Document Detail

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.
MedLine Citation:
PMID:  16210395     Owner:  NLM     Status:  MEDLINE    
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.
Véronique Josserand; Hélène Pélerin; Béatrice de Bruin; Benoît Jego; Bertrand Kuhnast; Françoise Hinnen; Frédéric Ducongé; Raphaël Boisgard; Frédéric Beuvon; Francine Chassoux; Catherine Daumas-Duport; Eric Ezan; Frédéric Dollé; Aloïse Mabondzo; Bertrand Tavitian
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-10-06
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  316     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2005-12-22     Completed Date:  2006-03-31     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  79-86     Citation Subset:  IM    
Commissariat à l'Energie Atomique, Service Hospitalier Frédéric Joliot, Orsay, France.
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MeSH Terms
Astrocytes / drug effects,  metabolism
Azetidines / diagnostic use
Biological Transport, Active / drug effects
Blood-Brain Barrier / physiology*
Brain / metabolism*,  radionuclide imaging*
Chemistry, Physical
Coculture Techniques
Microscopy, Fluorescence
Models, Biological
Molecular Weight
Pharmaceutical Preparations / metabolism*
Physicochemical Phenomena
Positron-Emission Tomography
Pyridines / diagnostic use
Radiopharmaceuticals / diagnostic use,  pharmacokinetics
Receptors, Nicotinic / drug effects,  metabolism
Reg. No./Substance:
0/2-fluoro-3-(2-azetidinylmethoxy)pyridine; 0/Azetidines; 0/Buffers; 0/Pharmaceutical Preparations; 0/Pyridines; 0/Radiopharmaceuticals; 0/Receptors, Nicotinic; 0/nicotinic receptor alpha4beta2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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