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J Med Chem ; 66(13): 8600-8613, 2023 07 13.
Article in English | MEDLINE | ID: mdl-37322876

ABSTRACT

The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([111In]In-DO3AiBu-Bn-FGK-Fab or [111In]In-DOTA-Bn-FGK-Fab). When injected into mice, both generated radiometabolites, [111In]In-DO3AiBu-Bn-F and [111In]In-DOTA-Bn-F, by the angiotensin-converting enzyme at similar rates. Both exhibited significantly lower renal radioactivity levels than a 111In-labeled Fab prepared by the conventional procedure ([111In]In-DOTA-Bn-SCN-Fab). The different elimination rates of each radiometabolite from the kidney significantly affected the renal radioactivity levels. [111In]In-DO3AiBu-Bn-FGK-Fab preferentially reduced the renal localization without impairing tumor accumulation. These findings would pave the way for developing a DOTA-based radiotheranostic platform for LMW Abs bearing cleavable linkers for renal brush border enzymes.


Subject(s)
Immunoconjugates , Radioactivity , Mice , Animals , Immunoglobulin Fab Fragments , Microvilli , Antibodies , Kidney/diagnostic imaging
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