DEVELOPMENT OF 99M-TC BRAIN IMAGING AGENTS

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The primary objective of this research is the development of neutral, lipophilic 99m-Tc agents that will be useful for monitoring regional cerebral blood flow by SPECT (single photon emission computed tomography). This will be accomplished by merging the techniques and expertise of inorganic chemistry with those of nuclear medicine. Important steps in this process include the following: (1) The sysntheis and characterization of new technetium complexes, using first macroscopic amounts of 99-Tc so that chemical characterizations can be accomplished, and then "no carrier added" 99m-Tc for the preparation of radiopharmaceuticals. Characterizations of new complexes will depend heavily on single crystal x-ray structural analysis, electrochemical analysis, and HPLC (high performance liquid chromatography). (2) The development of the brain imaging agents that function by a "redox trapping" mechanism wherin oxidation in the brain converts neutral molecules into cations which cannot diffuse back out across the blood-brain barrier. Such agents will be based on complexes in which the technetium center is itself redox active, and on complexes in which the redox active site is a dihydropyridine moeity. (3) The elucidation of the biologrical mechanism of action of existing 99m-Tc brain imaging agents which contain Tc(V) centers. Experiments will be conducted to probe the interactions that can occure between the biological milieu and the oxo-Tc(V) core, the Tc center itself, and the organic ligand used to generate the 99M-Tc(V) radioparmaceutical. (4) Comparison of the clinical utility and efficacy of 123-I-IMP and 99m-Tc-HMPAO (IMP = N-isoproply-p-iodoamphetamine; HMPAO = hexamethylpropylene amine oxime), two agents which must act by different biological mechanisms. These studies will employ qualitative and quantitative SPECT imaging techniques, tramsmission computed tomography, and, in selected cases, the 133-Xe washout technique. Subjects will include normal volunteers and patients with one of the following diagnoses: (i) transient ischemic attack (TIA), (ii) cerebrovascular accident, (iii) primary or metastatic tumor, (iv) idiopathic seizure disorder. (5) Comparison of the clinical utility and efficacy of 99-m-Tc-HMPAO and new 99m-Tc brain imaging radiopharmaceuticals, especially those that utilize the "redox trapping" mechanism. These studied will further delineate the qualitative and quantitative manifestations resulting from the use of agents that function by different biological mechanisms. (6) Evaluation of CO2 stress as a means of enhancing detection of abnormal regional cerebral blood flow in patients with TIA. The studies will evaluate both the clinical utility of the techinique, and the relative efficacy of different radiopharmaceuticals used with the technique.