Development of purine-derived 18F-labeled pro-drug tracers for imaging of MRP1 activity with PET.
Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluorinated side chains have been synthesized and evaluated as putative pro-drug tracers. The tracers were designed to undergo conjugation with glutathione within the brain and hence form the corresponding MRP1 substrate tracers in situ. 6-Bromo-7-(2-[(18)F]fluoroethyl)purine showed good brain uptake and rapid metabolic conversion. Dynamic PET imaging demonstrated a marked difference in brain clearance rates between wild-type and mrp1 knockout mice, suggesting that the tracer can allow noninvasive assessment of MRP1 activity in vivo.
Department of Chemistry and Institute of Nuclear Medicine, University College London , 235 Euston Road (T-5), London NW1 2BU, U.K.
Eva
E
Galante
Toshimitsu
T
Okamura
Kerstin
K
Sander
Tatsuya
T
Kikuchi
Maki
M
Okada
Ming-Rong
MR
Zhang
Mathew
M
Robson
Adam
A
Badar
Mark
M
Lythgoe
Matthias
M
Koepp
Erik
E
Årstad
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011355:Prodrugs; D011687:Purines; D019275:Radiopharmaceuticals; C421109:multidrug resistance-associated protein 1