In vitro and in vivo evaluation of 11C-SD5024, a novel PET radioligand for human brain imaging of cannabinoid CB1 receptors

Abstract

We recently developed a novel cannabinoid subtype-1 (CB1) receptor radioligand 11C-SD5024 for brain imaging. This study aimed to evaluate 11C-SD5024 both in vitro and in vivo and compare it with the other CB1 receptor ligands previously used in humans, i.e., 11C-MePPEP, 11C-OMAR, 18F-MK-9470, and 18F-FMPEP-d2. In vitro experiments were performed to measure dissociation constant (Ki) in human brain and to measure the lipophilicity of five CB1 receptor ligands listed above. In vivo specific binding in monkeys was measured by comparing total distribution volume (VT) at baseline and after full receptor blockade. The kinetics of 11C-SD5024 in humans were evaluated in seven healthy subjects with compartmental modeling. SD5024 showed Ki=0.47 nM, which was at an intermediate level among the five CB1 receptor ligands. Lipophilicity (LogD7.4) was 3.79, which is appropriate for brain imaging. Monkey scans showed high proportion of specific binding: ~80% of VT. In humans, 11C-SD5024 showed peak brain uptake of 1.5–3 standardized uptake value, which was slightly higher than those of 11C-OMAR and 18F-MK-9470. One-compartment model showed good fitting, consistent with the vast majority of brain uptake being specific binding found in the monkey. Regional VT values were consistent with known distribution of CB1 receptors. VT calculated from 80 and 120 min of scan data were strongly correlated (R2=0.97), indicating that 80 min provided adequate information for quantitation and that the influence of radiometabolites was low. Intersubject variability for VT of 11C-SD5024 was 22%, which was low among the five radioligands and indicated precise measurement. In conclusion, 11C-SD5024 has appropriate affinity and lipophilicity, high specific binding, moderate brain uptake, and provides good precision to measure the binding. The results suggest that 11C-SD5024 is slightly better than or equivalent to 11C-OMAR and that both are suitable for clinical studies, especially those that involve two scans in one day.

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“…Fourth, it is important to recognize that our outcome measure in this study, V T , represents specific plus nondisplaceable binding. Because of the lack of a suitable reference region devoid of CB 1 , we and others using different CB 1 receptor ligands (Ceccarini et al, 2014;Neumeister et al, 2012;Tsujikawa et al, 2014) cannot directly calculate binding potential (BP ND ), a measure of specific binding. Thus, an implicit assumption in the interpretation of our results is that there are no group differences in V ND , the distribution volume of nondisplaceable tracer uptake.…”

Imaging the Cannabinoid CB1 Receptor in Humans with [11C] OMAR: Assessment of Kinetic Analysis Methods, Test–Retest Reproducibility, and Gender Differences

“…It is further noted that these two studies shared several methodological commonalities, including use of the HRRT scanner and column-switching HPLC for radiometabolite analysis, and we conclude that the results obtained are highly concordant between the two sites. 10,28 but less than that of [ 11 C]SD5024 (peak SUV~2.5), 11 [ 11 C]MePPEP (peak SUV~4) 8 and [ 18 F]FMPEP-d 2 (peak SUV~5). 9 [ 11 C]OMAR has relatively modest CB1 affinity, with K i = 11 nmol/L, or 2.1 nmol/L, in contrast to other radiotracers that exhibit subnanomolar affinities.…”

“…9 [ 11 C]OMAR has relatively modest CB1 affinity, with K i = 11 nmol/L, or 2.1 nmol/L, in contrast to other radiotracers that exhibit subnanomolar affinities. 7,11 This relatively lower affinity imparts faster pharmacokinetics. The slow kinetics of some CB1 tracers has been acknowledged and discussed in the context of the challenges that arise in terms of required scan duration and quantification of PET data.…”

“…For [ 11 C]OMAR, radiometabolites were more polar than the parent in humans, a result that is consistent with those from mouse and baboon when [ 11 C]OMAR was first characterized, 12 where it was reported that at least 94% of radioactivity in mouse brain was attributable to unchanged [ 11 C]OMAR at 30 minutes after injection. Without the ability to directly assay radiometabolites in human brain, we sought to investigate empirically by conducting analyses of truncated data sets as was done for [ 11 7%). For all other regions, the differences were within 5% but there was an overall trend toward lower V T with an average reduction of 3.3% ± 1.8%.…”

Functional segmentation of dynamic PET studies: Open source implementation and validation of a leader-follower-based algorithm

“…In small animal studies, dynamic imaging based on custom tracers also makes it possible to assess lung inflammation [30] and specific biological receptor activity [15,39].…”