Abstract
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Objectives We have developed [11C]LY2795050 as a novel, selective antagonist PET tracer for the kappa opioid receptors (KOR) and demonstrated its suitability to image KOR in the monkey brain. The objective of this study was to assess the potential of this tracer for imaging KOR in humans and the reliability of binding parameter measurements.
Methods PET imaging in 7 healthy subjects (5 M, 2 F) was performed on the HRRT scanner. Each subject underwent 2 scans of 120 min duration in a single day. Arterial blood samples were drawn for input function measurement and metabolite analysis. Brain regional time activity curves were analyzed using a 2-tissue compartment (2T) model to estimate volume of distribution (VT) and binding potential (BPND). BPND values were also calculated with the simplified reference tissue model (SRTM) using cerebellum as the reference region. Test-retest variability of BPND estimates was assessed as 100*(BPND Test - BPND Retest) / [(BPND Test + BPND Retest) / 2].
Results In humans, [11C]LY2795050 displayed a moderate rate of peripheral metabolism, with ~40% of parent compound available at 30 min post-injection. The tracer entered the brain readily, with peak SUV of 2 to 3. Tissue kinetics was fast, with regional activity peaking within 30 min. The rank order of activity uptake and regional VT follows amygdala (AMY) > cingulate cortex (CIN) > globus pallidus (GP) ~ putamen (PUT) > temporal cortex (TEM) ~ frontal cortex (FNT) > hippocampus (HIP) ~ caudate (CAU) > cerebellum (CER). There was excellent correlation of binding parameters derived from 2T and SRTM. Mean regional BPND values from SRTM were 1.03, 0.68, 0.58, 0.53, 0.40, 0.37, 0.27, and 0.27, respectively, for AMY, CIN, GP, PUT, FNT, TEM, HIP,and CAU (n = 14). Test-retest variability was 8.2% for 2T and 7.2% for SRTM.
Conclusions The novel tracer [11C]LY2795050 is an appropriate agent for imaging and quantification of KOR in humans. This is the first report of imaging KOR in humans with a selective antagonist PET tracer