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


METHODS
Dynamic small-animal PET scans with [(18)F]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 [(18)F]MK-9470 was used as a quantitative measure and compared to the use of brain uptake, expressed as SUV, a simplified method of quantification.


RESULTS
The percentage of intact [(18)F]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 [(18)F]MK-9470 V(T), but was correlated. A correlation between [(18)F]MK-9470 V(T) and SUV in the brain was also found (R(2) = 0.26-0.33; p ≤ 0.03).


CONCLUSIONS
While the presence of a brain-penetrating radiometabolite fraction complicates the quantification of [(18)F]MK-9470 in the rat brain, its tracer kinetics can be modelled using a one-tissue compartment model with and without constrained radiometabolite input.
Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Leuven, Belgium. cindy.casteels@med.kuleuven.be
Cindy
C
Casteels
Michel
M
Koole
Sofie
S
Celen
Guy
G
Bormans
Koen
K
Van Laere
D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000097:blood / Q000378:metabolism; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013379:Substrate Specificity
C543264:Cnr1 protein, rat; D008024:Ligands; C528731:MK-9470; D011725:Pyridines; D011849:Radioactive Tracers; D043884:Receptor, Cannabinoid, CB1