Synthesis and evaluation of
2-chloro N-[(S)-{(S)-1-[11C]
methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11C]N-methyl- SSR504734) as a PET
radioligand for glycine transporter 1.
ABSTRACT
Background: Dysfunction
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: [11C]N-methyl-SSR504734
was synthesized by N-[11C]methylation
of SSR504734 via [11C]CH3OTf. In vitro brain distribution
of [11C]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: [11C]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, [11C]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 [11C]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: [11C]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.