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

Abstract

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.

[18F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging

“…With regard to the lack of changes in thalamus, it is interesting to note that a previous PET study in non-human primates with the GlyT1 ligand N-[ 11 C]methyl-SSR504734 also found that this region behaves differently from other brain regions, which was proposed to be due to a different GlyT1 occupancy or a different non-displaceable component. 67 In addition to the minor decrease of radioactivity between early and late measurements, the TACs for cerebral cortex showed a more pronounced decline during the late measurement that started roughly 200 min after tracer administration and that was not observed in cerebellum and midbrain (Figure 2F), supporting previous evidence for a reduced residence time of ALX5407 in forebrain compared to caudal brain regions. 22 Finally, it should be noted that in contrast to the prominent binding of [ 18 F]ALX5407 to the corpus callosum observed in our in vitro experiments (Figure 1), there was little accumulation of radioactivity in this tract during the μPET measurements with [ 18 F]ALX5406 (Figure 2D,E).…”

“…As can be seen by close inspection of the early and late measurements with [ 18 F]­ALX5406 (Figure F), radioactivity in all brain regions except for the thalamus decreased somewhat between the two successive μPET measurements, which could reflect clearance of small amounts of unconverted methyl ester or unbound [ 18 F]­ALX5407 from brain. With regard to the lack of changes in thalamus, it is interesting to note that a previous PET study in non-human primates with the GlyT1 ligand N -[ 11 C]­methyl-SSR504734 also found that this region behaves differently from other brain regions, which was proposed to be due to a different GlyT1 occupancy or a different non-displaceable component . In addition to the minor decrease of radioactivity between early and late measurements, the TACs for cerebral cortex showed a more pronounced decline during the late measurement that started roughly 200 min after tracer administration and that was not observed in cerebellum and midbrain (Figure F), supporting previous evidence for a reduced residence time of ALX5407 in forebrain compared to caudal brain regions .…”

Relative Strengths of Three Linearizations of Receptor Availability: Saturation, Inhibition, and Occupancy Plots

“…We analyzed the 24 remaining published reports that consisted of 104 sets of data. In seven cases, the authors submitted data (8,(17)(18)(19)(20)(21)(22), and for the remaining 17 reports, we extracted the data from published graphs with GetData Graph Digitizer digitization software (11,13,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The characterization of the data in terms of species, sex, age, drug, dose, and other identifiers is presented in Table 1.…”

Comparative evaluation of two glycine transporter 1 radiotracers [11C]GSK931145 and [18F]MK-6577 in baboons

“…Among these GlyT1 specific PET radioligands, [ 11 C]GSK931145, [ 18 F]MK‐6577, and [ 11 C]RO5013853 have shown promise in preclinical and clinical evaluations (Gunn et al, ; Joshi et al, ; Wong et al, ). Others, such as [ 11 C] N ‐methyl‐SSR504734 and [ 11 C]SA1, have also demonstrated their potential in imaging GlyT1 in nonhuman primates (Fuchigami et al, ; Toyohara et al, ).…”