Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain
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[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.
KeywordsType 1 cannabinoid receptor Small-animal PET [18F]MK-9470 Kinetic analysis Rat
Merck & Co is acknowledged for making available the [18F]MK-9470 precursor. The authors thank Peter Vermaelen, Ann Van Santvoort, Nathalie Gérard, Ivan Sannen and Julie Cornelis for their assistance in data acquisition, as well as the Leuven PET radiopharmacy team for tracer preparation. Financial support of the Research Council of the Katholieke Universiteit Leuven (OT/05/58), the Fund for Scientific Research, Flanders, Belgium (FWO/G.0548.06), and the K.U.Leuven In Vivo Molecular Imaging (IMIR) Consortium (KUL PF/10/017) is gratefully acknowledged. Cindy Casteels is a postdoctoral fellow and Koen Van Laere a senior clinical investigator of the Flemish Fund for Scientific Research.
Conflicts of interest
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