Oncotarget

Research Papers:

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 and Martin G. Pomper _

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Oncotarget. 2011; 2:1244-1253. https://doi.org/10.18632/oncotarget.415

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Abstract

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

1 The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School, Baltimore, MD

* Denotes equal contribution

Received: December 11, 2011; Accepted: December 28, 2011; Published: December 29, 2011;

Keywords: Prostate-specific membrane antigen (PSMA), NAALADase; bivalent urea inhibitor, molecular imaging, multivalency, SPECT imaging

Correspondence:

Martin G. Pomper, M.D., Ph.D., email:

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 (µ-, e-) 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.


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