TY - JOUR
T1 - Evaluation of [18F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood-brain barrier in rats
T2 - Kinetics, metabolism, and selectivity
AU - Savolainen, Heli
AU - Windhorst, Albert D.
AU - Elsinga, Philip H.
AU - Cantore, Mariangela
AU - Colabufo, Nicola A.
AU - Willemsen, Antoon T.M.
AU - Luurtsema, Gert
PY - 2017
Y1 - 2017
N2 - P-glycoprotein is a protective efflux transporter at the blood-brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [18F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes (VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VT values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h postinjection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood-brain barrier.
AB - P-glycoprotein is a protective efflux transporter at the blood-brain barrier showing altered function in many neurological disorders. The purpose of this study was to validate [18F]MC225 as a radiotracer for measuring P-glycoprotein function with positron emission tomography. Three groups of Sprague-Dawley rats were used to assess tracer uptake at baseline (group 1), after inhibition of P-glycoprotein (group 2), and after inhibition of both P-glycoprotein and breast cancer resistance protein (Bcrp, group 3). A two-tissue compartment model with a metabolite-corrected plasma input function provided the best fit to the positron emission tomography data, but parameter estimates were more reliable in a one-tissue compartment model, which was selected as the preferred model. Regional distribution volumes (VT) in the control group ranged from 6 to 11, which is higher than for other radiotracers. [18F]MC225 showed transporter selectivity, since inhibition of P-glycoprotein caused a two to fourfold increase in the cerebral VT values, but additional inhibition of Bcrp did not cause any further increase. Metabolic stability of [18F]MC225 was moderate (at 1 h postinjection 15% of plasma radioactivity and 76% of brain radioactivity represented intact parent). Thus, [18F]MC225 may be a useful radiotracer to measure especially increases of P-glycoprotein function at the blood-brain barrier.
KW - Blood-brain barrier
KW - Brain imaging
KW - Breast cancer resistance protein
KW - Kinetic modeling
KW - Positron emission tomography
UR - http://www.scopus.com/inward/record.url?scp=85014937383&partnerID=8YFLogxK
U2 - https://doi.org/10.1177/0271678X16654493
DO - https://doi.org/10.1177/0271678X16654493
M3 - Article
C2 - 27354093
SN - 0271-678X
VL - 37
SP - 1286
EP - 1298
JO - Journal of cerebral blood flow and metabolism
JF - Journal of cerebral blood flow and metabolism
IS - 4
ER -