Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans

Dean Foster Wong, Susanne Ostrowitzki, Yun Zhou, Vanessa Raymont, Carsten Hofmann, Edilio Borroni, Anil Kumar, Nikhat Parkar, James R Brasic, John Hilton, Robert F Dannals, Meret Martin-Facklam

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)282-290
Number of pages9
JournalNeuroImage
Volume75
DOIs
StatePublished - Jul 15 2013

Fingerprint

Glycine Plasma Membrane Transport Proteins
Intravenous Injections
Healthy Volunteers
Pons
Papio
Putamen
Brain
Thalamus
Reproducibility of Results
Glycine
Cerebellum
Clinical Trials
Liver

Keywords

  • Glycine reuptake inhibitor (GRI)
  • Glycine transporter type 1 (GlyT1)
  • N-methyl-d-aspartate (NMDA)
  • Positron emission tomography (PET)
  • Radioligand assays
  • Receptors
  • Schizophrenia

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Neurology
  • Medicine(all)

Cite this

Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans. / Wong, Dean Foster; Ostrowitzki, Susanne; Zhou, Yun; Raymont, Vanessa; Hofmann, Carsten; Borroni, Edilio; Kumar, Anil; Parkar, Nikhat; Brasic, James R; Hilton, John; Dannals, Robert F; Martin-Facklam, Meret.

In: NeuroImage, Vol. 75, 15.07.2013, p. 282-290.

Research output: Contribution to journalArticle

Wong, DF, Ostrowitzki, S, Zhou, Y, Raymont, V, Hofmann, C, Borroni, E, Kumar, A, Parkar, N, Brasic, JR, Hilton, J, Dannals, RF & Martin-Facklam, M 2013, 'Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans', NeuroImage, vol. 75, pp. 282-290. https://doi.org/10.1016/j.neuroimage.2011.11.052
Wong, Dean Foster ; Ostrowitzki, Susanne ; Zhou, Yun ; Raymont, Vanessa ; Hofmann, Carsten ; Borroni, Edilio ; Kumar, Anil ; Parkar, Nikhat ; Brasic, James R ; Hilton, John ; Dannals, Robert F ; Martin-Facklam, Meret. / Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans. In: NeuroImage. 2013 ; Vol. 75. pp. 282-290.
@article{65c87f19357c4526a4931b5b72233ebf,
title = "Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans",
abstract = "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.",
keywords = "Glycine reuptake inhibitor (GRI), Glycine transporter type 1 (GlyT1), N-methyl-d-aspartate (NMDA), Positron emission tomography (PET), Radioligand assays, Receptors, Schizophrenia",
author = "Wong, {Dean Foster} and Susanne Ostrowitzki and Yun Zhou and Vanessa Raymont and Carsten Hofmann and Edilio Borroni and Anil Kumar and Nikhat Parkar and Brasic, {James R} and John Hilton and Dannals, {Robert F} and Meret Martin-Facklam",
year = "2013",
month = "7",
day = "15",
doi = "10.1016/j.neuroimage.2011.11.052",
language = "English (US)",
volume = "75",
pages = "282--290",
journal = "NeuroImage",
issn = "1053-8119",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Characterization of [11C]RO5013853, a novel PET tracer for the glycine transporter type 1 (GlyT1) in humans

AU - Wong, Dean Foster

AU - Ostrowitzki, Susanne

AU - Zhou, Yun

AU - Raymont, Vanessa

AU - Hofmann, Carsten

AU - Borroni, Edilio

AU - Kumar, Anil

AU - Parkar, Nikhat

AU - Brasic, 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

UR - http://www.scopus.com/inward/citedby.url?scp=84876455629&partnerID=8YFLogxK

U2 - 10.1016/j.neuroimage.2011.11.052

DO - 10.1016/j.neuroimage.2011.11.052

M3 - Article

VL - 75

SP - 282

EP - 290

JO - NeuroImage

JF - NeuroImage

SN - 1053-8119

ER -