{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:22:00Z","timestamp":1788272520400,"version":"build-2803163510"},"reference-count":57,"publisher":"American Chemical Society (ACS)","issue":"1","license":[{"start":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccbyncnd_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>(R)-[11C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood\u2013brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[11C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[11C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[11C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[11C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[11C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[11C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (VT) and the efflux constant k2 estimations were affected by the evaluated scan durations, whereas the influx constant K1 estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg\/kg), in a 91 min scan duration, the whole-brain VT increased significantly up to 208% (p &amp;lt; 0.001) and K1 up to 159% (p &amp;lt; 0.001) compared with baseline scans. The k2 values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K1, calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primates.<\/jats:p>","DOI":"10.1021\/acs.molpharmaceut.0c01014","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T15:15:35Z","timestamp":1607958935000},"page":"416-428","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacokinetic Modeling of (\n                    <i>R<\/i>\n                    )-[11C]verapamil to Measure the P-Glycoprotein Function\nin Nonhuman Primates"],"prefix":"10.1021","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-4708","authenticated-orcid":true,"given":"Lara","family":"Garci\u0301a-Varela","sequence":"first","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Va\u0301llez","family":"Garci\u0301a","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeharu","family":"Kakiuchi","sequence":"additional","affiliation":[{"name":"Hamamatsu Photonics KK , , 5000 Hirakuchi , Hamakita, , ,","place":["Hamamatsu, Shizuoka, Japan, 434-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Ohba","sequence":"additional","affiliation":[{"name":"Hamamatsu Photonics KK , , 5000 Hirakuchi , Hamakita, , ,","place":["Hamamatsu, Shizuoka, Japan, 434-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Nishiyama","sequence":"additional","affiliation":[{"name":"Hamamatsu Photonics KK , , 5000 Hirakuchi , Hamakita, , ,","place":["Hamamatsu, Shizuoka, Japan, 434-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9545-0922","authenticated-orcid":true,"given":"Tetsuro","family":"Tago","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan Institute of Gerontology , , 35-2 Sakae-cho , Itabashi-ku, ,","place":["Tokyo, Japan, 173-0015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip H.","family":"Elsinga","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Tsukada","sequence":"additional","affiliation":[{"name":"Hamamatsu Photonics KK , , 5000 Hirakuchi , Hamakita, , ,","place":["Hamamatsu, Shizuoka, Japan, 434-8601"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5639-7746","authenticated-orcid":true,"given":"Nicola A.","family":"Colabufo","sequence":"additional","affiliation":[{"name":"University of Bari Aldo Moro , , ,","place":["Bari, Italy, 70125"]},{"name":"Spin-off Universita\u0300 degli Studi di Bari \u201cA. Moro\u201d , , via Dante 99 , Triggiano, ,","place":["Bari, Italy, 70019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi A.J.O.","family":"Dierckx","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aren","family":"van Waarde","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Toyohara","sequence":"additional","affiliation":[{"name":"Tokyo Metropolitan Institute of Gerontology , , 35-2 Sakae-cho , Itabashi-ku, ,","place":["Tokyo, Japan, 173-0015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Boellaard","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Luurtsema","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen , , Hanzeplein 1 , P.O. Box 30001, ,","place":["Groningen, The Netherlands, 9713 GZ"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,12,14]]},"reference":[{"key":"2026090110011146600_cit1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.2165\/00003495-198938010-00003","article-title":"Verapamil","volume":"38","author":"McTavish","year":"1989","journal-title":"Drugs"},{"key":"2026090110011146600_cit2","first-page":"1571","article-title":"Carbon-11-Labeled\nDaunorubicin and Verapamil for Probing P-Glycoprotein in Tumors with\nPET","volume":"37","author":"Elsinga","year":"1996","journal-title":"J. Nucl. 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A PET Study with [11C]Verapamil as a\nProbe for P-Glycoprotein Function","volume":"183","author":"de Klerk","year":"2010","journal-title":"Psychiatry\nRes., Neuroimaging"},{"key":"2026090110011146600_cit9","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1517\/17425255.2016.1168804","article-title":"ABC Transporters at\nthe Blood-Brain Barrier","volume":"12","author":"Mahringer","year":"2016","journal-title":"Expert Opin. Drug Metab.\nToxicol."},{"key":"2026090110011146600_cit10","doi-asserted-by":"publisher","first-page":"5830","DOI":"10.2174\/1381612822666160804092258","article-title":"Importance\nof P-Gp PET Imaging in Pharmacology","volume":"22","author":"Toyohara","year":"2016","journal-title":"Curr. 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Pharmacol."},{"key":"2026090110011146600_cit21","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/S0969-8051(03)00078-7","article-title":"(R)- and (S)-[11C]Verapamil\nas PET-Tracers for Measuring P-Glycoprotein Function: In Vitro and\nin Vivo Evaluation","volume":"30","author":"Luurtsema","year":"2003","journal-title":"Nucl. Med. Biol."},{"key":"2026090110011146600_cit22","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.2967\/jnumed.108.051235","article-title":"Tariquidar-Induced\nP-Glycoprotein\nInhibition at the Rat Blood-Brain Barrier Studied with (R)-11C-Verapamil\nand {PET}","volume":"49","author":"Bankstahl","year":"2008","journal-title":"J. Nucl. Med."},{"key":"2026090110011146600_cit23","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.2967\/jnumed.109.063289","article-title":"A Pilot Study to Assess\nthe Efficacy of Tariquidar to Inhibit P-Glycoprotein at the Human\nBlood-Brain Barrier with (R)-11C-Verapamil and PET","volume":"50","author":"Wagner","year":"2009","journal-title":"J. Nucl. Med."},{"key":"2026090110011146600_cit24","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/jcbfm.2015.19","article-title":"Approaching Complete\nInhibition of P-Glycoprotein at the Human Blood-Brain Barrier: An\n(R)-[11 C]Verapamil PET Study","volume":"35","author":"Bauer","year":"2015","journal-title":"J. Cereb. Blood\nFlow Metab."},{"key":"2026090110011146600_cit25","doi-asserted-by":"publisher","first-page":"S143","DOI":"10.1002\/jcph.722","article-title":"Use of PET\nImaging to Evaluate Transporter-Mediated Drug-Drug Interactions","volume":"56","author":"Langer","year":"2016","journal-title":"J. Clin. 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Pharmacol. Exp. Ther."},{"key":"2026090110011146600_cit33","doi-asserted-by":"publisher","first-page":"pyv036","DOI":"10.1093\/ijnp\/pyv036","article-title":"Large Variation\nin Brain Exposure of Reference CNS Drugs: A PET Study in Nonhuman\nPrimates","volume":"18","author":"Schou","year":"2015","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"2026090110011146600_cit34","doi-asserted-by":"publisher","first-page":"437","DOI":"10.2967\/jnumed.112.111732","article-title":"Modeling Cyclosporine A Inhibition\nof the Distribution of a P-Glycoprotein PET Ligand, 11C-Verapamil,\ninto the Maternal Brain and Fetal Liver of the Pregnant Nonhuman Primate:\nImpact of Tissue Blood Flow and Site of Inhibition","volume":"54","author":"Ke","year":"2013","journal-title":"J. Nucl. 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Biol."},{"key":"2026090110011146600_cit37","doi-asserted-by":"publisher","first-page":"3477","DOI":"10.1021\/acs.molpharmaceut.0c00514","article-title":"Pharmacokinetic\nModeling of [18F]MC225 for\nQuantification of the P-Glycoprotein Function at the Blood\u2013Brain\nBarrier in Non-Human Primates with PET","volume":"17","author":"Garci\u0301a-Varela","year":"2020","journal-title":"Mol.\nPharm."},{"key":"2026090110011146600_cit38","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1007\/s00259-013-2628-z","article-title":"Evaluation\nof 18F-BCPP-EF for Mitochondrial Complex 1 Imaging in the Brain of\nConscious Monkeys Using PET","volume":"41","author":"Tsukada","year":"2014","journal-title":"Eur. J. Nucl. Med.\nMol. 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Pain Med."},{"key":"2026090110011146600_cit48","first-page":"1531","article-title":"Quantitative Analysis of 11C-Verapamil\nTransfer at\nthe Human Blood-Brain Barrier for Evaluation of P-Glycoprotein Function","volume":"47","author":"Ikoma","year":"2006","journal-title":"J. Nucl. Med."},{"key":"2026090110011146600_cit49","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.2967\/jnumed.108.059162","article-title":"Imaging of Cyclosporine Inhibition\nof P-Glycoprotein Activity Using 11C-Verapamil in the Brain: Studies\nof Healthy Humans","volume":"50","author":"Muzi","year":"2009","journal-title":"J. Nucl. 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