[ 18 F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood–brain barrier with positron emission tomography. This study evaluates [ 18 F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K 1 increased by 40.7% and the volume of distribution ( V T ) by 30.4% after P-gp inhibition, while the efflux constant k 2 did not change significantly. Similar changes were found for all evaluated scan durations. K 1 did not depend on scan duration (10 min— K 1 = 0.2191 vs 91 min— K 1 = 0.2258), while V T and k 2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K 1 obtained with 1-TCM. For the 91-min scan, V T and K 1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function.

(R)-[11C]­verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood–brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[11C]­verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[11C]­verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[11C]­verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[11C]­verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[11C]­verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[11C]­verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V T) and the efflux constant k 2 estimations were affected by the evaluated scan durations, whereas the influx constant K 1 estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V T increased significantly up to 208% (p < 0.001) and K 1 up to 159% (p < 0.001) compared with baseline scans. The k 2 values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K 1, calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates.

In longitudinal PET studies, animals are repeatedly anesthetized which may affect the repeatability of PET measurements. The aim of this study was to assess the effect of anesthesia on the P-gp function as well as the reproducibility of [ 18 F]MC225 PET scans. Thus, dynamic PET scans with blood sampling were conducted in 13 Wistar rats. Seven animals were exposed to isoflurane anesthesia 1 week before the PET scan ("Anesthesiaexposed" PET). A second group of six animals was used to evaluate the reproducibility of measurements of P-gp function at the blood−brain barrier (BBB) with [ 18 F]MC225. In this group, two PET scans were made with a 1 week interval ("Test" and "Retest" PET). Pharmacokinetic parameters were calculated using compartmental models and metabolite-corrected plasma as an input function. "Anesthesia-exposed" animals showed a 28% decrease in whole-brain volume of distribution (V T ) (p < 0.001) compared to "Test", where the animals were not previously anesthetized. The V T at "Retest" also decreased (19%) compared to "Test" (p < 0.001). The k 2 values in whole-brain were significantly increased by 18% in "Anesthesia-exposed" (p = 0.005) and by 15% in "Retest" (p = 0.008) compared to "Test". However, no significant differences were found in the influx rate constant K 1 , which is considered as the best parameter to measure the P-gp function. Moreover, Western Blot analysis did not find significant differences in the P-gp expression of animals not pre-exposed to anesthesia ("Test") or pre-exposed animals ("Retest"). To conclude, anesthesia may affect the brain distribution of [ 18 F]MC225 but it does not affect the P-gp expression or function.