An improved preparation of [18F]FPBM: A potential serotonin transporter (SERT) imaging agent

• Published in: Nuclear medicine and biology Vol. 40; no. 8; pp. 974 - 979
• Main Authors: Zhu, Lin, Li, Genxun, Choi, Seok Rye, Plössl, Karl, Chan, Piu, Qiao, Hongwen, Zha, Zhihao, Kung, Hank F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013
• Subjects: 18F; Aniline Compounds - chemistry; Animals; Autoradiography; Brain; Brain - diagnostic imaging; Brain - metabolism; Haplorhini; PET imaging agent; Positron-Emission Tomography - methods; Radiochemistry; Radiolabeling method; Radiology; Receptors, Serotonin - metabolism; Serotonin transporter; St; Cd; Brain; DM; SPECT; DR; ADAM; DASB; Th; PET imaging agent; MD; Radiolabeling method; ic; nor- −CIT; SN; GP; HIP; SSRI; CER; SERT; Serotonin transporter; FPBM; VL; Me; 5-HT; PET; (+)-McN5652; 18F; Cerebellum; Substantia nigra; N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; serotonin; Caudate nucleus; striatum; Dorsal raphe nucleus; Medial amygdaloid nucleus; single photon emission computed tomography; Globus pallidus; Hippocampus; nor- < beta > − CIT; Mediodorsal thalamic nucleus; 2 < beta > − carbomethoxy-3 < beta > −(4-iodophenyl); selective serotonin reuptake inhibitor; Internal capsule; 2-(2′-((dimethylamino)methyl)-4′-(3-fluoropropoxy)phenylthio)benzenamine; trans-1,2,3,5,6,10- < beta > − hexahydro-6-[4-(methylthio)phenyl-[pyrrolo-[2,1- < alpha >]isoquinoline; thalamus; Dorsomedial hypothalamic nucleus; serotonin transporter; 2-((2-((dimethylamino)methyl)- phenyl)thio)-5-iodophenylamine; Ventrolateral thalamic nucleus; positron emission tomography; trans-1,2,3,5,6,10-−hexahydro-6-[4-(methylthio)phenyl-[pyrrolo-[2,1-]isoquinoline; 2−carbomethoxy-3−(4-iodophenyl); F; nor-−CIT
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2013.08.002

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 [18F]FPBM ([18F]2-(2′-((dimethylamino)methyl)-4′-(3-fluoropropoxy)phenylthio)benzenamine, 1). To improve and automate the radiolabeling of [18F]FPBM, 1, an intermediate, [18F]3-fluoropropyltosylate, [18F]4, was prepared first, and then it was reacted with the phenol precursor (4-(2-aminophenylthio)-3-((dimethylamino)methyl)phenol, 3) to afford [18F]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. This two-step radiolabeling reaction successfully produced the desired [18F]FPBM, 1, with an excellent radiochemical purity (>95%, n=8). Radiochemical yields were between 31% and 39% (decay corrected, total time of labeling: 70min, n=8). The SPE purification cannot completely remove pseudo-carriers in the final dose of [18F]FPBM, 1. The concentrations of major pseudo-carriers were measured by UV-HPLC (476–676, 68–95 and 50–71μg 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 [18F]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). An improved radiolabeling method by a SPE purification for preparation of [18F]FPBM, 1, was developed. The results suggest that it is feasible to use this labeling method to prepare [18F]FPBM, 1, without affecting in vivo SERT binding.