Hyperosmolar blood-brain barrier disruption in baboons: an in vivo study using positron emission tomography and rubidium-82

✓ Hyperosmolar blood-brain barrier (BBB) disruption remains controversial as an adjuvant therapy to increase delivery of water-soluble compounds to extracellular space in the brain in patients with malignant brain tumors. To understand the physiological effects of BBB disruption more clearly, the authors used positron emission tomography (PET) to study the time course of BBB permeability in response to the potassium analog rubidium-82 (82Rb, halflife 75 seconds) following BBB disruption in anesthetized adult baboons. Mannitol (25%) was injected into the carotid artery and PET scans were performed before and serially at 8- to 15-minute intervals after BBB disruption. The mean influx constant (K1), a measure of permeability-surface area product, in ipsilateral, mannitol-perfused mixed gray- and white-matter brain regions was 4.9 ± 2.4 µl/min/ml (± standard deviation) at baseline and increased more than 100% (ΔK1 = 9.4 ± 5.1 µl/min/ml, 18 baboons) in brain perfused by mannitol. The effect of BBB disruption on K1 correlated directly with the total amount of mannitol administered (p < 0.005). Vascular permeability returned to baseline with a halftime of 24.0 ± 14.3 minutes. The mean brain plasma volume rose by 0.57 ± 0.34 ml/100 ml in ipsilateral perfused brain following BBB disruption. This work provides a basis for the in vivo study of permeability changes induced by BBB disruption in human brain and brain tumors.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16662042 ◽

2016 ◽

Vol 37 (6) ◽

pp. 2185-2195 ◽

Cited By ~ 7

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.

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Measurement of Blood—Brain Barrier Permeability with Positron Emission Tomography and [68Ga]EDTA

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1984.48 ◽

1984 ◽

Vol 4 (3) ◽

pp. 323-328 ◽

Cited By ~ 41

Author(s):

R. M. Kessler ◽

J. C. Goble ◽

J. H. Bird ◽

M. E. Girton ◽

J. L. Doppman ◽

...

Keyword(s):

Positron Emission Tomography ◽

Blood Brain Barrier ◽

Quantitative Measure ◽

Brain Regions ◽

Emission Tomography ◽

Brain Barrier ◽

Blood Brain ◽

Positron Emission ◽

Area Product

Positron emission tomography (PET) was employed to examine time-dependent changes in blood–brain barrier (BBB) permeability to [68Ga]ethylenediaminetetraacetate (EDTA) in the rhesus monkey, following reversible barrier opening by intracarotid infusion of a hypertonic mannitol solution. The PET technique, when combined with measurements of plasma radioactivity, provided a quantitative measure of the cerebrovascular permeability-area product ( PA) at different times following mannitol infusion. Hypertonic mannitol treatment reversibly increased PA to [68Ga]EDTA more than 10-fold; much of the barrier effect was over by 10 min after mannitol treatment. The results show that PET can be used to measure transient changes in BBB integrity in specific brain regions, under in vivo, noninvasive conditions.

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A Method to Quantitate the Fractional Extraction of Rubidium-82 across the Blood—Brain Barrier Using Positron Emission Tomography

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1984.77 ◽

1984 ◽

Vol 4 (4) ◽

pp. 523-534 ◽

Cited By ~ 28

Author(s):

Adriaan A. Lammertsma ◽

David J. Brooks ◽

Richard S. J. Frackowiak ◽

Jon D. Heather ◽

Terry Jones

Keyword(s):

Positron Emission Tomography ◽

Blood Brain Barrier ◽

Cerebral Blood Volume ◽

Emission Tomography ◽

Brain Barrier ◽

Blood Brain ◽

Positron Emission ◽

Regional Cerebral Blood Volume ◽

The Impact ◽

Rubidium 82

Previously, rubidium-82 and positron emission tomography (PET) have been used to assess qualitatively the integrity of the blood-brain barrier (BBB). In this report, a method is described to measure the fractional extraction of rubidium across the BBB using the constant intravenous infusion of rubidium-82. In addition, the continuous inhalation of oxygen-15-labelled carbon dioxide is needed to measure regional CBF, and it is also necessary to measure regional cerebral blood volume. The assumptions underlying the model are identified, and the impact of deviations from these assumptions is described. From radiation dose and statistical considerations, it is shown that for normal cerebral tissue and the PET scanner used in this study, the rubidium extraction fraction can be quantitated only for regions as large as a cerebral hemisphere. However, quantitation is also possible for smaller regions where the focal extraction of rubidium is increased.

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Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography

British Journal of Pharmacology ◽

10.1038/sj.bjp.0701979 ◽

1998 ◽

Vol 124 (7) ◽

pp. 1413-1418 ◽

Cited By ~ 122

Author(s):

N. H. Hendrikse ◽

A. H. Schinkel ◽

E. G. E. De Vries ◽

E. Fluks ◽

W. T. A. Van der Graaf ◽

...

Keyword(s):

Positron Emission Tomography ◽

Blood Brain Barrier ◽

Emission Tomography ◽

Brain Barrier ◽

Pump Function ◽

P Glycoprotein ◽

Blood Brain ◽

Positron Emission

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.19 ◽

2015 ◽

Vol 35 (5) ◽

pp. 743-746 ◽

Cited By ~ 44

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.

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