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Positron Emission Tomography Studies on Binding of Central Nervous System Drugs and P-Glycoprotein Function in the Rodent Brain

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Abstract

The permeability of the blood–brain barrier (BBB) is one of the factors determining the bioavailability of drugs in the brain. The BBB only allows passage of lipophilic drugs by passive diffusion. However, some lipophilic drugs hardly enter the brain. The transmembrane protein P-glycoprotein (P-gp) is one of the carrier systems that is responsible for transportation of drugs out of the brain. P-Glycoprotein affects the pharmacokinetics of many drugs and can be inhibited by administration of modulators or competitive substrates. Identification and classification of central nervous system (CNS) drugs as P-gp substrates or inhibitors are of crucial importance in drug development. Positron emission tomography (PET) studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. P-Glycoprotein-mediated effects were observed for two 5-HT1a receptor ligands, [18F]MPPF vs. [carbonyl-11C]WAY100635. Under control conditions, the specific brain uptake of [18F]MPPF is five- to eightfold lower than that of [11C]WAY100635. After cyclosporin A (CsA) modulation, [18F]MPPF uptake in the rat brain increased five- to tenfold. Cerebral uptake of [carbonyl-11C]WAY100635 was also increased by modulation, but in general the increase was lower than that observed for [18F]MPPF (two- to threefold). Brain uptake of the β-adrenergic receptor ligands [11C]carazolol and [18F]fluorocarazolol was increased in P-gp knockout mice and CsA-treated rats. Both the specific and nonspecific binding of [18F]fluorocarazolol were doubled by CsA. Cerebral uptake of [11C]carazolol in rats was much lower than that of [18F]fluorocarazolol and no specific binding was measured. After CsA modulation, the uptake of [11C]carazolol increased five- to sixfold, but this uptake was not receptor-mediated. Quantitative PET studies in rodents on P-gp functionality demonstrated a dose-dependent increase of radioligands after administration of CsA. Studies with [11C]verapamil and [11C]carvedilol showed that complete modulation was achieved at 50 mg/kg CsA. The distribution volume of [11C]carvedilol increased from 0.25 in the control study to 1.0 after full modulation with CsA. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, which may result in improved drug therapy.

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  1. PET-Center, Groningen University Hospital, Groningen, The Netherlands

    Philip H. Elsinga PhD, N. Harry Hendrikse PhD, Joost Bart PhD, Aren van Waarde PhD & Willem Vaalburg PhD

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  1. Philip H. Elsinga PhD
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Elsinga, P.H., Hendrikse, N.H., Bart, J. et al. Positron Emission Tomography Studies on Binding of Central Nervous System Drugs and P-Glycoprotein Function in the Rodent Brain. Mol Imaging Biol 7, 37–44 (2005). https://doi.org/10.1007/s11307-005-0951-x

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