Systematic Investigation of Fatty Acids with Different Carbon-Chain Length as Albumin Binder to Improve Tumor Accumulation of Radioligands.

In the development of radiopharmaceuticals, high tumor accumulation is required for their diagnostic and therapeutic effectiveness. A key strategy to enhance such tumor accumulation is the incorporation of small-molecule albumin binders (ALBs) into radioligands, extending the blood circulation time through albumin interaction for efficient delivery to tumors. In this study, we systematically investigated the potential use of fatty acids (FAs) with various carbon-chain lengths (C12, C14, C16, and C18) as ALBs (FA12, FA14, FA16, and FA18). First, we synthesized four radiolabeled compounds composed of a macrocyclic radiometal chelator and various FAs ([111In]In-DFA12, [111In]In-DFA14, [111In]In-DFA16, and [111In]In-DFA18). In vitro albumin-binding assays and biodistribution studies using normal mice revealed a chain-length dependence: longer carbon chains led to higher albumin affinity and prolonged blood retention, with [111In]In-DFA18 exhibiting the most favorable pharmacokinetic profile. Based on these results, we developed [111In]In-PDFA18, a prostate-specific membrane antigen (PSMA)-targeted radioligand conjugated with FA18. Tumor accumulation of [111In]In-PDFA18 at 24 and 96 h postinjection (p.i.) (43.70 and 52.59% injected dose (ID)/g, respectively) was markedly higher and more prolonged compared with that of the non-FA18-conjugated control radioligand, [111In]In-PSMA-617 (14.86 and 5.36% ID/g). These findings suggest that FA18 is a promising ALB to improve the tumor accumulation of radioligands.