmacophores conjugated to CIM or TIM chelators were radiolabeled with (99m)Tc and evaluated in vitro and in vivo.
  
  
  RESULTS
  High-affinity, saturable binding to PSMA on LNCaP cells was observed with Kd values of 0.64 ± 0.46 nM for (99m)Tc-MIP-1427, 1.07 ± 0.89 nM for (99m)Tc-MIP-1404, 1.75 ± 0.32 nM for (99m)Tc-MIP-1428, and 4.35 ± 0.35 nM for (99m)Tc-MIP-1405. (99m)Tc-labeled PSMA inhibitors did not bind human prostate cancer PC3 cells, which lack PSMA, demonstrating specificity, and binding was abolished with 2-(phosphonomethyl)pentanedioic acid (PMPA), a structurally unrelated PSMA inhibitor. (99m)Tc-labeled PSMA inhibitors were shown to internalize at 37 °C. Uptake in LNCaP xenografts ranged from 9.3% to 12.4% injected dose per gram at 1 h after injection and from 7.2% to 11.0% at 4 h, with tumor-to-blood ratios ranging from 29:1 to 550:1 and tumor-to-skeletal muscle ratios ranging from 31:1 to 157:1 at 4 h. (99m)Tc-MIP-1404 exhibited the best combination of high tumor uptake and rapid clearance from kidney and nontarget tissues. (99m)Tc-MIP-1404 specifically bound to PSMA in vivo as demonstrated by the absence of uptake in PC3 xenografts and by competition with PMPA. SPECT/CT imaging corroborated the tissue distribution results, demonstrating uptake only in PSMA-expressing kidney and tumor tissue and clearance through the urinary bladder.
  
  
  CONCLUSIONS
  These (99m)Tc-labeled radiopharmaceuticals targeting PSMA may provide a SPECT molecular imaging option to assist in the initial diagnosis of prostate cancer and the management of patient care by monitoring disease progression.
authors.affiliation: Molecular Insight Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.forename: Genliang
authors.initials: G
authors.lastname: Lu
authors.forename: Ross D
authors.initials: RD
authors.lastname: Merkin
authors.forename: John C
authors.initials: JC
authors.lastname: Marquis
authors.forename: Craig N
authors.initials: CN
authors.lastname: Zimmerman
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000085:Acetates / Q000737:chemistry; D000818:Animals; D000954:Antigens, Surface; D001692:Biological Transport; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D015609:Organotechnetium Compounds / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011854:Radiochemistry; D011877:Radionuclide Imaging; D013667:Technetium; D014508:Urea / Q000737:chemistry
chemical_list: D000085:Acetates; D000954:Antigens, Surface; D002614:Chelating Agents; D015609:Organotechnetium Compounds; D011480:Protease Inhibitors; C000595576:technetium 99m 1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)-9,14-dioxo-2,8,13,15-tetraazaoctadecane-7,12,16,18-tetracarboxylic acid); C000595577:technetium 99m 7-amino-1-(1-(carboxymethyl)-1H-imidazol-2-yl)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid); D018698:Glutamic Acid; D013667:Technetium; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D008239:Lysine
keywords: PSMA; SPECT; imaging; prostate cancer