Imaging and Quantitation of Cannabinoid CB₁ Receptors in Human and Monkey Brains Using ¹⁸F-Labeled Inverse Agonist Radioligands

Abstract

We recently demonstrated that 11 C-MePPEP, a PET ligand for CB 1 receptors, has such high uptake in the human brain that it can be imaged for 210 min and that receptor density can be quantified as distribution volume (V T ) using the gold standard of compartmental modeling. However, 11 C-MePPEP had relatively poor retest and intersubject variabilities, which were likely caused by errors in the measurements of radioligand in plasma at low concentrations by 120 min. We sought to find an analog of 11 C-MePPEP that would provide more accurate plasma measurements. We evaluated several promising analogs in the monkey brain and chose the 18 F-di-deutero fluoromethoxy analog ( 18 F-FMPEP-d 2 ) to evaluate further in the human brain. Methods: 11 C-FMePPEP, 18 F-FEPEP, 18 F-FMPEP, and 18 F-FMPEP-d 2 were studied in 5 monkeys with 10 PET scans. We calculated V T using compartmental modeling with serial measurements of unchanged parent radioligand in arterial plasma and radioactivity in the brain. Nonspecific binding was determined by administering a receptorsaturating dose of rimonabant, an inverse agonist at the CB 1 receptor. Nine healthy human subjects participated in 17 PET scans using 18 F-FMPEP-d 2 , with 8 subjects having 2 PET scans to assess retest variability. To identify sources of error, we compared intersubject and retest variability of brain uptake, arterial plasma measurements, and V T . Results: 18 F-FMPEP-d 2 had high uptake in the monkey brain, with greater than 80% specific binding, and yielded less radioactivity uptake in bone than did 18 F-FMPEP. High brain uptake with 18 F-FMPEP-d 2 was also observed in humans, in whom V T was well identified within approximately 60 min. Retest variability of plasma measurements was good (16%); consequently, V T had a good retest variability (14%), intersubject variability (26%), and intraclass correlation coefficient (0.89). V T increased after 120 min, suggesting an accumulation of radiometabolites in the brain. Radioactivity accumulated in the skull throughout the entire scan but was thought to be an insignificant source of data contamination. Conclusion: Studies in monkeys facilitated our development and selection of 18 F-FMPEP-d 2 , compared with 18 F-FMPEP, as a radioligand demonstrating high brain uptake, high percentage of specific binding, and reduced uptake in bone. Retest analysis in human subjects showed that 18 F-FMPEP-d 2 has greater precision and accuracy than 11 C-MePPEP, allowing smaller sample sizes to detect a significant difference between groups.

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

“…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. 7,11 This relatively lower affinity imparts faster pharmacokinetics.…”

“…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.…”

[125I]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer’s disease

“…[ 11 C[MePPEP had also relatively poor retest and intersubject variabilities, probably due to short radioactive half-life of 11 C (20.4 min). An 18 F isotope labeled analogue of [ 11 C]MePPEP showed greater accuracy in quantification of receptor density as distribution volume, in comparison with the 11 C analogue (Terry et al, 2010b). A PET radioligand using a radionuclide with a longer half-life (e.g.…”

“…Iodinated derivatives were also described but they presented either relatively low affinity or low brain uptake (Gifford et al, 2002). The four, recently tested, novel PET radioligands, 18 F-MK-9470 (Burns et al, 2007), [ 11 C]JHU75528 (also known as [ 11 C]OMAR) (Horti et al, 2006; Wong et al, 2010) and 11 C-MePPEP (Donohue et al, 2008; Yasuno et al, 2008; Terry et al, 2009, 2010a,b), have various advantages and disadvantages for routine use. However, the selective high affinity CB 1 R radioligand 125 I SD-7015 (Donohue et al, 2009) appears as a superior tool for molecular imaging allowing in vitro and in vivo imaging studies of the CB 1 R and its changes in the human brain during physiological settings or under disease conditions.…”

The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue

“…The PET ligand (3R,5R)-5-(3-(18F-fluoromethoxy)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)-phenyl)pyrrolidin-2-one ( 18 F-FMPEP-d 2 ) has previously been validated for quantification of CB1 availability and occupancy in the CNS in humans (7).…”