Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

Abstract

Introduction Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human Positron Emission Tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [11C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (VND) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. Methods For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [11C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n = 1 and 30 mg, n = 5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (VT). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and VND. The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [11C]GR103545 in vivo KD was also estimated. Results Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that VT was reduced in all regions; thus no suitable reference region is available for the radiotracer. VND was estimated reliably from the occupancy plot of naltrexone blocking (VND = 3.4 ± 0.9 mL/cm3). The IC50 of PF-04455242 was calculated as 55 ng/mL. [11C]GR103545 in vivo KD value was estimated as 0.069 nmol/L. Conclusions [11C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.

A hybrid deconvolution approach for estimation of in vivo non-displaceable binding for brain PET targets without a reference region

“…V ND values we obtain with HYDECA average 27% of total binding in ventral striatum for [ 11 C]DASB, and 22% of the total binding in hippocampus for [ 11 C]CUMI-101, which is generally in line with reports for other PET tracers [31, 32]. …”

Test–Retest Reproducibility of Binding Parameters in Humans with 11C-LY2795050, an Antagonist PET Radiotracer for the κ Opioid Receptor

“…Although several radiotracers have been developed over the years, thus far only the KOR agonist 11 C-GR103545 has been investigated extensively in vivo in nonhuman primates (20, 21) and humans (22), and was found to be a suitable radiotracer for KOR imaging and quantification. As part of a comprehensive evaluation in humans, the test-retest performance of 11 C-GR103545 was assessed using methods similar to those described above for 11 C-LY2795050 (22). Mean aTRV of V T estimates was about 15% for 11 C-GR103545, as compared with <10% for 11 C-LY2795050.…”

A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo

“…This is a particular concern for low f P values, which are associated with a higher imprecision of measure. [20] 0.7 0.07 0.63 0.95 19.2, 0.84 Flumazenil [21] 1.0 0.438 0.56 0.11 35.9, 0.72 GR103545 [22] 3.4 0.20 3.20 1.20 20.7, 1.67 GSK189254 [23] 10.54 0.36 10.18 1.45 19.1, 1.30 GSK931145 [24] 0.31 0.008 0.30 1.58 13.4, 1.10 JNJ-42249152 [25] -0.01 0.12 [e] 1.08 6.1, 0.87 LuAE60157 [26] 2.3 0.15 2.45 1.21 30.2, 0.89 MDL100,907 [27] 18 0.29 17.7 1.76 47.7, 0.53 MDL100,907 [28] 21 0.29 20.71 1.85 47.7, 0.53 MK8278 [29] 4.8 0.18 4.62 1.41 28.4, 0.97 PHNO [30] 4.7 0.44 4.26 0.99 22.3, 0.66 Raclopride [31] 0.44 [f] 0.029 0.41 1.15 30.5, 0.64 Ro 15-4513 [32] 0.78 0.482 0.30 À 0.21 17.4, 0.96 Rolipram [33] 0.6 0.128 0.47 0.57 23.4, 0.71 Spiperone [34] 7.5 0.094 7.41 1.90 7.0, 0.91 WAY100635 [35] 0.89 0.058 0.83 1. 16 19.7, 0.72…”