Preparation of Low Valent Tc(1) Imaging Agents

描述（由申请人提供）：本提案中概述的研究项目具有开发一种或多种放射性标记的、位点特异性的胃泌素释放肽（GRP）诊断/治疗放射性药物的潜力。 简言之，该提案描述了[Dpr-（Y）-BBN（7-14）NH 2]形式的新缀合物的设计和开发，其中Dpr =二氨基丙酸，BBN =蛙皮素，Y =一系列亲水性氨基酸链，包括残基谷氨酸、天冬氨酸、谷氨酰胺和天冬酰胺。当用新的低价Tc-99 m合成子[99 mTc（H2O）3（CO）3]+放射性标记时，这些缀合物具有产生特异性靶向过表达GRP受体（GRPr）的人类癌症的高比活性产物的潜力。本研究的具体目标是：1）通过固相肽合成技术合成有限数量的[Dpr-（Y）-BBN（7-14）NH_2]形式的GRPr阳性配体：2）将新构建的配体金属化为低价的Tc（I）（CO）_3和Re（I）（CO）_3核; 3）使用GRPr阳性的人前列腺癌细胞系（PC-3）在体外评价金属化的[Dpr-（Y）-BBN（7-14）NH 2]-缀合物的结合亲和力; 4）评价那些显示高受体结合亲和力的99 mTc（I）标记的类似物的体内药代动力学（即，Kd= 5 nM）; 5）通过新开发的放射合成子[188 Re（H2O）3（CO）3]+优化并验证最有希望的[Dpr-（Y）-BBN（7-14）NH 2]-衍生物的“匹配对”188 Re-缀合物。将合成、纯化所有金属化缀合物，并在示踪剂（99 mTc和188 Re）和宏观（99 Tc和186 Re）水平上表征。在体外和体内筛选的每一个新的金属化的共轭物将用于评估受体介导的内化和癌细胞摄取的性能。即使是单一诊断类似物的鉴定也为未来通过FDA批准的临床试验在人类患者中评估这类新的放射性药物提供了动力。

DESCRIPTION (provided by applicant): The research project outlined in this proposal holds the potential for development of one or more radiolabeled, site-specific, Gastrin Releasing Peptide (GRP), diagnostic/therapeutic radiopharmaceuticals. Briefly, the proposal describes the design and development of new conjugates of the form [Dpr-(Y)-BBN(7-14)NH2], where Dpr = diaminopropionic acid, BBN = Bombesin, and Y = a series of hydrophilic amino acid tethers including the residues glutamic acid, aspartic acid, glutamine, and asparagine. These conjugates, when radiolabeled with the new low valent Tc-99m synthon [99mTc(H2O)3(CO)3]+, hold potential to produce high specific activity products that specifically target human cancers overexpressing the GRP receptor (GRPr). The specific objectives of this proposal are: 1) Synthesize a limited number of GRPr-positive ligands of the form [Dpr-(Y)-BBN(7-14)NH2] via solid phase peptide synthetic techniques; 2) Metallate the newly constructed ligands with Iow-valent Tc(I)(CO)3 and Re(I)(CO)3 cores; 3) Evaluate the binding affinity of the metallated [Dpr-(Y)-BBN(7-14)NH2]-conjugates in vitro, using GRPr-positive, human prostate, cancer cell lines (PC-3); 4) Evaluate the in vivo pharmacokinetics of those 99mTc(I)-labeled analogs demonstrating high receptor binding affinities (i.e., Kd=5nM) in normal (CF-1) mouse models; 5) Optimize and validate the "matched pair" 188Re-conjugate of the most promising [Dpr-(Y)-BBN(7-14)NH2]-derivative via the newly developed radiosynthon [l88Re(H2O)3(CO)3]+. All of the metallated conjugates, will be synthesized, purified, and characterized at both tracer (99mTc and 188Re) and macroscopic (99Tc and 186Re) levels. In vitro and in vivo screening of each of the new metallated conjugates will serve to evaluate the properties of receptormediated internalization and cancer cell uptake. Identification of even a single diagnostic analog provides impetus for future evaluation of this new class of radiopharmaceuticals, via FDA approved clinical trials, in human patients.