TY - JOUR
T1 - Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans
AU - Wong, Dean F.
AU - Ostrowitzki, Susanne
AU - Zhou, Yun
AU - Raymont, Vanessa
AU - Hofmann, Carsten
AU - Borroni, Edilio
AU - Kumar, Anil
AU - Parkar, Nikhat
AU - Brašić, James R.
AU - Hilton, John
AU - Dannals, Robert F.
AU - Martin-Facklam, Meret
PY - 2013/7/15
Y1 - 2013/7/15
N2 - We characterize a novel radioligand for the glycine transporter type 1 (GlyT1), [11C]RO5013853, in humans. Ten healthy male volunteers, 23-60years of age, were enrolled in this PET study; seven subjects participated in the evaluation of test-retest reliability and three subjects in whole body dosimetry. Subjects were administered intravenous bolus injections of approximately 1100MBq (30mCi) [11C]RO5013853 with a high specific activity of about 481GBq (13Ci)/μmol. Standard compartmental model analysis with arterial plasma input function, and an alternative noninvasive analysis method which was evaluated and validated by occupancy studies in both baboons and humans, were performed. Mean parameter estimates of the volumes of distribution (VT) obtained by a 2-tissue 5-parameter model were higher in the cerebellum, pons, and thalamus (1.99 to 2.59mL/mL), and lower in the putamen, caudate, and cortical areas (0.86 to 1.13mL/mL), with estimates showing less than 10% difference between test and retest scans. Tracer retention was effectively blocked by the specific glycine reuptake inhibitor (GRI), bitopertin (RG1678). [11C]RO5013853 was safe and well tolerated. Human dosimetry studies showed that the effective dose was approximately 0.0033mSv/MBq, with the liver receiving the highest absorbed dose.In conclusion, quantitative dynamic PET of the human brain after intravenous injection of [11C]RO5013853 attains reliable measurements of GlyT1 binding in accordance with the expected transporter distribution in the human brain. [11C]RO5013853 is a radioligand suitable for further clinical PET studies. Full characterization of a novel radiotracer for GlyT1 in humans is provided. The tracer has subsequently been used to assess receptor occupancy in healthy volunteers and to estimate occupancy at doses associated with best efficacy in a clinical trial with schizophrenic patients with predominantly negative symptoms.
AB - We characterize a novel radioligand for the glycine transporter type 1 (GlyT1), [11C]RO5013853, in humans. Ten healthy male volunteers, 23-60years of age, were enrolled in this PET study; seven subjects participated in the evaluation of test-retest reliability and three subjects in whole body dosimetry. Subjects were administered intravenous bolus injections of approximately 1100MBq (30mCi) [11C]RO5013853 with a high specific activity of about 481GBq (13Ci)/μmol. Standard compartmental model analysis with arterial plasma input function, and an alternative noninvasive analysis method which was evaluated and validated by occupancy studies in both baboons and humans, were performed. Mean parameter estimates of the volumes of distribution (VT) obtained by a 2-tissue 5-parameter model were higher in the cerebellum, pons, and thalamus (1.99 to 2.59mL/mL), and lower in the putamen, caudate, and cortical areas (0.86 to 1.13mL/mL), with estimates showing less than 10% difference between test and retest scans. Tracer retention was effectively blocked by the specific glycine reuptake inhibitor (GRI), bitopertin (RG1678). [11C]RO5013853 was safe and well tolerated. Human dosimetry studies showed that the effective dose was approximately 0.0033mSv/MBq, with the liver receiving the highest absorbed dose.In conclusion, quantitative dynamic PET of the human brain after intravenous injection of [11C]RO5013853 attains reliable measurements of GlyT1 binding in accordance with the expected transporter distribution in the human brain. [11C]RO5013853 is a radioligand suitable for further clinical PET studies. Full characterization of a novel radiotracer for GlyT1 in humans is provided. The tracer has subsequently been used to assess receptor occupancy in healthy volunteers and to estimate occupancy at doses associated with best efficacy in a clinical trial with schizophrenic patients with predominantly negative symptoms.
KW - Glycine reuptake inhibitor (GRI)
KW - Glycine transporter type 1 (GlyT1)
KW - N-methyl-d-aspartate (NMDA)
KW - Positron emission tomography (PET)
KW - Radioligand assays
KW - Receptors
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=84876455629&partnerID=8YFLogxK
U2 - 10.1016/j.neuroimage.2011.11.052
DO - 10.1016/j.neuroimage.2011.11.052
M3 - Article
C2 - 22155032
AN - SCOPUS:84876455629
VL - 75
SP - 282
EP - 290
JO - NeuroImage
JF - NeuroImage
SN - 1053-8119
ER -