Advances in PET Imaging of P-Glycoprotein Function at the Blood-Brain Barrier

Department of Public Health and Caring Sciences, Uppsala University , Rudbecklaboratoriet, 751 85 Uppsala, Sweden.
ACS Chemical Neuroscience (Impact Factor: 4.36). 02/2013; 4(2):225-37. DOI: 10.1021/cn3001729
Source: PubMed


Efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) restricts substrate compounds from entering the brain and may thus contribute to pharmacoresistance observed in patient groups with refractory epilepsy and HIV. Altered P-gp function has also been implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Positron emission tomography (PET), a molecular imaging modality, has become a promising method to study the role of P-gp at the BBB. The first PET study of P-gp function was conducted in 1998, and during the past 15 years two main categories of P-gp PET tracers have been investigated: tracers that are substrates of P-gp efflux and tracers that are inhibitors of P-gp function. PET, as a noninvasive imaging technique, allows translational research. Examples of this are preclinical investigations of P-gp function before and after administering P-gp modulating drugs, investigations in various animal and disease models, and clinical investigations regarding disease and aging. The objective of the present review is to give an overview of available PET radiotracers for studies of P-gp and to discuss how such studies can be designed. Further, the review summarizes results from PET studies of P-gp function in different central nervous system disorders.

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    • "[ 11 C]-Verapamil is a useful PET tracer to study P-gp function, but not an ideal one. Its drawbacks include its extensive metabolism and its low basal brain distribution, which may be improved by the partial chemical inhibition of P-gp during the PET session (Syvanen et al., 2013). Thus, [ 11 C]-verapamil PET kinetic modeling after i.v. "
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    ABSTRACT: Background and purpose: The respective impact and interplay between ABC (P-glycoprotein/P-gp/Abcb1a, Bcrp/Abcg2, Mrp/Abcc) and SLC transporter functions at the blood-brain and blood-retinal barriers (BBB, BRB) are incompletely understood. Experimental approach: We measured the initial cerebral and retinal distribution of selected ABC substrates by in situ carotid perfusion using P-gp/Bcrp-knockout mice and chemical ABC/SLC-modulation strategies. P-gp, Bcrp Mrp1 and Mrp4 were studied by confocal retina imaging. Key results: Chemical or physical disruption of P-gp increased [(3) H]-verapamil transport by ~10-fold at the BBB and ~1.5-fold at the BRB. [(3) H]-Verapamil transport involved influx mediated by an organic cation clonidine/diphenhydramine-sensitive proton-antiporter at both barriers, which impact was unmasked when P-gp was partially or fully inhibited/disrupted at the BBB. Studies of [(3) H]-mitoxantrone and [(3) H]-zidovudine transport suggested, respectively, that Bcrp efflux was less involved at the BRB than the BBB, whereas Mrps were significantly and quite similarly involved at both barriers. Confocal imaging showed that P-gp and Bcrp were expressed in intra-retinal vessels (inner BRB/iBRB) but absent from the blood/basal membrane of cells of the retinal pigment epithelium (outer BRB/oBRB/RPE) where, in contrast, Mrp1 and Mrp4 were localized. Conclusions and implications: P-gp, Bcrp, Mrp1, and Mrp4 are differentially expressed at the outer and inner BRB, resulting in an altered ability to limit substrate distribution at the retina as compared to the BBB. [(3) H]-Verapamil distribution is not P-gp-specific and involves a proton-antiporter at both the BBB and BRB. However, this transport is concealed by P-gp at the BBB, but not at the BRB, where P-gp activity is reduced.
    No preview · Article · Oct 2015 · British Journal of Pharmacology
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    ABSTRACT: The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrier.
    No preview · Article · Jun 2013 · Pharmaceutical Research
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    ABSTRACT: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar. Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar. [(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment. We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.
    No preview · Article · Jul 2013 · Nuclear Medicine and Biology
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