High sensitivity and low toxicity radiopharmaceuticals

描述（由申请人提供）：真正的分子成像是由靶向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体相放射性标记工艺，这将导致更高灵敏度的放射性药物，具有更高的安全边际（纳米剂量），用于分子成像和靶向放射治疗。该方法将导致快速生产超高比活性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。该工艺将有助于实现真正的“无载体”放射性药物制剂的时代，这将增强靶标摄取并避免过量活性感冒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给药概念。我们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和心脏肾上腺素能张力的可视化。两种合成方法将被用来获得不同变化的固相MIBG前驱体。第一种方法是聚合定制的含有机锡的二乙烯基苯单体，以生产一种刚性的高交联树脂。第二种是将有机锡连接剂添加到预制的多孔低交联聚合物珠中。不同的工艺将产生具有不同三维物理性质的固相聚合物。每个都将评估放射化学和制药性能，重点是放射性标签方法和具体的法规考虑，因为它们与最终的GMP生产有关。选择具有最佳性能的最一致和坚固的固相树脂进行放射性标记对于最终获得FDA批准至关重要。将对获得的产品的分析概况进行比较，以确定最安全和最有效的制造工艺。必须建立聚合物前体的规格，以生产大规模GMP质量的材料进行验证研究。最终目标是实现生产具有超高比活性的放射性药物的高度稳健的过程。

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.