Purpose: PET imaging using [¹¹C]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_E,brain), calculated from dynamic PET images without the need for arterial blood sampling, was evaluated as an outcome parameter for the interpretation of [¹¹C]metoclopramide PET data.

Procedures: k_E,brainparameter was obtained by linear regression of log-transformed brain time-activity curves (TACs). k_E,brainvalues (h^-1) 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_E,brainto measure complete P-gp inhibition was compared with outcome parameters derived from kinetic modeling using a 1-tissue compartment model (1-TCM). Finally, k_E,brain-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_E,brainvalues 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 k₂(36 ± 9%, p < 0.01) leading to an increase in the total brain volume of distribution (V_T, 101 ± 12%, p < 0.001). In all studied species, brain k_E,brain-maps displayed decreased P-gp-mediated efflux across the BBB.

Conclusions: k_E,brainof [¹¹C]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_T. k_E,brain-maps represent easy to compute parametric images reflecting the effect of P-gp on [¹¹C]metoclopramide elimination from the brain.