Test–Retest Repeatability of [¹⁸F]MC225-PET in Rodents: A Tracer for Imaging of P-gp Function

Abstract

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.

PET Imaging of [11C]MPC-6827, a Microtubule-Based Radiotracer in Non-Human Primate Brains

“…Uptake in the whole brain and specific regions of the brain including caudate nucleus, putamen, globus pallidus, subthalamic nucleus, paranigral nucleus, substantia nigra, amygdala, occipital cortex, hippocampus, and cerebellum were defined by their standardized uptake value (SUV), calculated by dividing the tracer concentration in each pixel by the injected dose per body mass. These data were used to generate time activity curves (TACs) [30] (Figure 3) using the PMOD NEURO (Ver 3.5, PMOD Technologies LLC, Zurich, Switzerland) software analysis tool [31]. The test-retest scans did not differ significantly regarding the injected dose (0.37 ± 0.05 GBq), specific activity (140.5 ± 3.7 GBq/µmol), and radiochemical purity (99.0 ± 0.5%).…”

“…Rel diff % was calculated as ((retest SUV − test SUV)/test SUV) × 100 and abs var % as ((retest SUV − test SUV)/((retest SUV + test SUV)/2) × 100. With respect to reproducibility evaluation [30], the relative difference of SUVs for whole brain and the organs of interests between the "test" and "retest" scans varied from −0.3% to −14%, and the absolute variability between the same parameters/regions from "test" and "retest" was < 0.5%. The intra-subject repeatability [30] expressed as the coefficient of variance in test scans showed an average of 16.78% ± 4.02% and in "retest" scans of 18.03% ± 3.01%.…”

“…With respect to reproducibility evaluation [30], the relative difference of SUVs for whole brain and the organs of interests between the "test" and "retest" scans varied from −0.3% to −14%, and the absolute variability between the same parameters/regions from "test" and "retest" was < 0.5%. The intra-subject repeatability [30] expressed as the coefficient of variance in test scans showed an average of 16.78% ± 4.02% and in "retest" scans of 18.03% ± 3.01%. When a two-way ANOVA (Sidak's comparison test, GraphPad Prism 7.05) was performed with SUVmean values of whole brain and the brain regions between the test scans (test-1 and test-2), there was no statistical significance (p > 0.999).…”

“…The intra-subject repeatability [30] expressed as the coefficient of variance in test scans showed an average of 16.78% ± 4.02% and in "retest" scans of 18.03% ± 3.01%. When a two-way ANOVA (Sidak's comparison test, GraphPad Prism 7.05) was performed with SUV mean values of whole brain and the brain regions between the test scans (test-1 and test-2), there was no statistical significance (p > 0.999).…”

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

“…This increase in k 2 caused a decrease in V T of the tracer inside the brain, however, it did not correspond to an increase in P-gp brain expression as was confirmed with western blot studies. 43 Therefore, if [ 18 F]MC225 is used to measure P-gp function at the BBB, the K 1 may be considered as the best parameter to assess the target function. Future studies such as a head to head comparison of both tracers are needed to clarify the mechanism of action of [ 11 C]metoclopramide and [ 18 F]MC225 and evaluate their sensitivity and specificity for measuring the P-gp transporter function.…”