Dr. Lisheng Cai is a staff scientist in the PET Pharmaceutical Sciences Section (PRSS), Molecular Imaging Branch (MIB), National Institute of Mental Health (NIMH). His long-term research goal is to develop new radiotracers for neuroreceptors, such as NMDA, and biomarkers for neuro-diseases, such as Alzheimer’s disease.

       Dr. Cai received his B. S. degree from Sichuan University in 1985. After a brief stint at Shanghai Institute of Organic Chemistry, he went to The University of Chicago for graduate study in organometallic chemistry with professor Jack Halpern. He earned his Ph. D. investigating the mechanism of the hydrogenation of transition metal polyhydrides in 1992. He and coworkers identified and applied proton NMR T1 relaxation time in distinction and identification of classical vs. non-classical polyhydrides. A number of polyhydrides were synthesized and their kinetics on losing dihydrogen was studied. Factors influencing this important elementary reaction was identified, including the position of the metal in the periodic table, charge on the whole molecule, and number of hydride in the molecule. Through detailed kinetic analysis and intermediate isolation, a complete mechanistic scheme was proposed for an osmium polyhydride (L₃OsH₄). From 1992 to 1995, he had been a postdoctoral associate in Harvard University with professor Richard Holm, studying the structural and functional modeling of metalloenzymes, the nitrogenase, sulfite/nitrite reductase, and hydrogenase. A conjugate between iron(III) porphyrin and iron-sulfur cube (Fe₄S₄) was synthesized and characterized as the structural model of sulfite/nitrite reductase. Its physical and chemical properties match those from the enzyme. A double iron-sulfur cube, mimicking the P-cluster of nitrogenase enzyme, was synthesized and characterized. This was the closest structural model at that time. The functional model of hydrogenase using nickel complexes was demonstrated to be the closest model at the time to catalyze the generation of dihydrogen from proton and electrons.

       From 1995 to 2002, he had been an assistant professor of chemistry at The University of Illinois at Chicago. His research involved 1) structural and functional model of dioxygenases, 2) homogeneous asymmetric catalysis, such as hydrogenation and cyclopropanation, 3) anti-cancer drugs for breast and ovarian cancers, including design, synthesis, and in vitro evaluations in cell cultures, 4) conjugates of magnetic nanoparticles for biological applications. His research group had constructed multiple bi-nuclear metal complexes. Their structures were established by X-ray single crystallography, and their magnetic properties were identified and studied. The iron bi-nuclear complex was demonstrated to react with dioxygen at room temperature, mimicking part of the dioxygenase activity in some enzymes. A number of asymmetric bi-nuclear complexes were shown to catalyze the cyclopropanation reaction to give high diastereo- and enantio-selectivity. During the research, a novel method to synthesize formamidines was discovered, using dimethyl formamide and a sulfonyl chloride. In order to explore the synergistic effort of an anticancer agent and an antiestrogen, his team made a number of conjugates between cis-dichlorodiammineplatinum(II) and tamoxifen analogs. These conjugates were examined in breast and ovarian cancer cell lines. A number of compounds reaching the cytotoxicity of tamoxifen were discovered. In order to examine the selective attachment of magnetic nanoparticles in biological targets, a number of dendratic compounds were synthesized and put on the surface of magnetic nanoparticles of iron. These new particles were examined and characterized by magnetic studies and electron microscopy.

       In 2002, Dr. Cai joined NIMH (Bethesda, MD) to develop Positron Emission Tomography (PET) radiotracers. The research relies on a multidisciplinary approach using the techniques of molecular modeling, organic chemistry, medicinal chemistry, radiochemistry, molecular biology, pathophysiology, physics, and PET technology. A number of IMPY derivatives have been evaluated as PET radiotracers of beta-amyloid aggregates in Alzheimer’s disease (AD). Further developments are in progress.

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