PSMA-Targeting Imaging and Theranostic Agents—Current Status and Future Perspective

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.

Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands

“…The development and clinical evaluation of the urea-based radioligand [ 68 Ga]Ga-PSMA-11, constructed of a Glu-urea-Lys binding moiety connected to the HBED-CC radiometal chelator through an aliphatic carbon chain linker, is considered as being a breakthrough in the field [ 18 , 19 ]. Since then, several urea-based PSMA-binding radioligands for both imaging and therapy have been developed [ 20 , 21 , 22 ]. In 2015, PSMA-617 ( Figure 1 ) was reported, which is constructed of the same urea-based binding moiety as PSMA-11, but with a modified linker consisting of 2-naphthyl-L-alanine and tranexamic acid [ 23 ].…”

“…PSMA-617 has shown promising targeting properties such as a low kidney uptake, fast background clearance, and high tumour retention. During the last years, [ 177 Lu]Lu-PSMA-617 has been involved in several clinical trials for radioligand therapy (RLT) of PCa [ 21 , 22 ] and very recently, [ 177 Lu]Lu-PSMA-617 was approved by the FDA as the first targeted RLT for treatment of progressive PSMA-positive metastatic castration-resistant PCa [ 24 ]. The improved characteristics of PSMA-617 are thought to be caused by the presence of 2-naphthyl-L-alanine in the linker structure, which favourably interacts with the S1 hydrophobic pocket [ 10 , 23 ].…”

Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists

“…The off-target accumulation likely reflects the lipophilic nature of [ 18 F]F-TZ(PSMA)-LEGU-TLR7, which is due to the presence of aromatic functionalities in the structure of T-SMPDCs. Linkers/spacers in the T-SMPDCs can be readily leveraged to overcome the issue [53]. It is noteworthy that the high off-target accumulation of T-SMPDCs is expected to be non-toxic or at least less toxic than the free molecule of GARD, because GARD is covalently loaded to the conjugate.…”

Nanobodies: COVID-19 and Future Perspectives

“…Nanobodies are expected to become important for cancer diagnosis: Molecules including monoclonal antibodies (Frigerio et al, 2021) used for PET diagnostics are useful for directed radiotherapies through the simple exchange of radioisotopes with, for instance, Lutetium 77 Lu. These radiotracers used for diagnostics and therapeutical applications are known as Theranostics (Debnath et al, 2022;Woźniak et al, 2022).…”