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-κ 2 -(2,2′-N 2 C 10 H 6 (Me)((CH 2 ) 7 131 I)-4,4′)- closo -3,1,2-ReC 2 B 9 H 11 ] 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(CH 2 ) 2 O(CH 2 ) 2 125 I-3,1,2-C 2 B 9 H 10 )] 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.