TECHNETIUM COMPLEXES OF PEPTIDES

人们对开发针对特定受体的锝（99mTc）标记的放射性药物非常感兴趣。在这些应用中，通常配体与受体结合分子结合，99mTc与配体结合形成螯合物。99mTc螯合剂的稳定性很重要，这样放射性才能传递到受体，并在成像过程中保持在受体部位。此外，99mTc螯合物的大小、形状和电荷对分子的受体结合部分与其受体的相互作用有显著影响。此外，螯合剂的设计应促进机体的良好清除和非靶器官的低吸收。这在以188Re为基础的放射治疗剂的开发中尤为重要。我们的目标是设计具有高稳定性和多种新颖结构的Tc螯合物。我们还将与康奈尔大学医学中心合作评估生物分布。我们计划研究含有天然氨基酸和非天然氨基酸的肽与锝结合的基本化学性质，以设计合适的Tc螯合体系。我们将使用三个“Tc核心”，它们都在示踪99mTc和宏观99Tc上可用。有[TcO]3+。[TcN]2+和Tc(CO)/3+。我们将比较类似体系中Tc和铼的化学性质，因为Re经常被用作Tc的“替代物”，并且必须建立新配体中的化学对应关系。188Re在放射治疗方面也有潜在的应用。我们的战略包括以下具体目标。a .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.将检查Tc与三肽和四肽的结合。我们将在我们的肽配体中使用传统和非传统的氨基酸。我们计划在选定的三肽系列中检查异构体的相互转化。C.利用从A和B中得到的信息，我们将检查在肽末端定位残基的影响；这样与金属离子的结合就会形成环状肽。在这种设计中，Tc将是分子的“完整”部分。为了实现上述目标，我们将制备配合物，在示踪尺度上，使用99mTc，在宏观尺度上，使用99Tc，弱β -发射器和Re。我们将通过使用半胱氨酸（和其他配体）挑战来检查稳定性，以获得相对规模的稳定性。结构和溶液化学将用宏观的99Tc进行研究。生物分布将在选定的99mTc样品上进行，188Re也将纳入选定的肽中。

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.