High sensitivity and low toxicity radiopharmaceuticals

高灵敏度、低毒性放射性药物

• 批准号: 6934810
• 负责人: JAMES F KRONAUGE
• 金额: $ 14.75万
• 依托单位: MOLECULAR INSIGHT PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934810
• 关键词: anions; antineoplastics; chemical synthesis; crosslink; drug design /synthesis /production; drug screening /evaluation; iodine; method development; molecular /cellular imaging; neoplasm /cancer chemotherapy; neoplasm /cancer radiodiagnosis; polymers; radiopharmacology; radiotracer; resin

DESCRIPTION (provided by applicant): True molecular imaging is generated by compounds that target specific bio-molecules or molecular pathways. We propose to develop a solid-phase radiolabeling process that will lead to higher sensitivity radiopharmaceuticals with a higher margin of safety (nano-dosing) for molecular imaging and targeted radiotherapeutics. The approach should lead to rapid production of ultra-high specific activity radioiodine labeled radiopharmaceuticals with no other chemical components in the final solution except the injection vehicle. This process will help realize the era of true "carrier free" radiopharmaceutical preparations that will enhance target uptake and avoid potential pharmacological and toxic effects of excess active cold drug. Our previous efforts support the use of solid phase radiolabeling methods to achieve this nano-dosing concept. Our target molecule for solid-phase production is radiolabeled meta-iodobenzylguanidine (MIBG), a radiopharmaceutical used in children to detect and treat tumors originating from the neural crest and visualization of adrenergic tone of the heart. Two synthetic approaches will be used to obtain different variations of the solid-phase MIBG precursor. The first involves polymerization of custom organo-tincontaining divinylbenzene monomers to produce a rigid highly cross-linked resin. The second adds the organo-tin linker to preformed, porous, low cross-linked polymer beads. The different processes will produce solid-phase polymers with different 3-dimensional physical properties. Each will be evaluated for radiochemical and pharmaceutical performance with emphasis on radiolabeling methods and specific regulatory considerations as they pertain to eventual GMP manufacture. Choosing the most consistent and robust solid-phase resin with the optimal performance for radiolabeling is essential for ultimate FDA approval. The analytical profile of the products obtained will be compared to determine the safest and most efficient manufacturing process. Specifications for the polymer precursor must be established to produce arge scale GMP quality material for validation studies. The ultimate goal is to achieve a highly robust process for the production of radioiodinated Pharmaceuticals at ultra-high specific activity.

描述（由申请人提供）：真正的分子成像是由针对特定生物分子或分子途径的化合物产生的。我们建议开发一种固相放射性标记工艺，该工艺将产生更高灵敏度的放射性药物，在分子成像和靶向放射治疗方面具有更高的安全边际（纳米剂量）。该方法应该能够快速生产超高比活度放射性碘标记的放射性药物，除了注射载体外，最终溶液中没有其他化学成分。这一过程将有助于实现真正的“无载体”放射性药物制剂时代，从而增强靶点吸收并避免过量活性冷药的潜在药理和毒性作用。我们之前的努力支持使用固相放射性标记方法来实现这种纳米剂量概念。我们用于固相生产的目标分子是放射性标记的间碘苄基胍 (MIBG)，这是一种用于儿童的放射性药物，用于检测和治疗源自神经嵴的肿瘤以及心脏肾上腺素能张力的可视化。将使用两种合成方法来获得固相 MIBG 前体的不同变体。第一个涉及定制含有机锡的二乙烯基苯单体的聚合，以生产刚性的高度交联的树脂。第二种将有机锡连接剂添加到预成型的多孔低交联聚合物珠中。不同的工艺将产生具有不同3维物理性质的固相聚合物。每个产品都将进行放射化学和制药性能评估，重点是放射性标记方法和与最终 GMP 生产相关的具体监管考虑因素。选择最一致、最坚固、具有最佳放射性标记性能的固相树脂对于 FDA 最终批准至关重要。将比较所获得的产品的分析概况，以确定最安全和最有效的制造工艺。必须制定聚合物前体的规格，以生产用于验证研究的大规模 GMP 质量材料。最终目标是实现一种高度稳健的工艺，用于生产超高比活度的放射性碘药物。