Abstract
Prostate-specific membrane antigen (PSMA) is a biomarker expressed on the surface of prostate cancer (PCa). In an effort to improve the detection and treatment of PCa, small urea-based PSMA inhibitors have been studied extensively. In the present study, we aimed to develop 99mTc-tricabonyl labeled urea-based PSMA conjugates containing isonitrile (CN-R)-coordinating ligands ([99mTc]Tc-15 and [99mTc]Tc-16). Both the PSMA conjugates were obtained at high radiochemical efficiency (≥98.5%). High in vitro binding affinity was observed for [99mTc]Tc-15 and [99mTc]Tc-16 (Kd = 5.5 and 0.2 nM, respectively) in PSMA-expressing 22Rv1 cells. Tumor xenografts were conducted using 22Rv1 cells and rapid accumulation of [99mTc]Tc-16 (1.87 ± 0.11% ID/g) was observed at 1 h post-injection, which subsequently increased to (2.83 ± 0.26% ID/g) at 4 h post-injection. However, [99mTc]Tc-15 showed moderate tumor uptake (1.48 ± 0.18% ID/g), which decreased at 4 h post-injection (0.81 ± 0.09% ID/g). [99mTc]Tc-16 was excreted from non-targeted tissues with high tumor-to-blood (17:1) and tumor-to-muscle ratio (41:1) at 4 h post-injection at approximately 4 times higher levels than [99mTc]Tc-15. Uptakes of [99mTc]Tc-15 and [99mTc]Tc-16 to PSMA-expressing tumor and tissues were significantly blocked by co-injection of 2-(Phosphonomethyl)-pentandioic acid (2-PMPA), suggesting that their uptakes are mediated by PSMA specifically. Whole-body single photon emission computed tomography imaging of [99mTc]Tc-16 verified the ex vivo biodistribution results and demonstrated clear visualization of tumors and tissues expressing PSMA compared to [99mTc]Tc-15. In conclusion, using [99mTc]Tc-16 rather than [99mTc]Tc-15 may be the preferable because of its relatively high tumor uptake and retention.
Highlights
Prostate cancer (PCa) is a commonly diagnosed disease and is the second leading cause of cancer death in the United States
Prostate-specific membrane antigen (PSMA) is expressed in most PCa tissues and its expression often increased in metastatic, poorly differentiated, androgen-independent, and hormone-refractory carcinoma [2,3,4]
Asymmetrical urea 1 was synthesized by treating L-glutamic acid di-tert-butyl ester
Summary
Prostate cancer (PCa) is a commonly diagnosed disease and is the second leading cause of cancer death in the United States. In 2018, approximately 164,690 men were diagnosed with PCa, leading to an estimated 29,430 deaths [1]. Prostate-specific membrane antigen (PSMA) is glutamate carboxypeptidase. II (GCPII) or N-acetyl-l-aspartyl-l-glutamate peptidase I (NAALADase I), and is a type II integral transmembrane glycoprotein (100–120 kDa). PSMA is expressed in most PCa tissues and its expression often increased in metastatic, poorly differentiated, androgen-independent, and hormone-refractory carcinoma [2,3,4]. The levels of PSMA expression correlate with the progression, stage, and the risk of disease [5,6]. PSMA is considered to be a promising, reliable, and an efficient biomarker for PCa imaging and therapeutic application
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