Preparation, Biological Evaluation, and First-in-Human Single-Photon Emission Computed Tomography (SPECT) Study of 99m Tc-Labeled Prostate-Specific Membrane Antigen (PSMA)-Targeted Radiotracers Containing Triazole with Reduced Kidneys Accumulation.

Prostate-specific membrane antigen (PSMA), a well-established biological marker for prostate cancer (PCa) imaging and therapy, is overexpressed on the surface of prostate cancer lesions. In this study, a triazole ring was introduced into the linker by click chemistry to generate a HYNIC-derived ligand ( T ), which exhibited good PSMA affinity ( K i = 2.23 nM). Eight stable 99m Tc-labeled complexes, [ 99m Tc]Tc-T-Mn ( n = 1-8), with hydrophilic properties were synthesized by incorporating different coligands at high radiochemical yields and purities without purification. The radioligands were concentrated in the kidneys of healthy Kunming male mice and were significantly blocked by the PSMA inhibitor ZJ-43. The uptake of the optimized complex [ 99m Tc]Tc-T-M2 was correlated with PSMA, and it had good PSMA affinity ( K d = 5.42 nM). [ 99m Tc]Tc-T-M2 accumulated on LNCaP (PSMA++) tumors and was significantly blocked by ZJ-43 at 2 h p.i., indicating high PSMA specificity. Relatively suitable kidney uptake was beneficial for reducing kidneys exposure in patients. SPECT/CT imaging of [ 99m Tc]Tc-T-M2 in LNCaP (PSMA++) or 22Rv1 (PSMA+) tumor-bearing mice revealed high tumor uptake, low background uptake (especially low kidney uptake (49.06 ± 9.20 %ID/g) at 2 h p.i.), and obvious inhibition by ZJ-43, whereas PC-3 (PSMA-) tumors were undetectable. A freeze-dried [ 99m Tc]Tc-T-M2 kit was successfully developed (T-M2 kit). Preliminary clinical trials showed that [ 99m Tc]Tc-T-M2 clearly identified small prostate cancer lesions and has potential for clinical application.