TY - JOUR T1 - Comparison of <sup>11</sup>C-EKAP and <sup>11</sup>C-FEKAP, two novel agonist PET radiotracers for imaging the kappa opioid receptor in humans JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 357 LP - 357 VL - 58 IS - supplement 1 AU - Mika Naganawa AU - Songye Li AU - Nabeel Nabulsi AU - Shu-fei Lin AU - David Labaree AU - Jim Ropchan AU - Hong Gao AU - Shannan Henry AU - David Matuskey AU - Richard Carson AU - Yiyun Huang Y1 - 2017/05/01 UR - http://jnm.snmjournals.org/content/58/supplement_1/357.abstract N2 - 357Objectives: The kappa opioid receptor (KOR) has been implicated in various neuropsychiatric disorders. We have previously developed KOR agonist (11C-GR103545) [1] and antagonist (11C-LY2795050) [2] tracers in humans. However, since 11C-GR103545 has slow kinetics (minimum scan time = 140 min) and the variability of outcome measures is higher than desirable, we developed novel KOR agonist radiotracers, 11C-EKAP and 11C-FEKAP. The aim of this study was to compare the kinetics of these radiotracers in human brain.Methods: Six healthy subjects (3M and 3F) completed a test-retest protocol with both 11C-EKAP and 11C-FEKAP (4 scans per subject) on two separate days. An additional twelve healthy subjects (6M and 6F) underwent a pair of baseline and blocking scans with 11C-EKAP on the same day. The blocking scan was started at 70 min after an oral dose of naltrexone (150 mg). All PET scans were acquired for 120 min on the high resolution research tomograph (HRRT) scanner. Arterial blood sampling and metabolite analysis were conducted to obtain the input function. Using an MR template and individual subject’s MR image, 14 regions of interest (ROIs) were defined including putamen, caudate, cortical regions, cerebellum and thalamus to generate regional time-activity curves (TACs). One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate distribution volumes (VT). Time-stability of VT values was assessed by comparing VT values from shortened time periods to the 120-min VT values. Test-retest reproducibility was evaluated using the absolute test-retest variability (aTRV, |test-retest|/{(test+retest)/2}). KOR occupancy by naltrexone and non-displaceable distribution volume (VND) were estimated using the occupancy plot [3]. To assess which tracer has higher specific binding, we applied a graphical method that plots VT values of one tracer against those of the other tracer [4].Results: Mean K1 values (mL/cm3/min) from the 1TC model ranged from 0.09 (centrum semiovale) to 0.20 (putamen, thalamus) for 11C-EKAP, and from 0.033 (centrum semiovale) to 0.076 (insula) for 11C-FEKAP. For both tracers, regional TACs were fitted well with the 2TC model, while a lack of fit was seen in all regions with the 1TC model; fitting with MA1 (t[asterisk]=20 min) was good. The parameters of the 2TC model were not reliably estimated in a few regions, especially in the amygdala. Mean MA1 VT values (mL/cm3) ranged from 5.3 (thalamus) to 20.4 (amygdala) for 11C-EKAP and ranged from 2.2 (thalamus) to 9.9 (amygdala) for 11C-FEKAP. Minimum scan time was 90 min for 11C-EKAP and 110 min for 11C-FEKAP. The rank order of VT was the same between 11C-EKAP, 11C-FEKAP, and 11C-GR103545. The aTRV was ~10% in all regions, except for the amygdala (17%), for 11C-EKAP and 15-20%, except for the cerebellum (24%), for 11C-FEKAP. For reference, 11C-GR103545 VT values ranged from 7 to 28 and aTRV was ~15%, except for the amygdala (40%) [1]. VT values of 11C-EKAP decreased dramatically after naltrexone administration, with occupancy of 93 ± 6%, with the mean VND estimate 3.5 ± 0.8 mL/cm3 and the range of regional BPND from 0.5 (thalamus) to 4.7 (amygdala). When applying the graphical analysis to compare KOR binding to the subjects in the test-retest protocol, who received both tracers, 11C-EKAP specific binding was estimated to be lower than 11C-FEKAP specific binding by ~20% (y-intercept = 0.71 [95%CI: 0.31 to 1.11]).Conclusion: Both tracers showed better kinetic properties than 11C-GR103545. Although 11C-EKAP BPND was predicted to be lower than 11C-FEKAP BPND by ~20%, given the shorter minimum scan time and better test-retest reproducibility, 11C-EKAP is judged as a better tracer than 11C-FEKAP for the imaging and quantification of KOR binding in humans. Research Support: NIH grant 5R33MH092664-05 ER -