Quantitative in vivo Imaging of Adenosine A2A Receptors in the Human Brain Using 11C-SCH442416 PET: A Pilot Study

Abstract

Abstract:11 C-SCH442416 was reported in preclinical studies with rodents and primates to be the first nonxanthine radioligand suitable for the in vivo imaging of adenosine A 2A receptors with positron emission tomography (PET). The aim of the present work was to investigate the suitability of 11 C-SCH442416 for the in vivo quantification of A 2A receptors in human brain. Methods:Five male healthy subjects were scanned with 364 MBq bolus injections of 11 C-SCH442416. 90 minutes of dynamic PET emission data were acquired, and arterial blood samples were taken throughout the scan to generate an arterial plasma input function. Using the individual MR images, regions-of-interest (ROIs) were defined for cerebellum, caudate, putamen and thalamus. Spectral analysis was used to determine the frequency components of the 11 C-SCH442416 tissue response for regional and voxel time-activity curves (TACs). Results:11 C-SCH442416 was rapidly metabolised in blood, the fraction of unmetabolised parent tracer in plasma being 41% at 15 minutes and 15% at 95 minutes, lower than that reported in rats and macaca nemestrina. No lipophilic radiolabelled metabolites were found in human plasma.Rapid uptake of 11 C-SCH442416 was observed in all brain regions, reaching a maximum at about 3 minutes. When spectral analysis was applied to regional brain time activity curves (TACs), relatively rapid reversible region dependent and slower irreversible, region independent but subject specific components were identified. These components were further separated into irreversible nonspecific binding, reversible nonspecific binding, reversible specific binding and a blood component. Binding potentials of the nondisplaceable binding BP ND were calculated using cerebellar volume of distribution as an estimate of the reversible nondisplaceable binding across the entire brain. Mean binding potentials BP ND were: 2.5 (putamen), 1.6 (caudate) and 0.5 (thalamus). Conclusion:Our study demonstrates that A 2A receptor binding can be quantified in striatal regions of the human brain with 11 C-SCH442416 PET. Despite the complex tracer kinetics and its low specific binding, reliable binding potentials could be estimated with spectral analysis.

An in vivo Positron Emission Tomography Study of Adenosine 2A Receptor Occupancy by Preladenant using 11C-SCH442416 in Healthy Subjects

“…The quantifiability of A 2A receptor availability in the striatum and thalamus has been demonstrated in the 11 C SCH 442416 PET study [21]. A single oral dose of 50-200 mg preladenant achieved full A 2A receptor blockade in the striatum.…”

“…Quantitative in vivo imaging of A 2A receptors in the human brain using 11 C-SCH442416 PET has been recently described [21]. The current study was designed to investigate the A 2A dose-receptor occupancy profile of preladenant in the human brain and to determine plasma concentrations and dose of preladenant that result in inhibition of 11 C-SCH 442416 binding at 1, 6 or 12 hours after single oral administration of 10, 50 and 200 mg.…”

“…An initial cohort of five subjects (Baseline Cohort 1) was administered 11 C-SCH442416 with the injected activity ranged from 349 to 381 MBq. Data for one subject could not be used because of an acquisition failure during the PET scan; thus data for four subjects were used as baseline [21]. The next cohort of two subjects (Cohort 2) received preladenant 200 mg orally under fasting conditions 12 hours before the administration of 11 C-SCH442416.…”

The role of neuroimaging in Parkinson’s disease

“…Second, they are over-expressed in activated microglia and are considered an alternative to TSPO as a target for imaging neuroinflammation (Tronel et al, 2017). (Grachev et al, 2014;Tronel et al, 2017). Studies with the former two tracers showed elevated availability of A 2A R in the striatum of PD patients with dyskinesia, but not in dyskinesia-free PD patients (Mishina et al, 2011;Ramlackhansingh et al, 2011).…”

In VivoPET Imaging of Adenosine 2A Receptors in Neuroinflammatory and Neurodegenerative Disease

“…In the healthy CNS, human in vivo PET studies demonstrate greatest A 2A receptor ligand binding in the basal ganglia, whereas low radiotracer accumulation was shown in cortical areas and cerebellum [ 19 , 129 – 131 ]. Subject age does not seem to affect striatal A 2A receptor radioligand binding [ 132 ].…”