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

The norepinephrine transporter (NET) is a pivotal target for imaging sympathetic nerves and neuroendocrine tumors, and positron emission tomography (PET) tracers have demonstrated substantial utility for precise clinical diagnosis among other imaging modalities. In this work, we constructed a series of aryl ¹⁸F-labeled PET tracers from the innovative phenoxyalkylguanidine scaffold, featuring longer, optimized alkoxy chains to enhance hydrophobic interactions. The tracers were efficiently prepared via the photocatalyzed ¹⁸ F-fluorination, among which the [ ¹⁸ F] o FPhOEG demonstrated high radiochemical conversion (82.8%), favorable lipophilicity (logD = -0.39), and superior NET affinity (IC ₅₀  = 0.097 µM). In vivo evaluations revealed high and sustained target uptake (myocardial SUVmax = 8.95 in rats; tumor SUVmax = 23.35 in mice). Notably, the newly developed phenoxyalkyl core structure enabled rapid hepatic clearance, leading to significantly improved heart-to-liver and tumor-to-liver ratios (3-fold higher than [ ¹⁸ F] m FBG), which are crucial for enhancing diagnostic contrast. Additionally, the tracer was successfully produced using a commercial automated synthesis module in high RCY from a readily available precursor, guaranteeing the clinical translation of [ ¹⁸ F] o FPhOEG for cardiac and oncologic diagnosis.