Systematic Optimization of Meta-Halogenated ¹⁸ F-Benzylguanidine Derivatives for PET Imaging of Cardiac Sympathetic Innervation

Benzylguanidine, a norepinephrine analogue with high NET affinity, serves as a promising scaffold for visualizing cardiac sympathetic function. This study investigated whether ¹⁸F-labeled benzylguanidine derivatives with systematical meta-halogen substitution could be optimized for PET imaging of cardiac sympathetic innervation. Five derivatives were radiolabeled efficiently with high purity and stability, and aromatic substitution markedly affected in vitro and in vivo. Among them, ¹⁸F-FPFBBG (¹⁸F-FBr) demonstrated the most favorable profile. Biodistribution in mice revealed high myocardial uptake (12.26 %ID/g). PET imaging in pigs further confirmed the excellent cardiac performance of ¹⁸F-FBr, showing intense and sustained myocardial uptake (SUVmean > 4) with low background activity and favorable myocardial retention. Moreover, desipramine blocking studies confirmed its NET-specific binding. Systematic meta-halogen modification significantly altered the biological and imaging properties of benzylguanidine-based PET radiotracers. ¹⁸F-FBr demonstrated its potential as a PET radiotracer for imaging cardiac sympathetic innervation.