TECHNETIUM COMPLEXES OF PEPTIDES

人们对开发针对特定受体的~(99m)Tc标记放射性药物有相当大的兴趣。在这些应用中，通常将配体连接到受体结合分子上，并将99mTc结合到配体上形成螯合物。99mTc络合物的稳定性很重要，这样放射性就能传递到受体，并在成像过程中保持在受体部位。此外，99mTc螯合物的大小、形状和电荷可以对分子的受体结合部分与其受体的相互作用产生显著影响。此外，络合物的设计应促进体内的良好清除和非靶器官的低摄取。这在以188Re为基础的放射治疗剂的开发中尤其关键。我们的目标是设计出具有高稳定性和多种新颖结构的TC络合物。我们还将与康奈尔大学医学中心合作评估生物分布。我们计划研究天然氨基酸和非天然氨基酸组成的多肽与锶结合的基础化学，以设计一种适合于Tc的螯合体系。我们将使用三个“Tc核”，它们都可以在示踪剂99mTc和宏观的99Tc刻度上获得。有[TCO]3+。[TCN]2+和Tc(CO)/3+。我们将比较类似体系的T_c和Re的化学，因为Re经常被用作T_c的“替代物”，并且必须建立新配体中化学的对应关系。此外，188Re还具有放射治疗应用的潜力。我们的战略包括以下具体目标。答：我们计划对TC与氨基酸和二肽的结合进行系统检查，以比较其稳定性和结构。B.检查TC与三肽和四肽的结合情况。我们将在我们的多肽配体中使用传统和非传统氨基酸。我们计划在一个精选的三肽系列中检测异构体的相互转化。利用从A和B得到的信息，我们将检查在肽末端定位残基的效果，从而与金属离子结合形成环肽。在这种设计中，T_c将成为分子的“整体”部分。为了完成上述工作，我们将使用99mTc在示踪尺度上制备络合物，并在宏观尺度上使用弱β发射体99Tc和Re制备络合物。我们将通过使用半胱氨酸(和其他配体)挑战来检查稳定性，以获得一个相对的稳定性等级。结构和溶液化学将使用宏观的99TC物种进行检查。将在选定的99mTc样品上进行生物分布，并将188Re加入选定的多肽中。

There is considerable interest in developing technetium (99mTc) labeled radio-pharmaceuticals targeted towards specific receptors. In these applications, generally a ligand is tethered to a receptor binding molecule and the 99mTc is bound to the ligand to form a chelate. The stability of the 99mTc chelate is important so that the radioactivity is delivered to the receptor and remains at the receptor site for the imaging session. Also, the size, shape and charge of the 99mTc chelate can have a dramatic effect on the interaction of the receptor binding portion of the molecule to its receptor. In addition, chelates should be designed to promote good clearance from the body and low uptake in non target organs. This is particularly critical in the development of radiotherapeutic agents, based on 188Re. Our goal is to design Tc chelates with high stability and with a variety of novel structures. We will also evaluate biodistribution in collaboration with Cornell University Medical Center. We plan to investigate the fundamental chemistry of technetium bound to peptides containing natural amino acids and non-natural amino acids in order to design a suitable chelating system for Tc. We will use three "Tc cores", all available on the tracer, 99mTc, and macroscopic, 99Tc, scales. There are [TcO]3+. [TcN]2+ and Tc(CO)/3+. We will compare Tc and rhenium chemistry of analogous systems, since Re is often used as a "surrogate" for Tc and the correspondence of the chemistry in new ligands must be established. Also 188Re has potential for radio-therapeutic applications. Our strategy consists of the following specific aims. A. We plan a systematic examination of the binding of Tc to amino acids and dipeptides to compare stabilities and structures. B. Examination of the binding of Tc to tri- and tetra-peptides will be performed. We will use traditional and non-traditional amino acids in our peptide ligands. We plan to examine the interconversions of isomers in a selected tripeptide series. C. Using information derived from A and B, we will examine the effect of positioning residues at the ends of a peptide; so that the binding to the metal ion will form a cyclic peptide. In this design, the Tc will be an "integral" portion of the molecule. To accomplish the above, we will prepare complexes, both on the tracer scale, using 99mTc, and on the macroscopic scale, using 99Tc, a weak beta-emitter and Re. We will examine stability by the use of cysteine (and other ligand) challenges to obtain a comparative scale of stabilities. The structure and solution chemistry will be examined using the macroscopic 99Tc species. Biodistribution will be performed on selected 99mTc samples and 188Re will also be incorporated into selected peptides.