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, [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.
Footnotes
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This study was supported in part by grants from the European FP5 OLIM program (Contract QLG1-CT-2000-00562), the Imagerie du Petit Animal (IPA) Centre National de la Recherche Scientifique-CEA program, and the French National Agency for AIDS Research.
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doi:10.1124/jpet.105.089102.
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ABBREVIATIONS: BBB, blood-brain barrier; CNS, central nervous system; PET, positron emission tomography; [18F]F-A-85380, 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy] pyridine; [18F]FPy 01 to 10, [18F]fluoropyridinyl derivatives 01 to 10; K[18F]F-K222, 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix 222); PSe, PS value strictly due to the endothelial monolayer; PSe-in, PSe measured from the apical to basal compartment; PSe-in, PSe measured from apical to basal compartment; PSe-out, PSe measured from basal to apical compartment; Q ratio, PSe-out/PSe-in ratio; DiI-acyl-LDL, 1-methyl-[14C]-1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-acetylated low-density lipoprotein; BEC, brain endothelial cell(s); HA, human astrocytes; GFAP, glial fibrillary acidic protein; HPLC, high-pressure liquid chromatography; PBS, phosphate-buffered saline; P-gp, P-glycoprotein; DV, distribution volume; mAb, monoclonal antibody; 99mTc, technetium-99m.
- Received May 9, 2005.
- Accepted October 3, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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