Diagnostic Twins: Exploring the Radiohybrid Concept with Iodine-123 and Lanthanum-133 for PSMA-Targeted SPECT and PET...

PSMA-targeted ligands containing macropa as highly effective chelators for ²²⁵Ac were developed for endoradiotherapy, alongside complementary diagnostic approaches using ¹³³La for PET and ¹²³I for SPECT within the radiohybrid concept. These ligands include mono- and bivalent PSMA-targeting structures with optional albumin-binding moieties, enabling both early- and late-stage imaging while maintaining identical pharmacological behavior. Radiolabeling was performed at the macropa side with ¹³³La and at the albumin-binding side with ¹²³I. All ligands showed high PSMA affinity (K_i = 2.3-9.4 nM) and remarkable internalization rates up to 97% in vitro. In vivo studies using LNCaP tumor-bearing mice demonstrated comparable tumor uptake across all conjugates, regardless of the radionuclide. Advantageously, quantitative PET and SPECT blood measurements correlated closely with ex vivo data and metabolite analysis, additionally confirming the high in vivo stability with minimal deiodination during renal excretion and highlighting the suitability for dosimetric applications.