Pharmacokinetic Modeling of [¹⁸F]MC225 for Quantification of the P-Glycoprotein Function at the Blood–Brain Barrier in Non-Human Primates with PET

Abstract

[ 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.

Pharmacokinetic Modeling of (R)-[11C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates

“…This study has provided more insights into the pharmacokinetic parameters of ( R )-[ 11 C]verapamil in nonhuman primates, allowing the comparison with other species. Moreover, these results enable the head-to-head comparison of the properties of a novel P-gp PET tracer, such as [ 18 F]MC225 37 or [ 11 C]metoclopramide, 31 with the P-gp tracer, ( R )-[ 11 C]verapamil, in nonhuman primates, a species larger than rodents and physiologically more similar to humans. 57 …”

“…The same acquisition protocol was used in a previous study. 37 Briefly, 1 week before the first PET scan, a brain T 1 -weighted magnetic resonance imaging (MRI) scan of the animal was made (Signa Excite HDTx 3.0T, GE Healthcare). 38 Brain PET scans were acquired using a high-resolution animal PET scanner (SHR-38000, Hamamatsu Photonics).…”

“…As has been described before, 37 after the administration of the tracer, 19 blood samples (0.5 mL) were drawn from a cannula placed in the posterior tibial artery at selected time points (8, 16, 24, 32, 40, 48, 56, and 64 s and 1.5, 2.5, 4, 6, 10, 20, 30, 45, 60, 75, and 90 min). Then, the plasma and blood were separated by centrifugation (12,000 rpm, 60 s), and the radioactivity was measured using a gamma counter (1480 Wizard, PerkinElmer).…”

Head to head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

“…[ 18 F]MC225 was selected as the most promising uorine-18 labeled tracer for in vivo measurement of P-gp function [34]. Recently, the kinetic properties of [ 18 F]MC225 were evaluated, and the results con rmed the ability of this tracer to measure changes in the P-gp function of rats [33] and non-human primates [35].…”

“…To this aim, the function of the P-gp transporter was explored in three rhesus monkeys (Macaca mulatta) under normal conditions as well as after the administration of the P-gp inhibitor, tariquidar. Based on previous publications that analyzed the pharmacokinetics of [ 18 F]MC225 and (R)-[ 11 C]verapamil in non-human primates [35,36], the 1-Tissue Compartment Model (1-TCM) was tted to the data of both tracers. Kinetic parameters such as the in ux constant K 1 , the volume of distribution (V T ), and the e ux constant k 2 were compared between the tracers at baseline and after-inhibition.…”