%0 Journal Article
%T Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11£¿C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11£¿C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1
%A Takeshi Fuchigami
%A Akihiro Takano
%A Bal¨¢zs Guly¨¢s
%A Zhisheng Jia
%A Sjoerd J Finnema
%A Jan D Andersson
%A Ryuji Nakao
%A Yasuhiro Magata
%A Mamoru Haratake
%A Morio Nakayama
%A Christer Halldin
%J EJNMMI Research
%D 2012
%I Springer
%R 10.1186/2191-219x-2-37
%X [11£¿C]N-methyl-SSR504734 was synthesized by N-[11£¿C]methylation of SSR504734 via [11£¿C]CH3OTf. In vitro brain distribution of [11£¿C]N-methyl-SSR504734 was tested in whole-hemisphere autoradiography (ARG) on human brain slices. Initial PET studies were performed using a cynomolgus monkey at baseline and after pretreatment with 0.1 to 1.5£¿mg/kg of SSR504734. Then, PET studies using rhesus monkeys were performed with arterial blood sampling at baseline and after pretreatment with 1.5 to 4.5£¿mg/kg SSR504734. Distribution volumes (VT) were calculated with a two-tissue compartment model, and GlyT1 occupancy by SSR504734 was estimated using a Lassen plot approach.[11£¿C]N-methyl-SSR504734 was successfully synthesized in moderate radiochemical yield and high specific radioactivity. In the ARG experiments, [11£¿C]N-methyl-SSR504734 showed specific binding in the white matter and pons. In the initial PET experiments in a cynomolgus monkey, [11£¿C]N-methyl-SSR504734 showed high brain uptake and consistent distribution with previously reported GlyT1 expression in vivo (thalamus, brainstem£¿>£¿cerebellum£¿>£¿cortical regions). However, the brain uptake increased after pretreatment with SSR504734. Further PET studies in rhesus monkeys showed a similar increase of brain uptake after pretreatment with SSR504734. However, the VT of [11£¿C]N-methyl-SSR504734 was found to decrease after pretreatment of SSR504734 in a dose-dependent manner. GlyT1 occupancy was calculated to be 45% and 73% at 1.5 and 4.5£¿mg/kg of SSR504734, respectively.[11£¿C]N-methyl-SSR504734 is demonstrated to be a promising PET radioligand for GlyT1 in nonhuman primates. The present results warrant further PET studies in human subjects.Glycine is a neurotransmitter of the inhibitory glycine receptors (GlyRs) but also serves as an essential co-agonist of the excitatory N-methyl-D-aspartate (NMDA) receptors [1,2]. It is known that the extracellular glycine concentration is modulated by two glycine transporters (GlyT1 and GlyT
%K Glycine transporter 1
%K SSR504734
%K 11£¿C
%K Positron emission tomography
%K Schizophrenia
%U http://www.ejnmmires.com/content/2/1/37