title: Evaluation of drug penetration into the brain: a double study by in vivo imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier.
abstract: The blood-brain barrier (BBB) permeabilities of 11 compounds were measured both in vitro with a newly developed coculture-based model of human BBB and in vivo with positron emission tomography (PET). The 11 compounds were fluoropyridinyl derivatives labeled with the positron-emitter fluorine-18, [(18)F]F-A-85380 [2-[(18)F]fluoro-3-[2(S)-2 azetidinylmethoxy]pyridine], and 10 selected N-substituted-azetidinyl and pyrrolidinyl closely related [(18)F]fluoropyridinyl derivatives (including [N'-aromatic/aliphatic]-thioureas, -ureas, and -amides). The in vitro BBB model, a new coculture system of primary human brain endothelial cells and astrocytes, was used to measure the permeability coefficient for each compound. Dynamic PET studies were performed in rats with the same compounds, and a two-compartment model analysis was used to calculate their in vivo permeability coefficients. The 11 derivatives differed in their degree of BBB passage and transport mechanism. The analysis of PET data showed a significant cerebral uptake for six derivatives, for which the in vitro evaluation indicated active influx or free diffusion. Five derivatives displayed low in vivo cerebral uptake, in agreement with the observation of an in vitro active efflux. Overall, there was a remarkable correlation between the in vitro and in vivo permeability coefficients (r = 0.99). This double study proves a close correlationship between the assessment of the BBB passage in vitro and in vivo. The in vitro model of human BBB offers the possibility of subtle discrimination of various BBB permeability degrees and transport mechanisms. Conversely, small animal PET imaging appears suitable to screen directly in vivo brain targeting of drugs or radiopharmaceutical candidates.
authors.affiliation: Commissariat à l'Energie Atomique, Service Hospitalier Frédéric Joliot, Orsay, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.forename: Hélène
authors.initials: H
authors.lastname: Pélerin
authors.forename: Béatrice
authors.initials: B
authors.lastname: de Bruin
authors.forename: Benoît
authors.initials: B
authors.lastname: Jego
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.forename: Françoise
authors.initials: F
authors.lastname: Hinnen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ducongé
authors.forename: Raphaël
authors.initials: R
authors.lastname: Boisgard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Beuvon
authors.forename: Francine
authors.initials: F
authors.lastname: Chassoux
authors.forename: Catherine
authors.initials: C
authors.lastname: Daumas-Duport
authors.forename: Eric
authors.initials: E
authors.lastname: Ezan
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Aloïse
authors.initials: A
authors.lastname: Mabondzo
authors.forename: Bertrand
authors.initials: B
authors.lastname: Tavitian
mesh_terms: D000465:Algorithms; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001384:Azetidines; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002021:Buffers; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018920:Coculture Techniques; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011725:Pyridines; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism
chemical_list: C119803:2-fluoro-3-(2-azetidinylmethoxy)pyridine; D001384:Azetidines; D002021:Buffers; D004364:Pharmaceutical Preparations; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2