Factors That Limit Positron Emission Tomography Imaging of P-Glycoprotein Density at the Blood鈥揃rain Barrier
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- 作者：Pavitra Kannan ; Victor W. Pike ; Christer Halldin ; Oliver Langer ; Michael M. Gottesman ; Robert B. Innis ; Matthew D. Hall
- 刊名：Molecular Pharmaceutics
- 出版年：2013
- 出版时间：June 3, 2013
- 年：2013
- 卷：10
- 期：6
- 页码：2222-2229
- 全文大小：307K
- 年卷期：v.10,no.6(June 3, 2013)
- ISSN：1543-8392
文摘
Efflux transporters located at the blood鈥揵rain 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鈥揵rain 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鈥揵rain 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鈥揵rain barrier, and inhibitors with substantially higher affinity will be needed for density imaging of P-gp and other blood鈥揵rain barrier transporters.