PSMA-Targeting SPECT Tracer with Positively Charged Mercaptoacetyl-Based Chelator: Preclinical Evaluation and Exploratory Clinical Study

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Abstract The BQ series comprises linker-optimized small-molecule PSMA inhibitors incorporating mercaptoacetyl-based chelators for technetium-99m labeling for SPECT/CT imaging of prostate cancer (PCa). Within this series, the negatively charged BQ0413 (maE3 chelator) showed promising clinical performance but high renal activity retention, while the neutral BQ0501 (maS3 chelator) exhibited improved pharmacokinetics with reduced kidney activity uptake, yet still showed suboptimal hepatobiliary clearance. These findings suggested the need for further optimization of excretion properties without loss of tumor targeting. We hypothesized that introducing positively charged lysine residues into the chelator scaffold would further modulate pharmacokinetics. Three tracers (BQ-maSKS, BQ-maKSK, and BQ-maK3) were generated by stepwise substitution of serine with lysine, resulting in increasing positive charge, and their properties were evaluated in comparison with BQ-maS3 (BQ0501). All tracers were stably labeled with technetium-99m and had similar lipophilicity, indicating that subsequent differences are due to tracer charge. Binding to PC3-pip cells was PSMA-specific, with low nanomolar affinity. No major differences in overall binding affinity were observed, although lysine substitution shifted dual binding interactions toward a lower-affinity component. A marked difference in tumor uptake was observed between the two models, with significantly higher accumulation in PSMA-positive PC3-pip tumors than in PSMA-negative PC-3 tumors. Blood clearance was rapid for all tested tracers. Tumor activity uptake exceeded 30%IA/g for all tracers except [99mTc]Tc-BQ-maK3, which had ∼2-fold lower uptake. [99mTc]Tc-BQ-maKSK demonstrated the most favorable pharmacokinetic profile, characterized by predominantly renal clearance and reduced hepatobiliary excretion compared with the reference tracer [99mTc]Tc-BQ-maS3. This resulted in lower activity uptake in the liver (4-fold), small intestine walls (3-fold), and the rest of the gastrointestinal tract with content (3-fold). It also improved tumor-to-background ratios, particularly tumor-to-liver (2.8-fold) and tumor-to-small intestines (2.5-fold). The results of in vivo biodistribution were confirmed using miscroSPECT/CT. Dosimetric analysis estimated an effective dose of 0.0006 mSv/MBq for [99mTc]Tc-BQ-maKSK, with the kidneys receiving the highest absorbed dose (0.0104 mGy/MBq). In an exploratory clinical study in patients (n = 2), the tracer was well tolerated and enabled visualization of primary prostate lesions (SUVmax 5.98 and 4.45), lymph node metastases (SUVmax 4.29–8.55), and bone metastases (SUVmax 2.68–10.83). In summary, introducing a positively charged lysine into the mercaptoacetyl-based chelator improved pharmacokinetics. [99mTc]Tc-BQ-maKSK exhibited the most favorable combination of tumor targeting and excretion profile among the tested tracers, along with favorable dosimetry. Pilot SPECT/CT imaging confirmed its capability to visualize primary tumors and metastatic lesions in prostate cancer patients.