Radiolabeled Small-Molecule Ligands for Prostate-Specific Membrane Antigen: In vivo Imaging in Experimental Models of Prostate Cancer

Surgical resection remains a definitive treatment for prostate cancer. Yet, prostate cancer surgery is performed without image guidance for tumor margin, extension beyond the capsule and lymph node positivity, and without verification of other occult metastases in the surgical field. Recently, several imaging systems have been described that exploit near-infrared (NIR) fluorescent light for sensitive, real-time detection of disease pathology intraoperatively. In this study, we describe a high-affinity (9 nM), single nucleophile-containing, small molecule specific for the active site of the enzyme PSMA. We demonstrate production of a tetra-sulfonated heptamethine indocyanine NIR fluorescent derivative of this molecule using a high-yield LC/MS purification strategy. Interestingly, NIR fluorophore conjugation improves affinity over 20-fold, and we provide mechanistic insight into this observation. We describe the preparative production of enzymatically active PSMA using a baculovirus expression system and an adenovirus that co-expresses PSMA and GFP. We demonstrate sensitive and specific in vitro imaging of endogenous and ectopically expressed PSMA in human cells and in vivo imaging of xenograft tumors. We also discuss chemical strategies for improving performance even further. Taken together, this study describes nearly complete preclinical development of an optically based small-molecule contrast agent for image-guided surgery.

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Evolution of Peptide-Based Prostate-Specific Membrane Antigen (PSMA) Inhibitors: An Approach to Novel Prostate Cancer Therapeutics

Current Medicinal Chemistry ◽

10.2174/0929867327666201006153847 ◽

2020 ◽

Vol 27 ◽

Author(s):

Andrew Siow ◽

Renata Kowalczyk ◽

Margaret A. Brimble ◽

Paul W.R. Harris

Keyword(s):

Prostate Cancer ◽

Clinical Application ◽

Rational Design ◽

Therapeutic Potential ◽

Rapid Development ◽

Cancer Therapeutics ◽

Prostate Specific Membrane Antigen ◽

Specific Membrane

Background: Prostate cancer is one of the most common cancers worldwide, with approximately 1.1 million cases diagnosed annually. The rapid development of molecular imaging has facilitated greater structural understanding which can help formulate novel combination therapeutic regimens and more accurate diagnosis avoiding unnecessary prostate biopsies. This accumulated knowledge also provides greater understanding into aggressive stages of the disease and tumour recurrence. Recently, much progress has been made on developing peptidomimetic-based inhibitors as promising candidates to effectively bind to the prostate-specific membrane antigen (PSMA) which is expressed by prostate cancer cells. Objective: In this review, recent advances covering small-molecule and peptide-based PSMA inhibitors will be extensively reviewed providing a base for the rational design of future PSMA inhibitors. Method: Herein, we review the literature on selected PSMA inhibitors that have been developed from 1996-2020, emphasizing recent synthetic advances and chemical strategies whilst highlighting therapeutic potential and drawbacks of each inhibitor. Results: Synthesized inhibitors presented in this review demonstrate the clinical application of certain PSMA inhibitors exhibited in vitro and in vivo. Conclusion: This review highlights the clinical potential of PSMA inhibitors, analyzing the advantages and setbacks of the chemical synthetic methodologies utilized, setting precedence for the discovery of novel PSMA inhibitors for future clinical application.

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