Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain

[F-18]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [F-18]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain. Dynamic small-animal PET scans with [F-18]MK-9470 were performed in Wistar rats on a FOCUS-220 system for up to 10 h. Both plasma and perfused brain homogenates were analysed using HPLC to quantify radiometabolites. Displacement and blocking experiments were done using cold MK-9470 and another inverse agonist, SR141716A. The distribution volume (V (T)) of [F-18]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification. The percentage of intact [F-18]MK-9470 in arterial plasma samples was 80 +/- 23 % at 10 min, 38 +/- 30 % at 40 min and 13 +/- 14 % at 210 min. A polar radiometabolite fraction was detected in plasma and brain tissue. The brain radiometabolite concentration was uniform across the whole brain. Displacement and pretreatment studies showed that 56 % of the tracer binding was specific and reversible. V (T) values obtained with a one-tissue compartment model plus constrained radiometabolite input had good identifiability (a parts per thousand currency sign10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [F-18]MK-9470 V (T), but was correlated. A correlation between [F-18]MK-9470 V (T) and SUV in the brain was also found (R (2) = 0.26-0.33; p a parts per thousand currency signaEuro parts per thousand 0.03). While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [F-18]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input.