Abstract
In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.
Highlights
Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that consists of 750 amino acids and with a molecular weight greater than 100 kD after glycosylation [1]
Given that the current development of the agents has shifted towards the systematic chemical modifications of the linkage between the targeting moiety and theranostic payloads, this review provides an overview of critical structural determinants of the chemical modifications for the development of generation Prostate-Specific Membrane Antigen (PSMA)-targeting agents
The rapid translation of the newly emerged PSMA-targeting imaging and theranostic agents into first-in-human trials is largely driven by the success of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL in clinical trials and practice together with the proven clinical value of [177Lu]Lu-PSMA-617 in the subsequent treatment of patients with metastatic castrate-resistant prostate cancer (mCRPC)
Summary
Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that consists of 750 amino acids and with a molecular weight greater than 100 kD after glycosylation [1]. The purpose of this review is to examine the history, current state, and future directions of PSMA-targeted imaging and therapy of prostate cancer. The main focus of this review is on PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors. Two PSMA-targeting radiotracers have received approval from the United States Food and Drug Administration (US-FDA), [68Ga]Ga-PSMA-11 and [18F]F-DCFPyl. favorable in patients with low prostate-specific antigen (PSA) level, both of them provide superior sensitivity and specificity profiles for recurrent or metastatic prostate cancer than the earlier approved PET radiotracers (e.g., [18F]fluciclovine and [11C]choline). PSMA is expressed by a very high proportion of prostate cancer tumors and at most stages of the disease. As an antigen protein and an enzyme, PSMA has served as a target of interest for imaging and therapeutic agent development. PSMA-targeting agents are developed from two categories of targeting moieties: (1) anti-PSMA antibodies or engineered protein fragments and (2) small molecule inhibitors of the enzymatic activity of PSMA
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