Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand

Abstract

Abstract[ 11 C]MePPEP is a high affinity, CB 1 receptor-selective, inverse agonist that has been studied in rodents and monkeys. We examined the ability of [ 11 C]MePPEP to quantify CB 1 receptors in human brain as distribution volume calculated with the "gold standard" method of compartmental modeling and compared results with the simple measure of brain uptake. A total of 17 healthy subjects participated in 26 positron emission tomography (PET) scans, with 8 having two PET scans to assess retest variability. After injection of [ 11 C]MePPEP, brain uptake of radioactivity was high (e.g., 3.6 SUV in putamen region at ~60 minutes) and washed out very slowly. A two-tissue compartment model yielded values of distribution volume (which is proportional to receptor density) that were both well identified (SE 5%) and stable between 60 and 210 minutes. The simple measure of brain uptake (average concentration of radioactivity between 40 and 80 minutes) had good retest variability (~8%) and moderate intersubject variability (16%, coefficient of variation). In contrast, distribution volume had two-fold greater retest variability (~15%) and, thus, less precision. In addition, distribution volume had three-fold greater intersubject variability (~52%). The decreased precision of distribution volume compared to brain uptake was likely due to the slow washout of radioactivity from brain and to noise in measurements of the low concentrations of [ 11 C]MePPEP in plasma. These results suggest that brain uptake can be used for within subject studies (e.g., to measure receptor occupancy by medications) but that distribution volume remains the gold standard for accurate measurements between groups.

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.…”

“…Kinetics of TACs was similar to that previously observed in nonhuman primates 12 with cerebral clearance generally faster than other CB1 ligands reported in humans. [8][9][10] Regional TACs averaged across scans are portrayed in Figure 3.…”

“…7 Radioligands that have been successfully advanced to use in human studies include [ 11 C]MePPEP, 8 12,13 A recent report investigated the quantification of [ 11 C]OMAR binding in healthy human subjects and patients with schizophrenia. 13 [ 11 C]OMAR was found to exhibit more rapid kinetics-including appreciable washout of radioactivity from most brain regions over the course of the scan duration-and the investigators appropriately chose to use analysis methods that account for reversible binding of the tracer.…”

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

“…Parametric images based on standardized uptake values (SUV) [activity concentration (MBq/ml) × body mass(g)/injected dose (MBq)] were generated as a measure of absolute CB 1 receptor binding [14,27]. No significant differences in body weight or injected activity were present between QA-and PBS-infused rats.…”

Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model

“…Parametric images based on standardized uptake values (SUV; activity concentration in megabecquerels per millilitre×body mass in grams/injected dose in megabecquerels) were generated as a measure of CB 1 binding [16,[23][24][25]. Relative uptake of […”