Imaging and quantitation of cannabinoid CB1 receptors in human and monkey brains using 18F-labeled inverse agonist radioligands

Abstract

We recently demonstrated that 11C-MePPEP, a PET ligand for CB1 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 (VT) using the gold standard of compartmental modeling. However, 11C-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 11C-MePPEP that would provide more accurate plasma measurements. We evaluated several promising analogs in the monkey brain and chose the 18F-di-deutero fluoromethoxy analog (18F-FMPEP- d2) to evaluate further in the human brain. Methods: 11C-FMePPEP, 18F-FEPEP, 18F-FMPEP, and 18F-FMPEP-d2 were studied in 5 monkeys with 10 PET scans. We calculated VT 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 receptor-saturating dose of rimonabant, an inverse agonist at theCB1 receptor. Nine healthy human subjects participated in 17 PET scans using 18F-FMPEP-d2, 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 VT. Results: 18F-FMPEP-d2 had high uptake in the monkey brain, with greater than 80% specific binding, and yielded less radioactivity uptake in bone than did 18F-FMPEP. High brain uptake with 18F-FMPEP- d2 was also observed in humans, in whom VT was well identified within approximately 60 min. Retest variability of plasma measurements was good (16%); consequently, VT had a good retest variability (14%), intersubject variability (26%), and intraclass correlation coefficient (0.89). VT 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 inmonkeys facilitated our development and selection of 18F-FMPEP-d2, compared with 18F-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 18FFMPEP-d2 has greater precision and accuracy than 11C-MePPEP, allowing smaller sample sizes to detect a significant difference between groups. Copyright © 2010 by the Society of Nuclear Medicine, Inc.