New PET Imaging Agent for the Serotonin Transporter: [18F]ACF (2-[(2-Amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine) (2002)
BibTeX
@MISC{Oya02newpet,
author = {Shunichi Oya and Seok Rye Choi and Heinz Coenen and Hank F. Kung},
title = {New PET Imaging Agent for the Serotonin Transporter: [18F]ACF (2-[(2-Amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine)},
year = {2002}
}
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Abstract
A new F-18-labeled phenylthiophenyl derivative specific for imaging of serotonin transporters (SERT) in the brain by positron emission tomography (PET) is described. Fluorinated phenylthiophenyl derivative, ACF, 2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine, was prepared by first coupling 2,5-dichloro-4-nitroaniline with 2-mercapto-N,N-dimethylbenzamide. The amino group of the coupled adduct was converted to a fluoro group through a Schiemann reaction. Subsequently, a one pot reduction of both nitro and amide groups by BH3-tetrahydrofuran yielded the nonradioactive ACF (yield 25%). In vitro binding assays using cell membrane homogenates of LLC cells expressing SERT, dopamine transporters (DAT), or norepinephrine transporters (NET) showed excellent binding affinity and selectivity for SERT (Ki) 0.05, 3020, and 650 nM for SERT, DAT, and NET, respectively). For preparation of the [18F]ACF, the NH2 group of the initially coupled adduct was converted to the trimethylammonium salt, which was replaced by [18F]fluoride in the presence of Kryptofix 222 and potassium carbonate. The final product, [18F]ACF, was obtained after a borane and stannous chloride reduction reaction. The combined two step reaction gave a radiochemical yield of 10-15 % (EOB) and a radiochemical purity of>99%. Synthesis of the novel PET tracer, [18F]ACF, as a probe for binding to SERT in the brain was successfully achieved. The new tracer [18F]-ACF showed excellent brain penetration and selective localization after an iv injection in rats (brain uptake at 2, 30, 60, 120, and 240 min was 3.27, 1.28, 0.69, 0.21, and 0.06 % dose/organ, respectively). The hypothalamus/cerebellum ratio at 60 min post iv injection was 3.55. This specific localization in the hypothalamus was blocked by pretreatment of (+)McN5652. This novel ligand is a potential PET tracer for in vivo evaluation of SERT in the brain.
Keyphrases
serotonin transporter new pet imaging agent coupled adduct new f-18-labeled phenylthiophenyl derivative specific schiemann reaction brain uptake nh2 group trimethylammonium salt specific localization radiochemical yield novel pet tracer norepinephrine transporter amide group amino group potassium carbonate hypothalamus cerebellum ratio nonradioactive acf excellent binding affinity vivo evaluation dose organ selective localization cell membrane homogenate final product min post iv injection positron emission tomography dopamine transporter fluoro group radiochemical purity vitro binding assay stannous chloride reduction reaction excellent brain penetration iv injection step reaction new tracer novel ligand potential pet tracer llc cell pot reduction
