Abstract
68Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68Ga-positron emission tomography (68Ga-PET). Nevertheless, current 68Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68Ga-SC691 and 68Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68Ga-PSMA-11.
Highlights
Prostate cancer (PCa) is the most common form of cancer in males in the USA
No Positron emission tomography (PET) agents have been approved for clinical use in PCa diagnosis except for 68Ga-prostate-specific membrane antigen (PSMA)-11, which was approved in December 2 02025
We further evaluated its affinity and specificity to PSMA-positive tumors by comparing its pharmacokinetics and PET imaging abilities with those of 68Ga-PSMA-11. 68Ga-SC691 displayed favorable pharmacokinetics and excellent uptake in PSMA-positive tumors, indicating that 68Ga-SC691 may serve as a new PET tracer for prostate cancer
Summary
Prostate cancer (PCa) is the most common form of cancer in males in the USA. It is estimated that there will be more than 190,000 new cases of prostate cancer and an estimated 33,000 deaths from this disease in the USA in 2020 alone, according to the National Cancer Institute[1]. Small molecule PSMA inhibitors fall into one of three major families: (1) thiols[17]; (2) phosphonate-, phosphate-18, and phosphoramidates; and (3) ureas[19] Among these inhibitors, small molecules with a Lys-urea-Glu scaffold as a pharmacophore were found to be able to accumulate in prostate cancer cells and efficiently. Unlike 18F-radiolabeled tracers, which need cyclotrons to produce 18F and complex procedures and facilities for the synthesis of 18F-radiopharmaceuticals, the ready availability and efficient complexing characteristics of 68Ga(III), together with its favorable biological properties, have made the use of 68Ga-based PSMA-targeted PET procedures grow rapidly, as evidenced by an increasing number of clinical t rials[26,27,28,29,30]. We further evaluated its affinity and specificity to PSMA-positive tumors by comparing its pharmacokinetics and PET imaging abilities with those of 68Ga-PSMA-11. 68Ga-SC691 displayed favorable pharmacokinetics and excellent uptake in PSMA-positive tumors, indicating that 68Ga-SC691 may serve as a new PET tracer for prostate cancer
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