Introduction: In vivo positron emission tomography (PET) imaging of the serotonin transporter (SERT) is a valuable tool in drug development and in monitoring brain diseases with altered serotonergic function. We have developed a two-step labeling reaction for the preparation of the high serotonin affinity ligand [(18)F]FPBM ([(18)F]2-(2'-((dimethylamino)methyl)-4'-(3-fluoropropoxy)phenylthio)benzenamine, 1).
Method: To improve and automate the radiolabeling of [(18)F]FPBM, 1, an intermediate, [(18)F]3-fluoropropyltosylate, [(18)F]4, was prepared first, and then it was reacted with the phenol precursor (4-(2-aminophenylthio)-3-((dimethylamino)methyl)phenol, 3) to afford [(18)F]FPBM, 1. To optimize the labeling, this O-alkylation reaction was evaluated under different temperatures, using different bases and varying amounts of precursor 3. The desired product was obtained after a solid phase extraction (SPE) purification.
Results: This two-step radiolabeling reaction successfully produced the desired [(18)F]FPBM, 1, with an excellent radiochemical purity (>95%, n = 8). Radiochemical yields were between 31% and 39% (decay corrected, total time of labeling: 70 min, n = 8). The SPE purification cannot completely remove pseudo-carriers in the final dose of [(18)F]FPBM, 1. The concentrations of major pseudo-carriers were measured by UV-HPLC (476-676, 68-95 and 50-71 μg for precursor 3, O-hydroxypropyl and O-allyloxy derivatives, 5 and 6, respectively). To investigate the potential inhibition of SERT binding of these pseudo-carriers, we performed in vitro competition experiments evaluated by autoradiography. Known amounts of 'standard' FPBM, 1, of the pseudo-carriers, 5 and 6, were added to the HPLC-purified [(18)F]1 dose. The inhibition of 'standard' FPBM, 1, binding to the SERT binding sites, using monkey brain sections, were measured (EC50=13, 46, 7.1 and 8.3 nM, respectively for 1, precursor 3, O-hydroxypropyl and O-allyloxy derivative of 3).
Conclusion: An improved radiolabeling method by a SPE purification for preparation of [(18)F]FPBM, 1, was developed. The results suggest that it is feasible to use this labeling method to prepare [(18)F]FPBM, 1, without affecting in vivo SERT binding.
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