Effect of Carbohydration on the Theranostic Tracer PSMA I&T

[Image: see text] To investigate the effect of carbohydrate moieties on the pharmacokinetic profile of prostate-specific membrane antigen (PSMA) inhibitors, carbohydrated derivatives of the established PSMA-targeted radiopharmaceutical PSMA I&T were developed and evaluated. As observed for the reference PSMA I&T, the (nat)Ga/(nat)Lu complexes of the respective galactose-, mannose-, and cellobiose-conjugated analogs showed high PSMA affinity. Carbohydration had almost no effect on the lipophilicity, whereas PSMA-mediated internalization was reduced. The specific binding toward human serum albumin (HSA) decreased from 78.6% for [(nat)Lu]PSMA I&T to 19.9% for the (nat)Lu-labeled cellobiose derivative. Compared to [(68)Ga]PSMA I&T, [(68)Ga]PSMA galactose displayed lower nonspecific tissue and kidney accumulation but also slightly lower tumor uptake in small-animal positron emission tomography (μPET) imaging. Biodistribution studies confirmed reduced unspecific uptake in nontarget tissue and decreased renal accumulation of the metabolically stable [(68)Ga]PSMA galactose derivative, resulting in overall improved tumor-to-tissue ratios. However, carbohydration has no significant beneficial in vivo effect on the targeting performance of PSMA I&T. Nevertheless, carbohydration expands the repertoire of feasible modifications within the linker area and might be a valuable tool for the future development of PSMA inhibitors with decreased kidney uptake.