Scalable droplet-based radiosynthesis of [¹⁸F]fluorobenzyltriphenylphosphonium cation ([¹⁸F]FBnTP) <i>via</i> a "numbering up" approach.

Abstract

The [¹⁸F]fluorobenzyltriphenylphosphonium cation ([¹⁸F]FBnTP) has emerged as a highly promising positron emission tomography (PET) tracer for myocardial perfusion imaging (MPI) due to its uniform distribution in the myocardium and favorable organ biodistribution demonstrated in preclinical studies. However, a complex and low-efficiency radiosynthesis procedure has significantly hindered its broader preclinical and clinical explorations. Recently, Zhang <i>et al.</i> developed a pinacolyl arylboronate precursor, enabling a one-step synthesis process that greatly streamlines the production of [¹⁸F]FBnTP. Building upon this progress, our group successfully adapted the approach to a microdroplet reaction format and demonstrated improved radiosynthesis performance in a preliminary optimization study. However, scaling up to clinical dose amounts was not explored. In this work, we demonstrate that scale-up can be performed in a straightforward manner using a "numbering up" strategy (<i>i.e.</i> performing multiple droplet reactions in parallel and pooling the crude products). The resulting radiochemical yield after purification and formulation was high, up to 66 ± 1% (<i>n</i> = 4) for a set of experiments involving pooling of 4 droplet reactions, accompanied by excellent radiochemical purity (>99%) and molar activity (339-710 GBq μmol^-1). Notably, we efficiently achieved sufficient activity yield (0.76-1.84 GBq) for multiple clinical doses from 1.6 to 3.7 GBq of [¹⁸F]fluoride in just 37-47 min.