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.
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.
Josserand
Véronique
V
Commissariat à l'Energie Atomique, Service Hospitalier Frédéric Joliot, Orsay, France.
Pélerin
Hélène
H
de Bruin
Béatrice
B
Jego
Benoît
B
Kuhnast
Bertrand
B
Hinnen
Françoise
F
Ducongé
Frédéric
F
Boisgard
Raphaël
R
Beuvon
Frédéric
F
Chassoux
Francine
F
Daumas-Duport
Catherine
C
Ezan
Eric
E
Dollé
Frédéric
F
Mabondzo
Aloïse
A
Tavitian
Bertrand
B
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
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