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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\u2019s disease and Parkinson\u2019s disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is <jats:italic>(R)-<\/jats:italic>[<jats:sup>11<\/jats:sup>C]verapamil PET. <jats:italic>(R)-<\/jats:italic>[<jats:sup>11<\/jats:sup>C]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. [<jats:sup>18<\/jats:sup>F]MC225 was developed to measure both increases and decreases in P-gp function.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Aim<\/jats:title>\n                <jats:p>The aim of this study was (1) to identify the pharmacokinetic model that best describes [<jats:sup>18<\/jats:sup>F]MC225 kinetics in the human brain and (2) to determine test-retest variability.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67\u2009\u00b1\u20095\u00a0years) were scanned twice (injected dose 201\u2009\u00b1\u200947\u00a0MBq) with a minimum interval of 2\u00a0weeks between scans. Each scanning session consisted of a 60-min dynamic [<jats:sup>18<\/jats:sup>F]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 (<jats:italic>V<\/jats:italic><jats:sub><jats:italic>T<\/jats:italic><\/jats:sub>), <jats:italic>K<\/jats:italic><jats:sub><jats:italic>i<\/jats:italic><\/jats:sub>, and the rate constants <jats:italic>K<\/jats:italic><jats:sub>1<\/jats:sub> and <jats:italic>k<\/jats:italic><jats:sub>2<\/jats:sub>). In addition, a reversible two-tissue compartment model with fixed <jats:italic>k<\/jats:italic><jats:sub>3<\/jats:sub>\/<jats:italic>k<\/jats:italic><jats:sub>4<\/jats:sub> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Sixty minutes post-injection, the parent fraction was 63.8\u2009\u00b1\u20094.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (<jats:italic>V<\/jats:italic><jats:sub><jats:italic>B<\/jats:italic><\/jats:sub>) showed the highest AIC weight score of 34.3\u2009\u00b1\u200917.6%. The TRVT of the <jats:italic>V<\/jats:italic><jats:sub><jats:italic>T<\/jats:italic><\/jats:sub> for [<jats:sup>18<\/jats:sup>F]MC225 PET scans was 28.3\u2009\u00b1\u200920.4% for the whole brain grey matter region using this preferred model.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>[<jats:sup>18<\/jats:sup>F]MC225 <jats:italic>V<\/jats:italic><jats:sub><jats:italic>T<\/jats:italic><\/jats:sub>, 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%.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>EudraCT <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/eudract.ema.europa.eu\/\">2020-001564-28<\/jats:ext-link>. Registered 25 May 2020.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-023-06363-5","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T07:02:16Z","timestamp":1691478136000},"page":"3917-3927","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET"],"prefix":"10.1007","volume":"50","author":[{"given":"Pascalle","family":"Mossel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wejdan M.","family":"Arif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giordana Salvi","family":"De Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara Garcia","family":"Varela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris W. 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