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

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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A Novel Positron Emission Tomography Imaging Protocol Identifies Seizure-Induced Regional Overactivity of P-Glycoprotein at the Blood-Brain Barrier

Journal of Neuroscience ◽

10.1523/jneurosci.6616-10.2011 ◽

2011 ◽

Vol 31 (24) ◽

pp. 8803-8811 ◽

Cited By ~ 50

Author(s):

J. P. Bankstahl ◽

M. Bankstahl ◽

C. Kuntner ◽

J. Stanek ◽

T. Wanek ◽

...

Keyword(s):

Positron Emission Tomography ◽

Blood Brain Barrier ◽

Positron Emission Tomography Imaging ◽

Emission Tomography ◽

Brain Barrier ◽

Imaging Protocol ◽

Tomography Imaging ◽

P Glycoprotein ◽

Blood Brain ◽

Positron Emission

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

Molecular Pharmaceutics ◽

10.1021/mp400011g ◽

2013 ◽

Vol 10 (6) ◽

pp. 2222-2229 ◽

Cited By ~ 16

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

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

Journal of Neurosurgery ◽

10.3171/jns.1996.84.3.0494 ◽

1996 ◽

Vol 84 (3) ◽

pp. 494-502 ◽

Cited By ~ 21

Author(s):

Bernhard Zünkeler ◽

Richard E. Carson ◽

Jeffrey Olson ◽

Ronald G. Blasberg ◽

Mary Girton ◽

...

Keyword(s):

Positron Emission Tomography ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Emission Tomography ◽

Brain Barrier ◽

Blood Brain ◽

Positron Emission ◽

The Mean ◽

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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Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study

Drug Metabolism and Disposition ◽

10.1124/dmd.114.058685 ◽

2015 ◽

Vol 43 (11) ◽

pp. 1795-1804 ◽

Cited By ~ 22

Author(s):

Li Liu ◽

Ann C. Collier ◽

Jeanne M. Link ◽

Karen B. Domino ◽

David A. Mankoff ◽

...

Keyword(s):

Positron Emission Tomography ◽

Blood Brain Barrier ◽

Human Blood ◽

Positron Emission Tomography Imaging ◽

Imaging Study ◽

Emission Tomography ◽

Brain Barrier ◽

Tomography Imaging ◽

P Glycoprotein ◽

Positron Emission

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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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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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Real-Time Positron Emission Tomography Evaluation of Topotecan Brain Kinetics after Ultrasound-Mediated Blood–Brain Barrier Permeability

Pharmaceutics ◽

10.3390/pharmaceutics13030405 ◽

2021 ◽

Vol 13 (3) ◽

pp. 405

Author(s):

Andrei Molotkov ◽

Patrick Carberry ◽

Martin A. Dolan ◽

Simon Joseph ◽

Sidney Idumonyi ◽

...

Keyword(s):

Positron Emission Tomography ◽

Blood Brain Barrier ◽

Adult Brain ◽

Emission Tomography ◽

Brain Barrier ◽

Pharmacokinetic Data ◽

Systemic Injection ◽

Blood Brain ◽

Positron Emission ◽

The Brain

Glioblastoma (GBM) is the most common primary adult brain malignancy with an extremely poor prognosis and a median survival of fewer than two years. A key reason for this high mortality is that the blood–brain barrier (BBB) significantly restricts systemically delivered therapeutics to brain tumors. High-intensity focused ultrasound (HIFU) with microbubbles is a methodology being used in clinical trials to noninvasively permeabilize the BBB for systemic therapeutic delivery to GBM. Topotecan is a topoisomerase inhibitor used as a chemotherapeutic agent to treat ovarian and small cell lung cancer. Studies have suggested that topotecan can cross the BBB and can be used to treat brain metastases. However, pharmacokinetic data demonstrated that topotecan peak concentration in the brain extracellular fluid after systemic injection was ten times lower than in the blood, suggesting less than optimal BBB penetration by topotecan. We hypothesize that HIFU with microbubbles treatment can open the BBB and significantly increase topotecan concentration in the brain. We radiolabeled topotecan with 11C and acquired static and dynamic positron emission tomography (PET) scans to quantify [11C] topotecan uptake in the brains of normal mice and mice after HIFU treatment. We found that HIFU treatments significantly increased [11C] topotecan brain uptake. Moreover, kinetic analysis of the [11C] topotecan dynamic PET data demonstrated a substantial increase in [11C] topotecan volume of distribution in the brain. Furthermore, we found a decrease in [11C] topotecan brain clearance, confirming the potential of HIFU to aid in the delivery of topotecan through the BBB. This opens the potential clinical application of [11C] topotecan as a tool to predict topotecan loco-regional brain concentration in patients with GBMs undergoing experimental HIFU treatments.

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