BENZODIAZEPINE DERIVED CARBORANES FOR NEUTRON CAPTURE THERAPY

BORON NEUTRON-CAPTURE THERAPY (BNCT) IS A BINARY SYSTEM FOR DELIVERING INTENSELY IONIZING RADIATION TO TUMORS USING A COMBINATION OF BORON-10 LABELED MOLECULES AND THERMAL NEUTRONS IN ORDER TO ACHIEVE A TUMORCIDAL EFFECT. RECENT EVIDENCE HAS INDICATED THAT THERE ARE PERIPHERAL TYPE BENZODIAZEPINE-BINDING SITES (PBS) ATTACHED TO BOTH NECROTIC TUMOR AND NORMAL CEREBRAL CORTEX. LIGANDS WHICH ARE CAPABLE OF BINDING SELECTIVELY TO PBS ACHIEVE HIGH CONCENTRATION LEVELS ON MALIGNANT CELLS. SUCH A LIGAND IS THE BENZODIAZEPINE ANTAGONIST PK 11195, A SUBSTITUTED ISOQUINOLINE. THE INITIAL OBJECTIVE OF THE PHASE I EFFORT WILL BE THE SYNTHESIS OF SEVERAL BORON-CONTAINING ISOQUINOLINES STRUCTURALLY RELATED TO PK 11195 AND THEIR EVALUATION AGAINST MALIGNANT GLIOMA CELLS, U251 HUMAN GLIOBLASTOMA. IF THESE STUDIES ARE SUCCESSFUL AND SUCH COMPOUNDS PROVE USEFUL IN TARGETING GLIOMA CELLS UNDER IN VITRO CONDITIONS, THEN THEIR EVALUATION UNDER IN VIVO CONDITIONS IN TUMOR-BEARING ANIMALS WOULD BE UNDERTAKEN DURING PHASE II. THE PHASE I IN VITRO RESULTS WILL PROVIDE THE DIRECTION FOR THE PREPARATION OF OTHER BORON-CONTAINING ISOQUINOLINES AS WELL AS THE CARBORANE PBS AGONISTS OF THE R05-4864 TYPE AND FOR THEIR EVALUATION, ULTIMATELY IN DISEASED ANIMALS, DURING PHASE II.