Development of rhenacarborane complexes as central nervous system (CNS) drug delivery agents

Abstract

The search for non-invasive neural therapeutics is a problematic pursuit often hindered by the blood-brain barrier (BBB), a gatekeeper of endothelial cells and tight junctions closely regulating exchange between the bloodstream and brain tissue. A recent study of the complex [3-NO-3,3-κ2-(2,2′-N2C10H6(Me)((CH2)7131I)-4,4′)-closo-3,1,2-ReC2B9H11] demonstrated its ability to not only safely pass through the BBB but also cleanly efflux out of neural tissue, suggesting potential use as a drug-delivery vehicle for central nervous system (CNS) delivery. However, due to the practical difficulty of asymmetric modification of the bipyridyl ligand, a more direct synthetic approach of carborane cage vertex adaptation has been investigated with the hope of utilizing such species for CNS therapeutics. A second prototype of [3,3-(CO)2-3-NO-closo-Re(8-O(CH2)2O(CH2)2125I-3,1,2-C2B9H10)] was rapidly absorbed into the bloodstream from the subcutaneous site of injection and displayed a 1.1%Inj/g for peak brain uptake, which rapidly stabilized to 0.10% while the previous complex merely peaked at 0.10%Inj/g in initial studies. It was also determined that peak brain uptake of 15mL/g was higher than lung and liver tissues, suggesting that the brain is somehow specifically targeted, although the exact rationale for selectivity remains to be explored.