TY - JOUR
T1 - Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET
AU - Mossel, Pascalle
AU - Arif, Wejdan M.
AU - de Souza, Giordana Salvi
AU - Varela, Lara Garcia
AU - van der Weijden, Chris W. J.
AU - Boersma, Hendrikus H.
AU - Willemsen, Antoon T. M.
AU - Boellaard, Ronald
AU - Elsinga, Philip H.
AU - Borra, Ronald J. H.
AU - Dierckx, Rudi A. J. O.
AU - Lammertsma, Adriaan A.
AU - Bartels, Anna L.
AU - Luurtsema, Gert
N1 - Funding Information: GL received a research grant from Siemens Healthineers. The other authors declare no competing interests. Publisher Copyright: © 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - 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 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 (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.
AB - 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 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 (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.
KW - ABC-transporter
KW - Neuro-imaging
KW - P-glycoprotein
KW - Pharmacokinetic modelling
KW - Test-retest
UR - http://www.scopus.com/inward/record.url?scp=85167363557&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00259-023-06363-5
DO - https://doi.org/10.1007/s00259-023-06363-5
M3 - Article
C2 - 37552369
SN - 1619-7070
VL - 50
SP - 3917
EP - 3927
JO - European journal of nuclear medicine and molecular imaging
JF - European journal of nuclear medicine and molecular imaging
IS - 13
ER -