Parametric Imaging of P-Glycoprotein Function at the Blood-Brain Barrier Using k-maps Generated from [C]Metoclopramide PET Data in Rats, Nonhuman Primates and Humans.

PURPOSE

PET imaging using [C]metoclopramide revealed the importance of P-glycoprotein (P-gp, ABCB1) in mediating the brain-to-blood efflux of substrates across the blood-brain barrier (BBB). In this work, the elimination rate constant from the brain (k), calculated from dynamic PET images without the need for arterial blood sampling, was evaluated as an outcome parameter for the interpretation of [C]metoclopramide PET data.

PROCEDURES

k parameter was obtained by linear regression of log-transformed brain time-activity curves (TACs). k values (h) obtained under baseline conditions were compared with values obtained after complete P-gp inhibition using tariquidar in rats (n = 4) and baboons (n = 4) or after partial inhibition using cyclosporine A in humans (n = 10). In baboons, the sensitivity of k to measure complete P-gp inhibition was compared with outcome parameters derived from kinetic modeling using a 1-tissue compartment model (1-TCM). Finally, k-maps were generated in each species using PMOD software.

RESULTS

The linear part of the log-transformed brain TACs occurred from 10 to 30 min after radiotracer injection in rats, from 15 to 60 min in baboons, and from 20 to 60 min in humans. P-gp inhibition significantly decreased k values by 39 ± 12% in rats (p < 0.01), by 32 ± 6% in baboons (p < 0.001), and by 37 ± 22% in humans (p < 0.001). In baboons, P-gp inhibition consistently decreased the brain-to-plasma efflux rate constant k (36 ± 9%, p < 0.01) leading to an increase in the total brain volume of distribution (V, 101 ± 12%, p < 0.001). In all studied species, brain k-maps displayed decreased P-gp-mediated efflux across the BBB.

CONCLUSIONS

k of [C]metoclopramide provides a simple outcome parameter to describe P-gp function in the living brain when arterial input function data are unavailable, although less sensitive than V. k-maps represent easy to compute parametric images reflecting the effect of P-gp on [C]metoclopramide elimination from the brain.