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

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-K-2-(2,2'-N2C10H6( Me)((CH2)7(131)I)-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)(2)O(CH2()2)(125)I-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 15 mL/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. (C) 2017 Elsevier B.V. All rights reserved.