Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET
Pascalle Mossel, Wejdan M. Arif, Giordana Salvi de Souza, Lara García-Varela, Chris W.J. van der Weijden, Hendrikus H. Boersma, Antoon T. M. Willemsen, Ronald Boellaard, Philip H. Elsinga, Ronald Borra, Rudi Dierckx, Adriaan A. Lammertsma, Anna L. Bartels, Gert Luurtsema
Abstract
Abstract 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)- [ 11 C]verapamil PET. (R)- [ 11 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. [ 18 F]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 [ 18 F]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 [ 18 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 ( V T ), K i , and the rate constants K 1 and k 2 ). In addition, a reversible two-tissue compartment model with fixed k 3 / k 4 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 ( V B ) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18 F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. Conclusion [ 18 F]MC225 V T , 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.