Design and Preclinical Evaluation of 18F-Labeled Phenoxyalkylguanidines as Novel Norepinephrine Transporter Radiotracers for Myocardial and Tumor Imaging

Abstract

The norepinephrine transporter (NET) is a key target for PET imaging of sympathetic nerves and neuroendocrine tumors. Herein, we developed a series of novel aryl 18F-labeled phenoxyalkylguanidine PET tracers with optimized alkoxy chains to improve NET-binding affinity, metabolic stability, and imaging performance. The tracers were readily synthesized by photocatalyzed 18F-fluorination. The lead compound, [18F] o FPhOEG, exhibited high radiochemical conversion (82.8%), favorable lipophilicity (logD = −0.39), and potent NET affinity (IC50 = 0.097 μM). In vivo studies demonstrated high and sustained target uptake (myocardial SUVmax = 8.95 in rats; tumor SUVmax = 23.35 in mice) and rapid hepatic clearance, resulting in heart-to-liver and tumor-to-liver ratios approximately 3-fold higher than those of the clinically used [18F] m FBG. Moreover, [18F] o FPhOEG was successfully produced on a commercial automated synthesizer from a readily available precursor, highlighting its promise for clinical translation in cardiac and oncological PET imaging.