The primary objective of this research is elucidation of the in vivo mechanism(s) of action of existing and potential 99m-Tc agents that are 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 to generate an integrated approach to understanding the chemical basis by which 99m-Tc agents are trapped within the human brain. Important aspects of this approach include the following: (1) Synthesis and characterization of new technetium complexes, using both macroscopic amounts of 99-Tc so that chemical characterizations can be accomplished, and """"""""no carrier added"""""""" 99m-Tc for the preparation of radiopharmaceuticals. Characterizations of new complexes will depend heavily on single crystal x-ray structural analysis, fast atom bombardment mass spectroscopy, electrochemical analyses, and HPLC. (2) Development of brain imaging agents that function by a """"""""redox trapping"""""""" mechanism wherein oxidation in the brain converts neutral molecules into cations which cannot diffuse back out across the blood-brain barrier. (3) Elucidation of the biological mechanism of action of CERETEC (99m-Tc d,l-HM-PAO), the only 99m-Tc brain perfusion agent currently approved for use in the United States. This will be accomplished by detailed chemical, biological and clinical studies which compare the properties and reactivities of closely related, but definably different, 99m-Tc PAO agents. Moreover, related complexes containing 5,7,5-chelate rings, rather than the 5,6,5-chelate rings of HM-PAO will be prepared and evaluated in animal models in order to determine how the stability of the oxo-Tc(V) core affects brain uptake and retention. (4) Development and evaluation of new in vivo electrochemical approaches to determining the actual chemical forms, and rates of conversion between forms, of 99m-Tc """"""""redox trapping"""""""" and PAO- derived brain imaging agents. (5) Evaluation of the relative clinical utilities of closely related 99m-Tc PAO analogs in the diagnosis of patients with stroke and Alzheimer's disease. An indirect benefit of these mechanistic studies is anticipated to be the identification of a 99m-Tc PAO agent which does not suffer the in vitro stability of CERETEC, but yet enjoys the equivalent, or superior, diagnostic capabilities of CERETEC.
