scholarly journals Factors That Limit Positron Emission Tomography Imaging of P-Glycoprotein Density at the Blood–Brain Barrier

2013 ◽  
Vol 10 (6) ◽  
pp. 2222-2229 ◽  
Author(s):  
Pavitra Kannan ◽  
Victor W. Pike ◽  
Christer Halldin ◽  
Oliver Langer ◽  
Michael M. Gottesman ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Positron Emission Tomography Imaging ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Tomography Imaging ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission

scholarly journals Diphenhydramine as a selective probe to study H+-antiporter function at the blood–brain barrier: Application to [11C]diphenhydramine positron emission tomography imaging

2016 ◽  
Vol 37 (6) ◽  
pp. 2185-2195 ◽  
Author(s):  
Sylvain Auvity ◽  
Hélène Chapy ◽  
Sébastien Goutal ◽  
Fabien Caillé ◽  
Benoit Hosten ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Positron Emission Tomography Imaging ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Tomography Imaging ◽  
Blood Brain ◽  
Positron Emission ◽  
The Brain

Diphenhydramine, a sedative histamine H1-receptor (H1R) antagonist, was evaluated as a probe to measure drug/H+-antiporter function at the blood–brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydramine transport at the blood–brain barrier was saturable, following Michaelis–Menten kinetics with a Km = 2.99 mM and Vmax = 179.5 nmol s−1 g−1. In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%. [14C]Diphenhydramine blood–brain barrier transport was proton and clonidine sensitive but was influenced by neither tetraethylammonium, a MATE1 (SLC47A1), and OCT/OCTN (SLC22A1-5) modulator, nor P-gp/Bcrp (ABCB1a/1b/ABCG2) deficiency. Brain and plasma kinetics of [11C]diphenhydramine were measured by positron emission tomography imaging in rats. [11C]Diphenhydramine kinetics in different brain regions were not influenced by displacement with 1 mg kg−1 unlabeled diphenhydramine, indicating the specificity of the brain positron emission tomography signal for blood–brain barrier transport activity over binding to any central nervous system target in vivo. [11C]Diphenhydramine radiometabolites were not detected in the brain 15 min after injection, allowing for the reliable calculation of [11C]diphenhydramine brain uptake clearance (Clup = 0.99 ± 0.18 mL min−1 cm−3). Diphenhydramine is a selective and specific H+-antiporter substrate. [11C]Diphenhydramine positron emission tomography imaging offers a reliable and noninvasive method to evaluate H+-antiporter function at the blood–brain barrier.

scholarly journals Approaching Complete Inhibition of P-Glycoprotein at the Human Blood–Brain Barrier: An (R)-[11C]Verapamil PET Study

2015 ◽  
Vol 35 (5) ◽  
pp. 743-746 ◽  
Author(s):  
Martin Bauer ◽  
Rudolf Karch ◽  
Markus Zeitlinger ◽  
Cécile Philippe ◽  
Kerstin Römermann ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Distribution Volume ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Whole Brain ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission ◽  
Pet Scans

As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate ( R)-[11C]verapamil in five healthy volunteers during continuous intravenous tariquidar infusion. Total distribution volume ( VT) of ( R)-[11C]verapamil in whole-brain gray matter increased by 273 ± 78% relative to baseline scans without tariquidar, which was higher than previously reported VT increases. During tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB.

P-glycoprotein at the Blood-Brain Barrier and Analysis of Drug Transport with Positron-Emission Tomography

2001 ◽  
Vol 41 (7) ◽  
pp. 48-54 ◽  
Author(s):  
N. H. Hendrikse ◽  
J. Bart ◽  
E.G.E. de Vries ◽  
H.J.M. Groen ◽  
W.T.A. van der Graaf ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Drug Transport ◽  
Emission Tomography ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission

scholarly journals Factors Governing P-Glycoprotein-Mediated Drug–Drug Interactions at the Blood–Brain Barrier Measured with Positron Emission Tomography

2015 ◽  
Vol 12 (9) ◽  
pp. 3214-3225 ◽  
Author(s):  
Thomas Wanek ◽  
Kerstin Römermann ◽  
Severin Mairinger ◽  
Johann Stanek ◽  
Michael Sauberer ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Drug Interactions ◽  
Blood Brain Barrier ◽  
Emission Tomography ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission

P-glycoprotein at the Blood-Brain Barrier and Analysis of Drug Transport with Positron-Emission Tomography

2001 ◽  
Vol 41 (99) ◽  
pp. 48-54 ◽  
Author(s):  
N.H. Hendrikse ◽  
J. Bart ◽  
E.G.E. de Vries ◽  
H.J.M. Groen ◽  
W.T.A. van der Graaf ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Drug Transport ◽  
Emission Tomography ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission

scholarly journals Evaluation of [18F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood–brain barrier in rats: Kinetics, metabolism, and selectivity

2016 ◽  
Vol 37 (4) ◽  
pp. 1286-1298 ◽  
Author(s):  
Heli Savolainen ◽  
Albert D Windhorst ◽  
Philip H Elsinga ◽  
Mariangela Cantore ◽  
Nicola A Colabufo ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Compartment Model ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Cancer Resistance ◽  
Tissue Compartment ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission

P-glycoprotein is a protective efflux transporter at the blood–brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [18F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes ( VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VT values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h post-injection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood–brain barrier.

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