title: Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA).
abstract: The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven (99m)Tc/Re-labeled compounds by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. K i values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [(99m)Tc(CO)3( L1)] (+) ( L1 = (2-pyridylmethyl)2N(CH2) 4CH(CO2H)NHCO-(CH2) 6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 +/- 4.0% injected dose per gram of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of (99m)Tc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the epsilon amine of the urea lysine and the chelator.
authors.affiliation: Russell H Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Banerjee
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Foss
authors.forename: Mark
authors.initials: M
authors.lastname: Castanares
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: James J
authors.initials: JJ
authors.lastname: Fox
authors.forename: John
authors.initials: J
authors.lastname: Hilton
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Lupold
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry; D004583:Electrons; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D012211:Rhenium / Q000737:chemistry; D013329:Structure-Activity Relationship; D013667:Technetium / Q000737:chemistry; D014508:Urea / Q000737:chemistry
chemical_list: D002614:Chelating Agents; D011480:Protease Inhibitors; D012211:Rhenium; D013667:Technetium; D014508:Urea; D043425:Glutamate Carboxypeptidase II