Abstract 4554: Synthesis and Biological Evaluation of New Ligands Targeting Prostate Specific Membrane Antigen (PSMA)
Authors: Wang Xinning , Heston Warren , Tian Haibin , Lee Zhenghong 
Published: February 2011

Abstract
According to the American Cancer Society, prostate cancer is the most prevalent cancer in American males. More accurate staging would facilitate treatment decisions and lead to a better outcome for patients. Particularly useful would be an imaging technique that could be correlated with a relevant tumor biomarker.
Prostate specific membrane antigen (PSMA) is a type II transmembrane protein having a molecular weight of ∼110,000. Pathology studies indicates that PSMA is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas. With its abundant expression in most prostate cancers, PSMA would therefore appear to be an ideal target for diagnosis and therapy.
A series of di-peptide inhibitors of PSMA linked by a central urea group has been reported. One of the leading compounds is (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid (Cys-CO-Glu, 1). It can be easily modified without compromising activity through the -SH group. Recently, an analogue of 1 containing 2-5A (RBI1033) has been synthesized, which showed binding activity far superior than compound 1 itself. The purpose of this study is to perform structure-activity relationship studies of RBI1033 to help identify highly selective ligands of membrane associated PSMA. By chemically linking amine-containing molecules to PSMA recognizing dipeptide Cys-C(O)-Glu through a 4-(N-maleimidomethyl) cyclohexane-1-amidate linkage, we were able to create a series of novel 2-5A PSMA ligands, three of which (3, 5 and 6) contain 2-5A unit in their structures, the other three (7, 11 and 12) don't. All new compounds synthesized were evaluated in a competitive binding assay using tritium labeled S-methylated derivative of 1 (3H-ZJ24) as the radioligand for binding to PSMA on LNCaP cells to examine the ability of the novel compounds to compete for binding with 3H-ZJ24. It was found that compounds 3, 5 and 6 which contain 2-5A in their structures showed IC50 values at 1.6 nM, 0.11 nM and 0.012 nM respectively, compared to parent compound 1 at 13.9 nM. Highest binding activity was found in compound 6 with phosphorothioated 2-5A trimer in its structure. In contrast, compound 7, 11 and 12 omitting 2-5A in their structures gave IC50s at 124 nM, 95.4 nM and 169.9 nM respectively. Therefore, the incorporation of 2-5A has significant effect on improving the binding activity of the ligand. In summary, we have synthesized a series of new compounds which had remarkably improved binding affinity to PSMA. These ligands can be subsequently coupled to imaging agents for systemic delivery to prostate tumors. The results of these experiments will provide a path to agents that will be synthetically achievable and likely be more cost effective than current antibody-based methods. (This work was supported by a grant from Department of Defense W81XWH-07-1-0656.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4554.