Synthesis and Evaluation of ^99m Tc Essential Analogue of DUPA PSMA Inhibitor for Its Potential Use in Prostate Cancer Imaging

ABSTRACT DUPA (2‐[3‐(1,3‐dicarboxy propyl) ureido] pentanedioic acid) is a known small molecule prostate‐specific membrane antigen (PSMA) enzyme inhibitor that targets the PSMA receptor found overexpressed on prostate cancer. The present work synthesizes and evaluates a 99m Tc (technetium) “metal essential” glutamate complex, which mimics the DUPA ligand, for its potential use in SPECT imaging of PSMA‐positive prostate cancers. Glutamic acid was synthetically modified on treatment with carbon disulfide in the presence of sodium carbonate to yield glutamate‐dithiocarbamate (gDTC) in moderate yields (∼60%). To a freshly prepared [[ 99m Tc]Tc≡N] 2+ intermediate, gDTC was added to yield the final complex in high radiochemical yield and purity (>95%). The complex was then bio‐evaluated in vitro in PSMA‐positive LNCaP cell lines in comparison to the standard [ 177 Lu]Lu‐PSMA‐617 tracer. [ 99m Tc]Tc‐analogue of DUPA ligand showed uptake in LNCaP cells (∼9.5%ID/10 6 cells @ 2 h; K d ∼ 25.2 ± 6.2 nM) in comparison to [ 177 Lu]Lu‐PSMA‐617 (∼5%ID/10 6 cells @ 2 h), however the percentage specificity observed was only 60% (vs. 90% for [ 177 Lu]Lu‐PSMA‐617) as ascertained from inhibition using 2‐PMPA (blocker). The in vivo distribution in normal Sprague‐Dawley (SD) rats indicated similar pharmacokinetics as that observed for [ 177 Lu]Lu‐PSMA‐617. The [ 99m Tc]Tc‐radiotracer showed high retention in the kidneys as observed for several radiolabeled PSMA analogues.