Core B: Molecualr Imaging Chemistry Core (MICC)

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A.3.II. Molecular Imaging Chemistry Core (MICC) The MICC serves as a crucial interface for various interdisciplinary projects, In addition to ensuring the timely availability of imaging probes necessary for bioassays proposed by various investigators, the chemistry core also provides a training environment for students and post-doctoral fellows in chelation chemistry, radio-pharmaceutical synthesis, optical probe conjugation and preparation of MR relaxivity agents. The following represent areas of progress in service and discovery research: 1) PET and SPECT Radiopharmaceuticals for Molecular Imaging of Reporter Gene Expression. Reporter genes have been used to evaluate promoter or regulatory elements that participate in gene expression, inducible promoters to analyze the induction of gene expression, and transgenes comprising endogenous promoters coupled to a reporter to evaluate endogenous gene expression. The WU ICMIC supports many projects that exploit the utility of noninvasive imaging techniques in probing transgene as well as endogenous gene expression. Radiolabeled compounds and fluorophores constitute many of these reporter probes and require a steady effort for synthesis, validation and quality control. A variety of projects use various mutant HSV1-tk reporter genes and radiolabeled nucleosides as PET reporter probes. The MICC routinely synthesizes various nucleoside pyrimidine and purine derivatives (e.g., [18F]FHBG). Research Project 4 requires 18F-FHBG for both small animal imaging and the clinical PET imaging trial. The synthesis and validation of several novel nucleosides as reporter substrates remains under active investigation. 2) Peptide-Based Radiopharmaceuticals for Imaging and Therapy. Several transduction sequences capable of permeating the plasma membrane of cells and thereby enabling delivery of biomolecules and various "cargos" have been synthesized as both single labeled conjugates (99mTc) and as dual labeled conjugates (99mTc and fluorescein). Peptide transduction sequences have been recently evaluated for ophthalmic applications as well as novel applications in the imaging and therapy of pancreatic and brain tumors. These Core activities may lead to novel Tc-99m-based imaging agents for analysis of brain tumors. 3) Peptide-Based Radiopharmaceuticals for Selective Imaging of Cell-Based Targeting. We continue to evaluate the ability of fIuorescent-TAT-permeation peptides conjugated with the antiapoptotic BH4 domain to penetrate lymphocytes for targeted therapy. Preliminary fluorescence experiments indicate that peptide conjugates effectively penetrate lymphocytes. 4) Peptide-Based "Smart" Probes for Molecular Imaging. Biocompatible, far-red and near-infrared fluorescence (NIRF) imaging probes capable of generating a strong signal upon enzyme activation within intracellular compartments have become increasingly exploited to evaluate biochemical pathways and in vivo imaging. Using a membrane permeant TAT peptide motif as delivery vehicle, Alexa Fluor and NIRF probes have now been synthesized which can be activated through an enzyme-cleavable amino acid sequence. Novel small activatable probes with QSY21-Alexa Fluor 647 quenching strategies have recently been synthesized and validated. We continue to co-develop with the laboratory of Sam Achilefu, Ph.D., new peptide conjugates for ICMIC projects.