P-glycoprotein (P-gp) is an ATP-dependent efflux transporter located at the blood–brain barrier (BBB), involved in the transport of a variety of neurotoxic substances out of the brain. Alterations in P-gp function play an essential role in the pathophysiological mechanisms underlying neurodegenerative disorders. The most widely used tracer to measure BBB P-gp function in vivo is (R)-[11C]verapamil [1]. However, (R)-[11C]verapamil is an avid P-gp substrate, and its low uptake hampers the measurement of increases in P-gp function. In order to overcome this limitation, [18F]MC225 was developed as a novel PET tracer to measure P-gp function in vivo. [18F]MC225 is a weaker P-gp substrate and has shown higher brain uptake than (R)-[11C]verapamil at baseline in preclinical studies [2]. This may facilitate the evaluation of both increases and decreases in P-gp function. In addition, the longer half-life of fluorine-18 enables the use of [18F]MC225 in centers without an onsite cyclotron.
These standardized uptake value (SUV) images show one of the first [18F]MC225 PET brain scans in a healthy human subject in both unblocked (A) and blocked (B) P-gp state. Blocking was achieved by continuous intravenous administration of the specific P-gp inhibitor cyclosporin (2.5 mg/kg/h), starting 30 min prior to the scan. Quantitatively, the whole brain grey matter volume of distribution VT changed from VT = 4.38 at baseline to VT = 5.48 after cyclosporin administration, showing higher uptake at baseline levels compared with previously described data of [11C]verapamil (VT = 1.28 at baseline, VT = 2.00 after P-gp inhibition) [3], illustrating [18F]MC225 as a promising tracer to measure BBB P-gp function in humans.
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García-Varela L, Arif WM, Vállez García D, Kakiuchi T, Ohba H, Harada N, et al. Pharmacokinetic modeling of [18F]MC225 for quantification of the P-glycoprotein function at the blood-brain barrier in non-human primates with PET. Mol. Pharm. 2020 https://doi.org/10.1021/acs.molpharmaceut.0c00514
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Open access funding provided by University Medical Center Groningen (UMCG). This study was funded by Siemens Healthineers (grant number C00227575 17).
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All procedures performed involving the human participant were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patient.
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GL received a research grant from Siemens Healthineers for appointing a PhD candidate. The other authors declare no competing interests.
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Mossel, P., Garcia Varela, L., Arif, W.M. et al. Evaluation of P-glycoprotein function at the blood–brain barrier using [18F]MC225-PET. Eur J Nucl Med Mol Imaging 48, 4105–4106 (2021). https://doi.org/10.1007/s00259-021-05419-8
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DOI: https://doi.org/10.1007/s00259-021-05419-8