Ordinary capillaries (top vessel) have small gaps between the cells that form their wall, so most dissolved molecules — regardless of fat- or water-solubility — slip through into surrounding tissue almost freely; only very large molecules struggle.
Brain capillaries (bottom vessel) are sealed by tight junctions that leave no gaps at all. To reach brain tissue a molecule must dissolve directly into and diffuse through the lipid (fat) membrane of the vessel-lining cells themselves. Only molecules that are both lipophilic (fat-soluble) and reasonably small can do this efficiently — everything else bounces off and stays in the blood, however well it might work on brain cells if it ever got there.
- Lipophilicity — how readily the molecule dissolves into a fatty membrane. Low values (hydrophilic) are blocked at the BBB; high values pass through it.
- Molecular size — even a fat-soluble molecule crosses the BBB membrane more slowly, and eventually not at all, as it gets larger. Peripheral gaps are far more forgiving of size.
This is exactly why many drugs that work well elsewhere in the body are useless for neurological or psychiatric conditions: they simply can't reach adequate concentration in brain tissue, independent of how well they'd act on brain cells directly.