Brain delivery enabled by transient blood-brain barrier disruption induced by regadenoson: a PET imaging study

Regadenoson, an agonist of adenosine A2 receptors, enables transient blood-brain barrier (BBB) disruption. The relevance of regadenoson as a pharmacological strategy for brain delivery was investigated using in vivo PET imaging in rats.

Kinetic modeling of brain PET data was performed to estimate the impact of regadenoson (0.05 mg.kg^-1, i.v.) on BBB permeation compared with control rats (n = 4-6 per group). Three radiolabeled compounds of different sizes, which do not cross the intact BBB, were tested.

Regadenoson significantly increased the BBB penetration (+116 ± 13%, p < 0.001) of [¹⁸F]2-deoxy-2-fluoro-D-sorbitol ([¹⁸F]FDS, MW = 183 Da), a small-molecule marker of BBB permeability. The magnitude of the effect was different across brain regions, with a maximum increase in the striatum. Recovery of BBB integrity was observed 30 min after regadenoson injection. Regadenoson also increased the brain penetration (+72 ± 45%, p < 0.05) of a radiolabeled nanoparticle [⁸⁹Zr]AGuIX (MW = 9 kDa). However, the brain kinetics of a monoclonal antibody ([⁸⁹Zr]mAb, MW = 150 kDa) remained unchanged (p > 0.05).

PET imaging showed the features and limitations of BBB disruption induced by regadenoson in terms of extent, regional distribution, and reversibility. Nevertheless, regadenoson enables the brain delivery of small molecules or nanoparticles in rats.