Optimization of ODAP-Urea-based dual-modality PSMA targeting probes for sequential PET-CT and optical imaging

Prostate-specific membrane antigen (PSMA) is emerging as a promising target to specifically image prostate cancer. Dual-modality probe combining radionuclide imaging and near-infrared fluorescence navigation targeting PSMA would enable both the preoperative staging and intraoperative detection of the tumor lesions. To overcome one of the key barriers for achieving high contrast imaging at both early and late time points, we optimized the pharmacokinetics of dual-modality probes based on oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA inhibitors recently developed. Four dual-modality probes with variable hydrophilicity were synthesized and evaluated. They displayed good optical properties (λ_em max = 835 nm, QY = 0.67%-1.50%), high affinity to PSMA (K_i = 2.09 ± 1.71-4.15 ± 2.20 nM) and PSMA specific cellular uptake (0.48 ± 0.01% - 0.64 ± 0.04% IA/10⁵ LNCaP cells) upon labeled with ⁶⁸Ga. In vivo studies showed that [⁶⁸Ga]Ga-P3 exhibited an optimum pharmacokinetic property with high specific tumor uptake (SUVmax = 1.88 ± 0.36, at 1 h) in medium level PSMA expressing 22Rv1 tumor model and high tumor-to-muscle ratio (12.56 ± 2.63, at 1 h). Specific fluorescence imaging could also be achieved with high contrast for later time points (tumor-to-background ratio = 11.63 ± 4.16 at 24 h). This study demonstrates that ODAP-Urea-based P3 has the potential for PET imaging and intraoperative optical imaging of prostate cancer.