Core B: Molecualr Imaging Chemistry Core (MICC)

A.3.II.分子成像化学核心（MICC） MICC是各种跨学科项目的重要接口，除了确保 及时提供各种研究者提出的生物测定所需的成像探针， 化学核心还提供了一个培训环境，为学生和博士后研究员在螯合 化学、放射药物合成、光学探针共轭和MR弛豫制备 剂.以下是服务和发现研究的进展领域： 1)PET和SPECT放射性药物用于报告基因表达的分子成像。 报道基因已被用于评估参与基因表达的启动子或调控元件。 用于分析基因表达的诱导的诱导型启动子，以及转基因，其包含 内源启动子偶联至报告基因以评估内源基因表达。WU ICMIC 支持许多利用非侵入性成像技术探测转基因的项目， 以及内源性基因表达。放射性标记的化合物和荧光团构成了许多这些 报道探针，并需要稳定的合成，验证和质量控制的努力。各种项目 使用各种突变的HSV 1-tk报告基因和放射性标记的核苷作为PET报告探针。的 MICC常规地合成各种核苷嘧啶和嘌呤衍生物（例如，[18F]FHBG）。 研究项目4需要18F-FHBG用于小动物成像和临床PET成像试验。 作为报告底物的几种新型核苷的合成和验证仍处于活跃状态 调查 2)用于成像和治疗的基于肽的放射性药物。 几种转导序列能够渗透细胞的质膜，从而使 生物分子和各种“货物”的递送已经被合成为两种单标记缀合物 （99 mTc）和双标记缀合物（99 mTc和荧光素）。肽转导序列已经被广泛应用于 最近评估了眼科应用以及在成像和治疗中的新应用， 胰腺和脑肿瘤这些核心活性可能导致新的基于Tc-99 m的成像剂，用于 分析脑肿瘤。 3)基于肽的放射性药物用于基于细胞的靶向的选择性成像。 我们继续评估与抗凋亡蛋白缀合的荧光TAT渗透肽的能力， BH 4结构域穿透淋巴细胞用于靶向治疗。初步荧光实验 表明肽缀合物有效地穿透淋巴细胞。 4)用于分子成像的基于肽的“智能”探针。 生物相容的远红外和近红外荧光（NIRF）成像探针，其能够产生 在细胞内区室中酶激活时强信号已经被越来越多地利用 以评估生物化学途径和体内成像。使用膜渗透性达特肽基序作为 现在已经合成了递送载体、Alexa Fluor和NIRF探针，其可以通过以下方式激活： 酶可裂解的氨基酸序列。具有QSY 21-Alexa Fluor 647的新型小可活化探针 最近已经合成并验证了猝灭策略。我们将继续与 实验室的山姆·萨福，博士，ICMIC项目的新型肽缀合物。

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.