A sstR2-targeted radiohybrid theranostic agent for PET imaging and β- therapy with excellent preclinical performance

Abstract The radiohybrid (rh) design of radiopharmaceuticals has recently produced new theranostics suitable for both positron emission tomography (PET) imaging and peptide receptor radionuclide therapy (PRRT). This approach aims to address the limitations of current medical radionuclides by offering a new strategy for combining radionuclides that previously lacked both therapeutic and diagnostic applications. Here, we report on a somatostatin receptor subtype 2 (sstR2)-targeted radiohybrid compound, rhTATE4, which features a bifunctional silicon-based fluoride acceptor (SiFA) - named (SiFA) SeFe - for 18 F-labeling, along with a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator for 177 Lu-coordination. The rh-theranostic agent demonstrates similar in vitro behavior compared to the gold standards 177 LuLu-DOTA-TATE and SiFA lin -TATE, along with an exceptionally high tumor uptake (53.58 ± 5.51% ID/g for the radiofluorinated version) after 1 h post-injection in AR42J tumor-bearing mice, making it ideal for imaging. Moreover, clearance from normal tissues and considerable tumor retention (10.32 ± 7.04%ID/g) for 177 LuLu-TATE4 were observed at 24 p.i., suggesting good therapeutic applicability.