TRICARBONYL COMPLEXES OF TRANSITION METALS WITH BENZO-HETEROCYCLIC DERIVATIVES OF THE CYCLOPENTADIENYL ANION WITH HIGH PENETRATION OF THE BLOOD-BRAIN BARRIER FOR APPLICATION IN DIAGNOSIS AND THERAPY OF DISEASES OF THE CNS

摘要

31 The present invention relates to complex compounds of transition metals with emphasis on 99mTc and Re, which exhibit high blood-brain barrier permeability so that they may be used as diagnostic/therapeutic agents for CNS diseases. The novel compounds have the general structural formula where the M(CO)3+ tricarbonyl-metal core forms a complex with the cyclopentadienyl anion linked to heterocyclic moieties of the benzothiazole, benzimidazole and benzoxazole families. The blood-brain barrier permeability for three of the novel compounds with Μ = 99mTc ranges between 7.04 and 3.99 %ID/gr at 2 min post injection. Moreover, the novel compounds exhibit effective binding in vitro to β-amyloid fibrils as well as to amyloid plaques that characterize Alzheimer's disease, they inhibit the β-amyloid peptide induced cytotoxicity in cell cultures, and they drastically reduce the β-amyloid peptide induced ROS production also linked with Alzheimer's disease. Consequently, they have proven potential for application as diagnostic/therapeutic agents against Alzheimer's disease. Furthermore, their high blood-brain barrier penetration potential, renders them strong candidates for application as pharmaceutical agents of CNS diseases.