Radiochemistry and Preclinical PET Imaging of (68)Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen.

Radiotracers incorporating the urea-based Glu-NH-C(O)-NH-Lys group have gained prominence due to their role in targeting prostate-specific membrane antigen (PSMA)-a clinical biomarker of prostate cancer. Here, the synthesis, radiolabeling, and in vitro and in vivo characterization of two Ga-68-radiolabeled Glu-NH-C(O)-NH-Lys radiotracers conjugated to the desferrioxamine B (DFO) chelate were evaluated. Two linker groups based on amide bond and thiourea coupling chemistries were employed to develop Ga-68-DFO-Nsucc-PSMA (Ga-68-4) and Ga-68-DFO-pNCS-Bn-PSMA (Ga-68-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of Ga-68-4 and Ga-68-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer Ga-68-HBED-CC-PSMA (Ga-68-1) (HBED = N,N'-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N'-diacetic acid). Results indicated that the target binding affinity, protein association, blood pool and background organ clearance properties, and uptake in PSMA-positive lesions are strongly dependent on the nature of the chelate, the linker, and the spacer groups. Protein dissociation constants (K-d values) were found to be predictive of pharmacokinetics in vivo. Compared to Ga-68-1, Ga-68-4 and Ga-68-7 resulted in decreased tumor uptake but enhanced blood pool clearance and reduced residence time in the kidney. The study highlights the importance of maximizing protein binding affinity during radiotracer optimization.