A modular strategy to prepare multivalent inhibitors of prostate-specific membrane antigen (PSMA)

Sangeeta Ray Banerjee, Mrudula Pullambhatla, Hassan Shallal, Ala Lisok, Ronnie C. Mease, Martin G. Pomper

Research output: Contribution to journalArticle

Abstract

We have developed a modular scaffold for preparing high-affinity, homo-multivalent inhibitors of the prostate-specific membrane antigen (PSMA) for imaging and therapy of prostate cancer (PCa). Our system contains a lysine-based (α-, ε-) dialkyne residue for incorporating a PSMA binding Lys-Glu urea motif exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety. The utility of the multivalent scaffold was examined by synthesizing bivalent compounds 2 and 3 and comparing them with the monovalent analog 1. Determination of inhibition constants (Ki) revealed that bivalent 2 (0.2 nM) and 3 (0.08 nM) are significantly more potent (~ 5 fold and ~ 11 fold, respectively) inhibitors of PSMA than monovalent 1 (0.9 nM). A single photon emission computed tomography (SPECT)-CT imaging study of [111In]3 demonstrated high and specific uptake in PSMA+ PC-3 PIP tumor until at least 48 h post-injection, with rapid clearance from non-target tissues, including kidney. A biodistribution study revealed that [111In]3 demonstrated 34.0 ± 7.5 percent injected dose per gram of tissue in PSMA+ tumor at 24 h post-injection and was capable of generating target-to-non-target ratios of ~ 379 in PSMA+ PC-3 PIP tumors vs. isogenic PSMA-negative PC3-flu tumors in vivo. The click chemistry approach affords a convenient strategy toward multivalent PSMA inhibitors of enhanced affinity and superior pharmacokinetics for imaging.

Original languageEnglish (US)
Pages (from-to)1244-1253
Number of pages10
JournalOncotarget
Volume2
Issue number12
DOIs
StatePublished - Dec 2011

Keywords

  • Bivalent urea inhibitor
  • Molecular imaging
  • Multivalency
  • Naaladase
  • Prostate-specific membrane antigen (PSMA)
  • SPECT imaging

ASJC Scopus subject areas

  • Oncology

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