TY - JOUR
T1 - Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs to Investigate the Function of P-Glycoprotein in the Blood-Brain Barrier
AU - Raaphorst, Renske M.
AU - Luurtsema, Gert
AU - Schuit, Robert C.
AU - Kooijman, Esther J.M.
AU - Elsinga, Philip H.
AU - Lammertsma, Adriaan A.
AU - Windhorst, Albert D.
PY - 2017/9/20
Y1 - 2017/9/20
N2 - P-glycoprotein is an efflux transporter located in the blood-brain barrier. (R)-[11C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer's disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[18F]fluoroethylverapamil ([18F]1) and (R)-O-[18F]fluoroethylnorverapamil ([18F]2) has been described. [18F]1 was obtained in reaction of (R)-norverapamil with the volatile [18F]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% ± 1.2%. [18F]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% ± 9.9%. Both tracers, [18F]1 and [18F]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [18F]1 and [18F]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6- and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [18F]1 and [18F]2, PET scans in Mdr1a/b(-/-), Bcrp1(-/-), and WT mice were acquired, in which [18F]2 showed a more specific brain uptake in Mdr1a/b(-/-) mice and no increased signal in Bcrp1(-/-) mice. [18F]2 was selected as the best performing tracer and should be evaluated further in clinical studies.
AB - P-glycoprotein is an efflux transporter located in the blood-brain barrier. (R)-[11C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer's disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[18F]fluoroethylverapamil ([18F]1) and (R)-O-[18F]fluoroethylnorverapamil ([18F]2) has been described. [18F]1 was obtained in reaction of (R)-norverapamil with the volatile [18F]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% ± 1.2%. [18F]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% ± 9.9%. Both tracers, [18F]1 and [18F]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [18F]1 and [18F]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6- and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [18F]1 and [18F]2, PET scans in Mdr1a/b(-/-), Bcrp1(-/-), and WT mice were acquired, in which [18F]2 showed a more specific brain uptake in Mdr1a/b(-/-) mice and no increased signal in Bcrp1(-/-) mice. [18F]2 was selected as the best performing tracer and should be evaluated further in clinical studies.
KW - ABC transporters
KW - BCRP
KW - F
KW - P-gp
KW - blood-brain barrier
KW - positron emission tomography
KW - verapamil
UR - http://www.scopus.com/inward/record.url?scp=85029686973&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/acschemneuro.7b00086
DO - https://doi.org/10.1021/acschemneuro.7b00086
M3 - Article
C2 - 28650628
SN - 1948-7193
VL - 8
SP - 1925
EP - 1936
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 9
ER -