In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey

Xiaoyun Zhou, Ronald Boellaard, Kiichi Ishiwata, Muneyuki Sakata, Rudi A J O Dierckx, Johan R de Jong, Shingo Nishiyama, Hiroyuki Ohba, Hideo Tsukada, Erik F J de Vries, Philip H Elsinga

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

11C-preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aimed to evaluate the suitability of 11C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. Methods:11C-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in A2AR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A2AR occupancy was studied with caffeine blockade. Results: Regional uptake of 11C-preladenant was consistent with the distribution of A2ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. Conclusion:11C-preladenant PET is suitable for noninvasive quantification of A2ARs and assessment of A2AR occupancy in A2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A2AR quantification.

Original languageEnglish
Pages (from-to)762-767
Number of pages6
JournalJournal of Nuclear Medicine
Volume58
Issue number5
DOIs
Publication statusPublished - May 2017

Cite this

Zhou, Xiaoyun ; Boellaard, Ronald ; Ishiwata, Kiichi ; Sakata, Muneyuki ; Dierckx, Rudi A J O ; de Jong, Johan R ; Nishiyama, Shingo ; Ohba, Hiroyuki ; Tsukada, Hideo ; de Vries, Erik F J ; Elsinga, Philip H. / In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey. In: Journal of Nuclear Medicine. 2017 ; Vol. 58, No. 5. pp. 762-767.
@article{c7d83b6f4f2745d390ede56ec836b214,
title = "In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey",
abstract = "11C-preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aimed to evaluate the suitability of 11C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. Methods:11C-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in A2AR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A2AR occupancy was studied with caffeine blockade. Results: Regional uptake of 11C-preladenant was consistent with the distribution of A2ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. Conclusion:11C-preladenant PET is suitable for noninvasive quantification of A2ARs and assessment of A2AR occupancy in A2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A2AR quantification.",
keywords = "Animals, Brain, Carbon Radioisotopes, Consciousness, Macaca mulatta, Male, Metabolic Clearance Rate, Molecular Imaging, Positron-Emission Tomography, Pyrimidines, Radiopharmaceuticals, Receptor, Adenosine A2A, Tissue Distribution, Triazoles, Evaluation Studies, Journal Article",
author = "Xiaoyun Zhou and Ronald Boellaard and Kiichi Ishiwata and Muneyuki Sakata and Dierckx, {Rudi A J O} and {de Jong}, {Johan R} and Shingo Nishiyama and Hiroyuki Ohba and Hideo Tsukada and {de Vries}, {Erik F J} and Elsinga, {Philip H}",
note = "{\circledC} 2017 by the Society of Nuclear Medicine and Molecular Imaging.",
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language = "English",
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pages = "762--767",
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Zhou, X, Boellaard, R, Ishiwata, K, Sakata, M, Dierckx, RAJO, de Jong, JR, Nishiyama, S, Ohba, H, Tsukada, H, de Vries, EFJ & Elsinga, PH 2017, 'In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey' Journal of Nuclear Medicine, vol. 58, no. 5, pp. 762-767. https://doi.org/10.2967/jnumed.116.182410

In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey. / Zhou, Xiaoyun; Boellaard, Ronald; Ishiwata, Kiichi; Sakata, Muneyuki; Dierckx, Rudi A J O; de Jong, Johan R; Nishiyama, Shingo; Ohba, Hiroyuki; Tsukada, Hideo; de Vries, Erik F J; Elsinga, Philip H.

In: Journal of Nuclear Medicine, Vol. 58, No. 5, 05.2017, p. 762-767.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey

AU - Zhou, Xiaoyun

AU - Boellaard, Ronald

AU - Ishiwata, Kiichi

AU - Sakata, Muneyuki

AU - Dierckx, Rudi A J O

AU - de Jong, Johan R

AU - Nishiyama, Shingo

AU - Ohba, Hiroyuki

AU - Tsukada, Hideo

AU - de Vries, Erik F J

AU - Elsinga, Philip H

N1 - © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

PY - 2017/5

Y1 - 2017/5

N2 - 11C-preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aimed to evaluate the suitability of 11C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. Methods:11C-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in A2AR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A2AR occupancy was studied with caffeine blockade. Results: Regional uptake of 11C-preladenant was consistent with the distribution of A2ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. Conclusion:11C-preladenant PET is suitable for noninvasive quantification of A2ARs and assessment of A2AR occupancy in A2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A2AR quantification.

AB - 11C-preladenant was developed as a novel PET ligand for the adenosine A2A receptors (A2ARs). The present study aimed to evaluate the suitability of 11C-preladenant PET for the quantification of striatal A2ARs and the assessment of A2AR occupancy in the conscious monkey brain. Methods:11C-preladenant was intravenously injected into conscious monkeys (n = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume (VT) was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential (BPND) in A2AR-rich regions. BPND obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on BPND and DVR-1 were investigated. VT and BPND were also obtained after preblocking with unlabeled preladenant (1 mg/kg), A2AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). A2AR occupancy was studied with caffeine blockade. Results: Regional uptake of 11C-preladenant was consistent with the distribution of A2ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on k4 to stabilize fits. The highest VT was observed in A2AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). BPND values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in A2AR-rich regions). Preladenant preinjection decreased the tracer uptake in A2AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. Conclusion:11C-preladenant PET is suitable for noninvasive quantification of A2ARs and assessment of A2AR occupancy in A2AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for A2AR quantification.

KW - Animals

KW - Brain

KW - Carbon Radioisotopes

KW - Consciousness

KW - Macaca mulatta

KW - Male

KW - Metabolic Clearance Rate

KW - Molecular Imaging

KW - Positron-Emission Tomography

KW - Pyrimidines

KW - Radiopharmaceuticals

KW - Receptor, Adenosine A2A

KW - Tissue Distribution

KW - Triazoles

KW - Evaluation Studies

KW - Journal Article

U2 - 10.2967/jnumed.116.182410

DO - 10.2967/jnumed.116.182410

M3 - Article

VL - 58

SP - 762

EP - 767

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

SN - 0161-5505

IS - 5

ER -