title: Factors that limit positron emission tomography imaging of p-glycoprotein density at the blood-brain barrier.
abstract: Efflux transporters located at the blood-brain barrier, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), regulate the passage of many drugs in and out of the brain. Changes in the function and density of these proteins, in particular P-gp, may play a role in several neurological disorders. Several radioligands have been developed for measuring P-gp function at the blood-brain barrier of human subjects with positron emission tomography (PET). However, attempts to measure P-gp density with radiolabeled inhibitors that bind to these proteins in vivo have not thus far provided useful, quantifiable PET signals. Herein, we argue that not only the low density of transporters in the brain as a whole but also their very high density in brain capillaries act to lower the concentration of ligand in the plasma and thereby contribute to absent or low signals in PET studies of P-gp density. Our calculations, based on published data and theoretical approximations, estimate that whole brain densities of many efflux transporters at the blood-brain barrier range from 0.04 to 5.19 nM. We conclude that the moderate affinities (>5 nM) of currently labeled inhibitors may not allow measurement of efflux transporter density at the blood-brain barrier, and inhibitors with substantially higher affinity will be needed for density imaging of P-gp and other blood-brain barrier transporters.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Kannan
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters