Abstract 592: Theranostic 68Ga/131I compounds for PSMA targeted radioligand therapy

Abstract Introduction: Prostate cancer is the most common cancer in men and continues to be a common cause of cancer related death. With progression to castration resistant metastatic prostate cancer, treatment options are scarce. Radioligand therapy has emerged as a successful treatment for these patients, significantly prolonging survival when other treatments fail. Thus far, approved PSMA targeting radiopharmaceuticals mainly use DOTA-based precursors to chelate gallium-68 for diagnosis and lutetium-177 for therapy. Here we suggest a gallium-68/iodine-131 theranostic pair as an alternative radiohalogenated treatment option. Method: Four compounds based on a common urea PSMA binding motif with additional peptidic linkers were synthesized. These compounds are suitable for both radiohalogenation as well as radiometal labeling via DOTA-chelator(s). For comparative screening, all compounds were labelled with 68Ga in >95% radiochemical purity. Subsequently, BALB/c nude mice carrying LNCaP xenografts were intravenously injected with 8-13 MBq of compound [1]-[4]. Mice were PET/CT scanned one and two hours after injection. After final scan, mice were euthanized and organs harvested for ex vivo biodistribution. Based on tumor and off-target accumulation, a lead compound is selected for iodine-131 labelling by dematallation to assess distribution and dosimetry. Results: All compounds screened demonstrated favorable tumor uptake and fast clearance. Ex vivo Tumor, blood and kidney accumulation is presented in Table 1 Table 1: %ID/g and T/B and T/K in tumor, blood and kidney of compound 1-4 as well as PSMA-617. 68Ga[1] 68Ga[2] 68Ga[3] 68Ga[4] [68Ga]Ga-PSMA617 Tumor %ID/g 6.7 4.9 7.7 6.1 7.4 Blood %ID/g 0.2 2.8 0.2 1.1 0.4 Kidney %ID/g 19.9 22.7 3.8 22.6 2.0 T/B ratio 43.0 1.7 30.8 5.6 16.9 T/K ratio 0.3 0.2 2.0 0.3 3.6 , alongside tumor- (T/B) and tumor-to-kidney (T/K) ratios. Notably, compound 3 demonstrated high tumor uptake similar to PSMA-617, as well as low renal retention and faster blood clearance. Conclusion: Here we tested four different compounds in a mouse model of prostate cancer and identified compound 3 as lead candidate for further translational investigation using iodine-131. Citation Format: Lars Hvass, Marcel Martin, Anne Clausen, Panagiota Iakovidou, Marius Müller, Umberto Battisti, Vladimir Shalgunov, Agustin Lenero, Nadia Pedersen, Sophie Stotz, Matthias Herth, Andreas Kjaer. Theranostic 68Ga/131I compounds for PSMA targeted radioligand therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 592.