Synthesis and characterization of [125I]2-iodo N-[(S)-{(S)-1-methylpiperidin-2-yl}(phenyl)methyl]3-trifluoromethyl-benzamide as novel imaging probe for glycine transporter 1

Fuchigami, Takeshi; Haratake, Mamoru; Magata, Yasuhiro; Haradahira, Terushi; Nakayama, Morio

doi:10.1016/j.bmc.2011.09.010

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Therefore, it was suggested that this series of compounds can bind to both rodent and human GlyT1. The present human ARG results seemed not to be in line with the previous report [24]. Several factors such as species differences and condition of the ARG slices should be taken into consideration.…”

Section: Discussioncontrasting

confidence: 91%

“…The low 11 C radioactivity in the white matter, where GlyT1 binding was reported to be high in in vitro ARG studies, was consistent with our previous ex vivo studies of 125 I]IMPB [24] and previous PET studies with other GlyT1 ligands [19-21]. Compared with in vitro ARG results, low uptake in the white matter might be related to low blood flow in the white matter [33,34].…”

Section: Discussionsupporting

confidence: 88%

“…It was previously reported that N -methyl-SSR504734 has high affinity for GlyT1 (1.6 nM) [25] and a potent GlyT1 inhibitory activity (IC 50 = 2.4 nM) [24]. The same structure with 11 C] N -methyl-SSR504734 was reported recently [23].…”

Section: Introductionmentioning

confidence: 54%

“…Previously, 125 I]IMPB, which is a 11 C] N -methyl-SSR504734 analog, showed excellent high specific binding to rat brain slices under in vitro ARG studies. In addition, both IMPB and N -methyl-SSR504734 showed very high inhibitory activity against the human GlyT1 (IMPB, IC 50 = 2.4 nM; N -methyl-SSR504734, IC 50 = 7.5 nM) as determined in a 3 H]glycine uptake assay using JAR cells [24]. Therefore, it was suggested that this series of compounds can bind to both rodent and human GlyT1.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, SSR504734-related radioligands such as 11 C]SA1 showed high brain uptake and a consistent accumulation with the GlyT1 distribution in the mouse and monkey brain [23]. More recently, we developed 125 I]2-iodo N -[( S )-{( S )-1-methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ( 125 I]IMPB) as a promising SPECT ligand candidate [24]. …”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2012

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BackgroundDysfunction of the glycine transporter 1 (GlyT1) has been suggested to be involved in psychiatric disorders such as schizophrenia. GlyT1 inhibitors have therefore been considered to have antipsychotic therapeutic potential. Positron emission tomography (PET) imaging probes for GlyT1 are, consequently, expected to be useful for investigating the mechanism of such disease conditions and for measuring occupancy of GlyT1 inhibitors in vivo. The aim of this study was to assess the potential 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 imaging agent for GlyT1.Methods[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.Results[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.Conclusions[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.

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Section: Discussioncontrasting

confidence: 91%