title: Preferred stereoselective transport of the D-isomer of cis-4-[18F]fluoro-proline at the blood-brain barrier.
abstract: Generally, L-amino acids are preferably transported into mammalian cells compared with their D-isomers, and only L-amino acids are incorporated into proteins. Former studies, however, indicated that D-[H]proline is accumulated in the brain of mice after injection, while L-[3H]proline is not. We investigated the differential cerebral uptake of the D- and L-isomers of the PET tracer cis-4-[18F]fluoroproline (D-/L-cis-FPro) and of D-/L-[3H]proline (D-/L-Pro) in rats by dual tracer autoradiography and the uptake of D-cis-FPro in two human subjects by PET. The standardized uptake value (SUV) of D-cis-FPro in the cerebral cortex of rats 2 h p.i. was 3.05+/-1.18 (n=9) versus 0.06+/-0.01 (n=4) for L-cis-FPro (P<0.001) and 1.29+/-0.27 (n=4) for D-Pro versus 0.30+/-0.14 (n=9) for L-Pro (P<0.001). Analysis of the rat brain tissue after injection of D-cis-FPro (n=3) revealed no radioactivity in the proteins but a relevant part in the form of L-trans-FPro. The PET studies yielded a four- to five-fold higher SUV and influx rate constant in the human cortex for D-cis-FPro than for L-cis-FPro. We conclude that D-cis-FPro and D-Pro are preferably transported at the blood-brain barrier compared with their L-isomers and isomerized to the L-form within the brain. Thus, D-Pro in the plasma might be a source of intracerebral L-proline, which has been shown to act as a modulator of excitatory neurotransmission.
authors.affiliation: Institute of Medicine, Research Centre Jülich, Jülich, Germany. k.j.langen@fz-juelich.de
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.forename: Kurt
authors.initials: K
authors.lastname: Hamacher
authors.forename: Dagmar
authors.initials: D
authors.lastname: Bauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Bröer
authors.forename: Dirk
authors.initials: D
authors.lastname: Pauleit
authors.forename: Hans
authors.initials: H
authors.lastname: Herzog
authors.forename: Frank
authors.initials: F
authors.lastname: Floeth
authors.forename: Karl
authors.initials: K
authors.lastname: Zilles
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Coenen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011392:Proline / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D019275:Radiopharmaceuticals; C431803:fluoro-proline; D011392:Proline