Discovery of Novel LAT1-Targeted PET Tracers from ¹⁸ F-Labeled Aromatic Amino Acids via Photocatalyzed ¹⁸ F-Fluorination

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 <i>L</i>-[¹⁸F]<b>1j</b> (SUV_max = 1.55 ± 0.16) showed better orthotopic glioma (U87MG mice) uptake and boundary delineation than the clinically used [¹⁸F]<b>FET</b> (SUV_max = 0.96 ± 0.22). Additionally, <i>L</i>-[¹⁸F]<b>1j</b> was successfully synthesized via a commercial automated synthesis module, demonstrating a high potential for clinical translation.