title: An improved preparation of [18F]FPBM: a potential serotonin transporter (SERT) imaging agent.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, Beijing, 100875, P. R. China; Department of Radiology, University of Pennsylvania, Philadelphia, PA 19014, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Genxun
authors.initials: G
authors.lastname: Li
authors.forename: Seok Rye
authors.initials: SR
authors.lastname: Choi
authors.forename: Karl
authors.initials: K
authors.lastname: Plössl
authors.forename: Piu
authors.initials: P
authors.lastname: Chan
authors.forename: Hongwen
authors.initials: H
authors.lastname: Qiao
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Zha
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D000882:Haplorhini; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D011985:Receptors, Serotonin / Q000378:metabolism*
chemical_list: C527727:2-(2-((dimethylamino)methyl)-4-(3-fluoropropoxy)phenylthio)benzenamine; D000814:Aniline Compounds; D011985:Receptors, Serotonin
keywords: (+)-McN5652; (18)F; (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; 2-((2-((dimethylamino)methyl)- phenyl)thio)-5-iodophenylamine; 2-(2′-((dimethylamino)methyl)-4′-(3-fluoropropoxy)phenylthio)benzenamine; 2<beta>−carbomethoxy-3<beta>−(4-iodophenyl); 5-HT; ADAM; Brain; CER; Caudate nucleus; Cd; Cerebellum; DASB; DM; DR; Dorsal raphe nucleus; Dorsomedial hypothalamic nucleus; FPBM; GP; Globus pallidus; HIP; Hippocampus; Internal capsule; MD; Me; Medial amygdaloid nucleus; Mediodorsal thalamic nucleus; PET; PET imaging agent; Radiolabeling method; SERT; SN; SPECT; SSRI; Serotonin transporter; St; Substantia nigra; Th; VL; Ventrolateral thalamic nucleus; ic; nor-<beta>−CIT; positron emission tomography; selective serotonin reuptake inhibitor; serotonin; serotonin transporter; single photon emission computed tomography; striatum; thalamus; trans-1,2,3,5,6,10-<beta>−hexahydro-6-[4-(methylthio)phenyl-[pyrrolo-[2,1-<alpha>]isoquinoline