Metal-Based PSMA Radioligands

Abstract

Prostate cancer is one of the most common malignancies for which great progress has been made in identifying appropriate molecular targets that would enable efficient in vivo targeting for imaging and therapy. The type II integral membrane protein, prostate specific membrane antigen (PSMA) is overexpressed on prostate cancer cells in proportion to the stage and grade of the tumor progression, especially in androgen-independent, advanced and metastatic disease, rendering it a promising diagnostic and/or therapeutic target. From the perspective of nuclear medicine, PSMA-based radioligands may significantly impact the management of patients who suffer from prostate cancer. For that purpose, chelating-based PSMA-specific ligands have been labeled with various diagnostic and/or therapeutic radiometals for single-photon-emission tomography (SPECT), positron-emission-tomography (PET), radionuclide targeted therapy as well as intraoperative applications. This review focuses on the development and further applications of metal-based PSMA radioligands.

Modular Synthesis of DOTA‐Metal‐Based PSMA‐Targeted Imaging Agents for MRI and PET of Prostate Cancer

“…The clinical limitations of nontargeted molecular imaging agents for prostate cancer (PCa) has led to an exponential increase of investigational targeted imaging agents for magnetic resonance imaging (MRI), positron emission tomography (PET), and single‐photon emission computed tomography (SPECT) in both preclinical and clinical research over the past five years . In particular, the use of targeted PET agents was found to be remarkably effective in the detection, staging, and active surveillance of PCa …”

“…The success of targeted molecular imaging agents (TMIAs) for PCa has largely been made possible by the discovery of prostate‐specific membrane antigen (PSMA) overexpression in PCa cells . PSMA, also known as glutamate carboxypeptidase II (GCPII), NAALADase, and folate hydrolase FOLH1, is a well‐characterized trans ‐membrane glycoprotein . Its expression is elevated with increasing PCa stage and grade making it an excellent biomarker for staging, metastasis detection, and image‐guided interventions .…”

“…Elucidation of the structure of the PSMA binding site using protein crystallography led to the development of small molecule inhibitors which included amide, phosphonate, and urea substrate analogues . Among the most effective of these was a small molecule synthesized by a peptidomimetic urea linkage of lysine to glutamic acid in place of the naturally occurring peptide amide substrate.…”

“…[1,2] In particular, the use of targeted PET agents was found to be remarkably effective in the detection, staging, and active surveillance of PCa. [3][4][5][6][7][8] Ta rgeteda gentsf or MRI, as well as dual modal agentsf or SPECT/Optical Imaging, have also been shown to be effective in pre-clinical imaging of active PCa. [9][10][11][12][13] Recently,astudy using simultaneousP ET/MRI has reported remarkablyh igh accuracy( 80-97.5%)i nt he detection of multiple stages of PCa, underscoring the need for reliable synthetic methods for targeted probesfor both PET andM RI of PCa.…”

“…[15][16][17] PSMA, also known as glutamate carboxypeptidase II (GCPII), NAALADase,a nd folate hydrolase FOLH1, is a well-characterized trans-membrane glycoprotein. [6] Its expression is elevated with increasingP Ca stage and grade making it an excellentb iomarker for staging, metastasis detection, and image-guided interventions. [4,6] PSMA is also expressed on the neovasculature of other types of carcinomas such as breast and thyroid, making it an important biomarker in the larger scope of cancerresearch as well.…”