Synthesis of potent ligands for targeting prostate specific membrane antigen receptor

Abstract

Carcinoma of prostate is one of the most common malignancy among men in the United States of America and it is the second most cause of cancer related death worldwide after lung cancer. The method of diagnosis involvesmeasurement of PSA (prostate specific antigen) level inman’s blood.Increased level of PSA in blood doesn’t always indicate the presence of prostate cancer as it also increases duringdisorders like BPH (benign prostatic hyperplasia), which is enlargement of prostate gland and prostatitis, which is inflammation in prostate gland. There is a constant ambiguity in determining the presence of disease with the help of PSA level examination. Thus it is important to discover an efficient biomarker for the early diagnosis of prostate cancer. Prostate specific membrane antigen (PSMA) is a useful biomarker fortargeting and imaging purposes. Its levelincreases to several foldsduring prostate cancer and also it catalyzes the hydrolysis of N-acetylaspartyl acetate (NAAG), a neurotransmitter to provide N-acetyl aspartate and glutamate, which is another neurotransmitter. Increased level of glutamate causes neuro disorders and sometimes death. Several ligands have beendesignedby making use of the interactions shown by NAAG with the PSMA protein. In this work, we have synthesized PSMA selective diagnostic agent 25through solid phase synthesisso that it can be utilized for targeting and imaging of prostate cancer cells. Computational studyshowsthat the small molecule inhibitor 2, which is used as a targeting ligand in the conjugate 25, has better binding affinityto PSMA protein as compared to other known ligands.