Novel [18F]-Labeled Meta-Bromobenzylguanidine Derivatives: Potential Positron Emission Tomography Imaging Probes for the Norepinephrine Transporter.

Abstract

To develop novel norepinephrine transporter (NET)-targeting positron emission tomography (PET) probes with optimal pharmacokinetic properties, a series of meta-bromobenzylguanidine derivatives was synthesized. 4-Fluorodiethoxyethane-3-bromobenzylguanidine (compound 12) showed relatively good affinity for the NET (IC50 = 1.00 ± 0.04 μM). The corresponding radiotracer 18F-12 was prepared in high radiochemical purity (>98%) via a three-step method. The in vitro cellular uptake results demonstrated that 18F-12 was specifically taken up by NET-expressing SK-N-SH cells by the uptake-1 mechanism. Biodistribution studies in mice showed that 18F-12 exhibited high cardiac uptake (10.45 ± 0.66 %ID/g at 5 min p.i. and 6.44 ± 0.40 %ID/g at 120 min p.i.), faster liver clearance, and a lower dose of absorbed radiation than [123I]-labeled meta-iodobenzylguanidine ([123I]MIBG). Small animal PET imaging confirmed the high heart-to-background ratio of 18F-12 and the uptake-1 mechanism specific for the NET in rats, indicating its potential as a promising PET radiotracer for cardiac sympathetic nerve imaging.