TY - JOUR
T1 - Pre-clinical characterization of [11C]R05013853 as a novel radiotracer for imaging of the glycine transporter type 1 by positron emission tomography
AU - Borroni, Edilio
AU - Zhou, Yun
AU - Ostrowitzki, Susanne
AU - Alberati, Daniela
AU - Kumar, Anil
AU - Hainzl, Dominik
AU - Hartung, Thomas
AU - Hilton, John
AU - Dannals, Robert F.
AU - Wong, Dean F.
N1 - Funding Information:
Special thanks to Arman Rahmin, Ph.D, the HRRT physicist in charge, Juergen Messer for the autoradiographic studies and Maria Thomas, Ph.D, for scientific editorial assistance. This study was funded by F. Hoffmann-La Roche Ltd. contract to JHU. JHU faculty receive salary support through a number of sponsored research sources including Wong NIH career award K24 DA000412, and none receive direct funding from Roche except via sponsored JHU contracts. Support for third-party editing assistance for this manuscript, furnished by archimed medical communication ag, was provided by F. Hoffmann-La Roche Ltd.
PY - 2013/7/15
Y1 - 2013/7/15
N2 - A specific positron emission tomography (PET) radiotracer for the glycine transporter type 1 (GlyT1) would constitute an imaging biomarker to investigate the distribution of GlyT1 in normal individuals and those with neuropsychiatric disorders. In addition it could demonstrate the ability of a novel drug to reach its target in the brain and enable receptor occupancy studies, thus facilitating drug development. In this article we describe the evaluation in non-human primates of two candidate PET radiotracers ([11C]RO5013852 and [11C]RO5013853) previously characterized in the rat. Both radiotracers showed acceptable uptake in the baboon brain and heterogeneous distribution consistent with that reported for GlyT1. In vivo blockade studies with two specific glycine reuptake inhibitors (GRIs), RO5013853 and bitopertin (RG1678, reduced uptake of both tracers to homogenous levels across brain regions and demonstrated specificity of the signal. [11C]RO5013853 showed a larger specific signal and slightly higher brain uptake and was therefore selected for further characterization. Quantitative compartmental analysis of PET data showed that the 2-tissue compartment model with 5 parameters was the most appropriate to describe the kinetics of [11C]RO5013853. Two additional methods were used: a) the Logan graphical analysis using plasma input and, b) a linear parametric imaging approach with the 2-tissue compartmental model. These produced VT estimates of comparable magnitude, namely, pons, thalamus and cerebellum>caudate, putamen and cortical regions. High resolution autoradiography with tritiated RO5013853 was used to confirm the binding pattern observed by PET. In vivo metabolism studies in the baboon demonstrated the formation of a single, radiolabeled metabolite more polar than the parent compound. Finally, [11C]RO5013853 was used to quantify the degree of cerebral GlyT1 occupancy observed in the baboon following oral administration of bitopertin, a selective GRI presently in Phase III clinical trial. Plasma concentrations of approximately 150-300ng/mL were estimated to produce 50% GlyT1 occupancy in the thalamus, the cerebellum and the pons.[11C]RO5013853 is a promising radiotracer for in vivo imaging of the GlyT1. It can be easily radiolabeled, exhibits moderate metabolism, displays a good specific signal, and is suitable for receptor occupancy studies of therapeutic compounds that target the GlyT1. The successful characterization of [11C]RO5013853 in healthy volunteers is presented in this NeuroImage issue (Wong et al., 2013).
AB - A specific positron emission tomography (PET) radiotracer for the glycine transporter type 1 (GlyT1) would constitute an imaging biomarker to investigate the distribution of GlyT1 in normal individuals and those with neuropsychiatric disorders. In addition it could demonstrate the ability of a novel drug to reach its target in the brain and enable receptor occupancy studies, thus facilitating drug development. In this article we describe the evaluation in non-human primates of two candidate PET radiotracers ([11C]RO5013852 and [11C]RO5013853) previously characterized in the rat. Both radiotracers showed acceptable uptake in the baboon brain and heterogeneous distribution consistent with that reported for GlyT1. In vivo blockade studies with two specific glycine reuptake inhibitors (GRIs), RO5013853 and bitopertin (RG1678, reduced uptake of both tracers to homogenous levels across brain regions and demonstrated specificity of the signal. [11C]RO5013853 showed a larger specific signal and slightly higher brain uptake and was therefore selected for further characterization. Quantitative compartmental analysis of PET data showed that the 2-tissue compartment model with 5 parameters was the most appropriate to describe the kinetics of [11C]RO5013853. Two additional methods were used: a) the Logan graphical analysis using plasma input and, b) a linear parametric imaging approach with the 2-tissue compartmental model. These produced VT estimates of comparable magnitude, namely, pons, thalamus and cerebellum>caudate, putamen and cortical regions. High resolution autoradiography with tritiated RO5013853 was used to confirm the binding pattern observed by PET. In vivo metabolism studies in the baboon demonstrated the formation of a single, radiolabeled metabolite more polar than the parent compound. Finally, [11C]RO5013853 was used to quantify the degree of cerebral GlyT1 occupancy observed in the baboon following oral administration of bitopertin, a selective GRI presently in Phase III clinical trial. Plasma concentrations of approximately 150-300ng/mL were estimated to produce 50% GlyT1 occupancy in the thalamus, the cerebellum and the pons.[11C]RO5013853 is a promising radiotracer for in vivo imaging of the GlyT1. It can be easily radiolabeled, exhibits moderate metabolism, displays a good specific signal, and is suitable for receptor occupancy studies of therapeutic compounds that target the GlyT1. The successful characterization of [11C]RO5013853 in healthy volunteers is presented in this NeuroImage issue (Wong et al., 2013).
KW - Autoradiography
KW - Bitopertin
KW - Glycine transporter type 1 (GlyT1)
KW - PET
KW - RG1678
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=84876450048&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876450048&partnerID=8YFLogxK
U2 - 10.1016/j.neuroimage.2011.11.090
DO - 10.1016/j.neuroimage.2011.11.090
M3 - Article
C2 - 22178811
AN - SCOPUS:84876450048
SN - 1053-8119
VL - 75
SP - 291
EP - 300
JO - NeuroImage
JF - NeuroImage
ER -