RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 79
OP 86
DO 10.1124/jpet.105.089102
VO 316
IS 1
A1 Véronique Josserand
A1 Hélène Pélerin
A1 Béatrice de Bruin
A1 Benoît Jego
A1 Bertrand Kuhnast
A1 Françoise Hinnen
A1 Frédéric Ducongé
A1 Raphaël Boisgard
A1 Frédéric Beuvon
A1 Francine Chassoux
A1 Catherine Daumas-Duport
A1 Eric Ezan
A1 Frédéric Dollé
A1 Aloïse Mabondzo
A1 Bertrand Tavitian
YR 2006
UL http://jpet.aspetjournals.org/content/316/1/79.abstract
AB 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, [18F]F-A-85380 [2-[18F]fluoro-3-[2(S)-2 azetidinylmethoxy]pyridine], and 10 selected N-substituted-azetidinyl and pyrrolidinyl closely related [18F]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. The American Society for Pharmacology and Experimental Therapeutics