99mTc and 188Re Complexes for Conjugation to Peptides

描述(申请人提供)：靶向氚(99mTc)和Re(188Re) 放射性药物由确定靶标特异性的靶向载体组成。 (受体，生化过程)，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99mTc/188Re螯合物和靶向载体(图1)组成的新结合物，它将具有非凡的稳定性、靶向能力和快速消除游离放射性。该方案的目的是设计、合成和测试基于两个Tc/Re“核”的简单的Tc/Re络合物(络合物)， [Mv=O]~(3+)和MI(CO)~(3+)，M=99mTc，188Re和互补多肽配体体系。(目标1和2)选择多肽配体是为了了解导致以下因素的因素(结构、亲脂性、立体化学)：1)放射性标记后形成一个主要产物(对于立体异构体，为两个)；2)金属络合物在体内和体外检测中保持完整(高稳定性)；以及3)通过肾脏(肾脏系统)消除尿液中完整的金属络合物。这一认识是设计靶向99mTc和188Re放射性药物的关键，因为我们假设金属络合物对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。在这个项目中设计的螯合物可以很容易地通过标准的固相肽合成(SPPS)技术连接到目标载体(生物分子)上，用于进一步的体内测试 靶点及其作为成像或放射治疗制剂的应用。AIM 3是一项与纽约大学医学院的合作项目，它建议将AIMS 1和AIMS 2中最好的螯合物连接到HU177抗体的活性部位--13个氨基酸的多肽上。多肽和抗体都与IV型胶原的抗原结合，当肿瘤附近的胶原作为血管生成的一部分解体时，IV型胶原就会暴露出来。99mTc和188Re结合物将用于体内示踪多肽和抗体，以及在成像和治疗中的应用。我们建议的研究不同于其他Tc和Re放射性药物研究，因为我们将工作 示踪剂(99mTc，188Re，[10[-10]-10[-12]M])和宏观物种(99Tc和Re[10[-2]-10[-3]M])。这对于全面了解放射性药物的结构、形态和化学是至关重要的。在这项工作中，我们使用了99mTc和188Re放射性药物研究中没有使用过的技术，并将提供重要的结构和化学信息。这些技术包括但不限于，制备与示踪物种有关的99TC宏观类似物的制备高效液相色谱，以及圆二色谱和17O核磁共振波谱的使用。

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.