Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA)

Sangeeta R. Banerjee, Catherine A. Foss, Mark Castanares, Ronnie C. Mease, Youngjoo Byun, James J. Fox, John Hilton, Shawn E. Lupold, Alan P. Kozikowski, Martin G. Pomper

Research output: Contribution to journalArticle

Abstract

The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven 99mTc/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. Ki 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, [99mTc(CO) 3(L1)]+ (L1 = (2-pyridylmethyl)2N(CH 2)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 99mTc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the ε amine of the urea lysine and the chelator.

Original languageEnglish (US)
Pages (from-to)4504-4517
Number of pages14
JournalJournal of medicinal chemistry
Volume51
Issue number15
DOIs
StatePublished - Aug 14 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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