Discovery ofNovelLAT1-Targeted PET Tracers from 18F-Labeled AromaticAmino Acids via Photocatalyzed 18F-Fluorination

作者：Yang Xie, Yueqi Wang, Mingxing Hu, Lili Pan, Zheng Cheng, Kai Lu, Yarong Cao, Mufeng Li, Honghai Yin, Wei Chen · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c02177 · 被引用次数：5 · 研究领域：Amino Acid Enzymes and Metabolism、Cancer, Hypoxia, and Metabolism、Glioma Diagnosis and Treatment

Abstract Positron emission tomography (PET) tracers targeting amino acid metabolic dysregulation offer unique advantages for diagnosing and monitoring malignant brain tumors. Though the large neutral amino acid transporter 1 (LAT1) serves as a biomarker for many malignancies, clinically applicable LAT1-targeted PET tracers remain limited. This study combines LAT1 structural information and efficient photocatalyzed 18F-deoxyfluorination to explore the structure-activity relationship (SAR) of unnatural aromatic amino acid-derived LAT1 ligands. Small hydrophobic alkyl/alkoxy substituents and diverse linkers were introduced to the phenyl ring to fit LAT1’s flexible hydrophobic binding domain, leading to the discovery of novel LAT1-targeted tracers with excellent tumor uptake. The methylated phenylalanine PET tracer L-[18F]1j (SUVmax = 1.55 ± 0.16) showed better orthotopic glioma (U87MG mice) uptake and boundary delineation than the clinically used [18F]FET (SUVmax = 0.96 ± 0.22). Additionally, L-[18F]1j was successfully synthesized via a commercial automated synthesis module, demonstrating a high potential for clinical translation.