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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.
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.
Epilepsy is the chronic neurological disorder affecting 70 million people globally. One of the fascinating attributes of brain microvasculature is the (BBB), which controls a chain of distinct features that securely regulate the molecules, ions, and cells movement between the blood and the parenchyma. The barrier's integrity is of paramount importance and essential for maintaining brain homeostasis, as it offers both physical and chemical barriers to counter pathogens and xenobiotics. Dysfunction of various transporters in the (BBB), mainly ATP binding cassette (ABC), is considered to play a vital role in hampering the availability of antiepileptic drugs into the brain. ABC (ATP-binding cassette) transporters constitute a most diverse protein superfamily, which plays an essential part in various biological processes, including cell homeostasis, cell signaling, uptake of nutrients, and drug metabolism. Moreover, it plays a crucial role in neuroprotection by out-flowing various internal and external toxic substances from the interior of a cell, thus decreasing their buildup inside the cell. In humans, forty-eight ABC transporters have been acknowledged and categorized into subfamilies A to G based on their phylogenetic analysis. ABC subfamilies B, C, and G, impart a vital role at the BBB in guarding the brain against the entrance of various xenobiotic and their buildup. The illnesses of the central nervous system have received a lot of attention lately Owing to the existence of the BBB, the penetration effectiveness of most CNS medicines into the brain parenchyma is very limited (BBB). In the development of neurological therapies, BBB crossing for medication delivery to the CNS continues to be a major barrier. Nanomaterials with BBB cross ability have indeed been extensively developed for the treatment of CNS diseases due to their advantageous properties. This review will focus on multiple possible factors like inflammation, oxidative stress, uncontrolled recurrent seizures, and genetic polymorphisms that result in the deregulation of ABC transporters in epilepsy and nanotechnology enabled delivery across BBB in epilepsy.
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