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

[¹⁸F]MK-9470 is an inverse agonist for the type 1 cannabinoid (CB1) receptor allowing its use in PET imaging. We characterized the kinetics of [¹⁸F]MK-9470 and evaluated its ability to quantify CB1 receptor availability in the rat brain.

Dynamic small-animal PET scans with [¹⁸F]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 [¹⁸F]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 [¹⁸F]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 (≤10 %). Ignoring the radiometabolite contribution using a one-tissue compartment model alone, i.e. without constrained radiometabolite input, overestimated the [¹⁸F]MK-9470 V _T, but was correlated. A correlation between [¹⁸F]MK-9470 V _T and SUV in the brain was also found (R ² = 0.26–0.33; p ≤ 0.03).

While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [¹⁸F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input.