99mTc and 188Re Complexes for Conjugation to Peptides

描述（由申请人提供）：靶向锝（99 m Tc）和铼（188 Re） 放射性药物由决定靶点特异性的靶向载体组成 （受体，生物化学过程），并连接到与放射性金属形成络合物（或螯合物）的有机配体。我们的长期目标是设计由99 m Tc/ 188 Re螯合物和靶向载体组成的新缀合物（图1），该缀合物将具有优异的稳定性、靶向能力和快速消除未结合的放射性。本提案的目的是设计、合成和测试基于两个Tc/Re“核”的简单Tc/Re络合物（螯合物）， [Mv =O] 3+和MI（CO）3 +，M= 99 mTc，188 Re和互补肽配体系统。(Aims 1和2）选择肽配体以提供对这些因素的理解（结构，亲脂性，立体化学），导致1）形成一个主要产品（二，在立体异构体的情况下）在放射性标记后，2）金属螯合物在体内和体外测定中保持完整（高稳定性）和3）通过肾脏（肾系统）消除尿中的完整金属螯合物。这种理解是关键的设计有针对性的99 m Tc和188 Re放射性药物，因为我们假设，金属螯合物的放射性金属的稳定性和整个分子的生物分布有深远的影响。在该项目中设计的螯合物可以通过标准固相肽合成（SPPS）技术容易地缀合至靶载体（生物分子），用于进一步体内测试对靶分子的特异性。 靶向和作为成像剂或放射治疗剂应用。目的3，与纽约大学医学院的合作努力提出将来自目的1和2的最佳螯合物缀合至作为HU 177抗体的活性位点的13个氨基酸的肽。所述肽和所述抗体都与IV型胶原蛋白的抗原结合，所述IV型胶原蛋白的抗原在胶原蛋白作为血管生成的一部分在肿瘤附近散开时暴露。99 mTc和188 Re结合物将被测试用于肽和抗体的体内追踪以及在成像和治疗中的应用。 用示踪剂（99 mTc，188 Re，[10[ -10] -10[ -12] M]）和宏观（99 Tc和Re [10[-2] -10[-3] M]）物质。这对于全面了解放射性药物的结构、形态和化学性质至关重要。在这项工作中，我们采用的技术，还没有被用于99 m Tc和188 Re放射性药物的研究，并将提供重要的结构和化学信息。这些技术包括但不限于制备99 Tc宏观类似物的制备型HPLC，其可以与示踪剂物质相关，以及圆二色性和17 O NMR光谱的使用。

DESCRIPTION (provided by applicant): Targeted technetium ( 99m Tc) and rhenium ( 188 Re) radiopharmaceuticals consist of a targeting vector that determines the specificity for the target (receptor, biochemical process) and is linked to an organic ligand that forms a complex (or chelate) with the radiometal. Our long-range goal is to design new conjugates consisting of the 99m Tc/ 188 Re chelate and the targeting vector (Figure 1) that will have exceptional stability, targeting ability and rapid elimination of unbound radioactivity. The objective of this proposal is to design, synthesize and test simple Tc/Re complexes (chelates) based on two Tc/Re "cores", [M v =O] 3+ and M I (CO)3 + , M= 99m Tc, 188 Re, and complementary peptide ligand systems. (Aims 1 and 2) The peptide ligands are chosen to provide an understanding of the factors (structure, lipophilicity, stereochemistry) that lead to 1) the formation of one major product (two, in the case of stereoisomers) upon radiolabeling, 2) the metal chelates remaining intact in in vivo and in vitro assays (high stability) and 3) elimination of the intact metal chelates in the urine via the kidneys (renal system). This understanding is key to the design of targeted 99m Tc and 188 Re radiopharmaceuticals because we hypothesize that the metal chelate has a profound effect on the stability of the radiometal and the biodistribution of the entire molecule. The chelates designed in this project can be easily conjugated to target vectors (biomolecules) by standard solid phase peptide synthesis (SPPS) techniques for further in vivo testing for specificity to the target and application as imaging or radiotherapy agents. Aim 3, a collaborative effort with New York University School of Medicine proposes to conjugate the best chelates from Aims 1 and 2 to a 13 amino acid peptide that is the active site of the HU177 antibody. Both the peptide and the antibody bind to an antigen of collagen type IV that is exposed when collagen unravels in the vicinity of tumors as part of angiogenesis. The 99m Tc and 188 Re conjugates will be tested for in vivo tracking of the peptide and antibody and for applications in imaging and therapy.Our proposed study differs from other Tc and Re radiopharmaceutical studies because we will work with both the tracer ( 99m Tc, 188 Re, [10[ -10] -10[ -12] M]) and the macroscopic ( 99 Tc and Re [10[-2] -10[-3] M]) species. This is critical to gain a complete understanding of the structure, speciation and chemistry of the radiopharmaceutical. In this effort we employ techniques that have not been used for 99m Tc and 188 Re radiopharmaceutical studies and will provide important information on structures and chemistry. These techniques include, but are not limited to, preparative HPLC to prepare the 99 Tc macroscopic analogs, that can be related to the tracer species, and the use of Circular Dichroism and 17 O NMR Spectroscopy.