Nitroimidazole containing cyclicpeptide [68Ga]Ga-ZJUIQB-G002 as a new FAP-targeting radionuclide tracer.

Abstract

Fibroblast activation protein (FAP) is one of the most extensively studied and promising targets for cancer diagnosis and therapy. Although small-molecule FAP-targeting radiopharmaceuticals are widely used, their clinical utility is often limited by rapid tumor washout and suboptimal therapeutic efficacy. To address these limitations, we designed a series of new FAP-targeting probes by incorporating a 2-nitroimidazole moiety into the FAP-2286 scaffold, a cyclic peptide known for prolonged tumor retention relative to conventional small-molecule FAP inhibitors. Among the resulting constructs, NOTA-ZJUIQB-G002 has potent hFAP-binding affinity (Kd = 0.032 nM), and [68Ga]Ga-NOTA-ZJUIQB-G002 exhibited markedly enhanced tumor uptake and improved tumor-to-background ratios (tumor/kidney > 3.0; tumor/intestine > 10.0) in PET studies using HEK293. hFAP xenograft models. The tracer also showed rapid clearance from most normal tissues while maintaining sustained tumor retention, resulting in favorable imaging contrast. In a more physiologically relevant U87 tumor-bearing mice without FAP gene transfection, [177Lu]Lu-DOTA-ZJUIQB-G002 exhibited improved tumor uptake but relatively higher renal uptake, highlighting the influence of tumor models on the in vivo pharmacokinetic behavior of FAP-targeting radioligands. Collectively, these findings demonstrate the potential of nitroimidazole-containing FAP-targeting radioligands for tumor imaging and future theranostic applications and support further investigation of this scaffold for FAP-targeted radiopharmaceutical development.

Abstract as supplied by the indexing source. © the authors / publisher.