Evaluation of ¹⁸F-LY2459989 for imaging the kappa opioid receptor in humans

Objectives: The kappa opioid receptor (KOR) has been implicated in various neuropsychiatric disorders. We have previously evaluated a pair of PET radiotracers for KOR imaging: ¹¹C-GR103545 (agonist) [1] and ¹¹C-LY2795050 (antagonist) [2] in humans. Since the short half-life of carbon-11 poses some challenges in tracer synthesis and kinetic analysis, we developed the first ¹⁸F-labeled KOR radiotracer, ¹⁸F-LY2459989, using newly developed radiochemistry methodology [3] and demonstrated its superior imaging and binding properties over ¹¹C-LY2795050 in nonhuman primates [4]. The goal of this study was to evaluate the kinetic and binding properties of ¹⁸F-LY2459989 in humans for comparison with ¹¹C-LY2795050.

Methods: Four healthy male subjects completed a test-retest protocol with ¹⁸F-LY2459989 on two separate days. The injected dose and mass were 159 ± 88 MBq and 1.5 ± 3.1 ug, respectively. All PET scans were acquired for 120 min on a 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 (V_T). Time-stability of V_T values was assessed by comparing V_T values from shortened time periods to the 120-min V_T values. Test-retest reproducibility was evaluated using the absolute test-retest variability (aTRV, |test-retest|/{(test+retest)/2}). To compare the specific binding of these two tracers, we applied a graphical method that plots V_T values of ¹⁸F-LY2459989 (x-axis) against those of ¹¹C-LY2795050 (y-axis) [5].

Results: Mean K₁ values (mL/cm³/min) from the 1TC model ranged from 0.048 (centrum semiovale) to 0.14 (thalamus and putamen) for ¹⁸F-LY2459989 and were similar to those of ¹¹C-LY2795050. Plasma free fraction (f_P) was 3.2 ± 0.9% (cf. 0.77 ± 0.16% for ¹¹C-LY2795050 [2]). For both tracers, 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]=30 min) was good. Except in few regions, the parameters of the 2TC model were reliably estimated. Upon excluding the unreliable parameters, an excellent correlation was observed between V_T values derived from 2TC and MA1 (V_{T (MA1)} = 0.99 × V_{T (2TC)} - 0.01, R² = 0.99). Given these results, MA1 was chosen as a suitable model for ¹⁸F-LY2459989 evaluation. Mean MA1 V_T values (mL/cm³) ranged from 2.8 (cerebellum) to 8.3 (amygdala) across subjects, and were highest in the amygdala, insula, and cingulate cortex, and lowest in the cerebellum. Minimum scan time was 90 min. The aTRV for MA1 V_T was excellent (~7%) across all regions. In comparison, ¹¹C-LY2795050 V_T values ranged from 2.0 to 4.0 and aTRV was ≤10% except for the amygdala (12%), with a minimum scan time of 70 min [2,6]. When applying the graphical analysis to compare KOR binding, ¹⁸F-LY2459989 specific binding was estimated to be higher than ¹¹C-LY2795050 specific binding (y-intercept = 1.13, [95% CI: 0.91 to 1.36], BP_ND(¹⁸F-LY2459989)/BP_ND(¹¹C-LY2795050)=4.53).

Conclusions: ¹⁸F-LY2459989 displays favorable kinetic and binding characteristics and can be used for PET imaging and quantification of KOR in the human brain. MA1 is the model of choice for kinetic analysis. Compared to ¹¹C-LY2795050, ¹⁸F-LY2459989 shows higher regional V_T and BP_ND values. Research support: NIH grant R21MH092664 and R33MH092664 Reference: [1] Naganawa M, et al, Neuroimage, 2014;99:69-79; [2] Naganawa M, et al, J Cereb Blood Flow Metab, 2014;34:1818-25; [3] Cai Z et al. ACS Chem Neurosci 2017;8:12-6; [4] Li S et al. J Nucl Med 2018;59:140-6; [5] Guo Q et al. J Cereb Blood Flow Metab 2014;34:1162-8; [6] Naganawa M, et al, J Nucl Med, 2015;56:243-8.