The Role of P-Glycoprotein at the Blood–Brain Barrier in Neurological and Psychiatric Disease

Mossel, Pascalle; Bartels, Anna L.; Deyn, Peter Paul De; Luurtsema, Gert

doi:10.1007/978-3-030-57231-0_3

Cited by 2 publications

(3 citation statements)

References 178 publications

(157 reference statements)

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“…These tracers aim to improve the evaluation of the P-gp function, as they are capable of measuring both increases and decreases in the P-gp function. In general, a new P-gp tracer should preferably meet the following requirements [117,118]…”

Section: Pet Tracers For Measuring P-gp Functionmentioning

confidence: 99%

“…They discovered that, in comparison to (S)-verapamil, (R)-verapamil was less metabolized in humans [93,94]. Nowadays, (R)-[ 11 C]verapamil is the most often used PET tracer to test P-gp function [118,119] in the brains of both animals [119][120][121] and humans [122][123][124][125].…”

Section: [ 11 C]verapamil and (R)-[ 11 C]verapamilmentioning

confidence: 99%

“…The symbol " √ " signifies the use of tracers in those fields with promising results, while "×" indicates the use of tracers in those fields with insignificant results. A blank space indicates the absence of related research.In general, a new P-gp tracer should preferably meet the following requirements[117,118]: (a) radiosynthesis should have a high radiochemical yield, and the tracer should be produced with high molar activity; (b) the tracer should have adequate specificity and sensitivity; (c) the tracer's metabolism should be low during the scanning time; and (d) the tracer should have moderate plasma protein and blood cell binding. Below, we address the commonly used PET tracers for evaluating the function of P-gp.…”

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confidence: 99%

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Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges

Liu,

Mossel,

Schwach

et al. 2023

Pharmaceuticals

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Adenosine triphosphate binding cassette (ABC) transporters are a broad family of membrane protein complexes that use energy to transport molecules across cells and/or intracellular organelle lipid membranes. Many drugs used to treat cardiac diseases have an affinity for these transporters. Among others, P-glycoprotein (P-gp) plays an essential role in regulating drug concentrations that reach cardiac tissue and therefore contribute to cardiotoxicity. As a molecular imaging modality, positron emission tomography (PET) has emerged as a viable technique to investigate the function of P-gp in organs and tissues. Using PET imaging to evaluate cardiac P-gp function provides new insights for drug development and improves the precise use of medications. Nevertheless, information in this field is limited. In this review, we aim to examine the current applications of ABC transporter PET imaging and its tracers in the heart, with a specific emphasis on P-gp. Furthermore, the opportunities and challenges in this novel field will be discussed.

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Section: Pet Tracers For Measuring P-gp Functionmentioning

confidence: 99%

Section: [ 11 C]verapamil and (R)-[ 11 C]verapamilmentioning

confidence: 99%

mentioning

confidence: 99%

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Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges

Liu,

Mossel,

Schwach

et al. 2023

Pharmaceuticals

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Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

Mossel

Arif

Souza

et al. 2023

Eur J Nucl Med Mol Imaging

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Introduction P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer’s disease and Parkinson’s disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[11C]verapamil PET. (R)-[11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [18F]MC225 was developed to measure both increases and decreases in P-gp function. Aim The aim of this study was (1) to identify the pharmacokinetic model that best describes [18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. Methods Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (VT), Ki, and the rate constants K1 and k2). In addition, a reversible two-tissue compartment model with fixed k3/k4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. Results Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (VB) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the VT for [18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. Conclusion [18F]MC225 VT, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. Trial registration EudraCT 2020-001564-28. Registered 25 May 2020.

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The Role of P-Glycoprotein at the Blood–Brain Barrier in Neurological and Psychiatric Disease

Cited by 2 publications

References 178 publications

Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges

Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges

Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

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