High sensitivity and low toxicity radiopharmaceuticals

描述(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，这将导致分子成像和靶向放射治疗的更高灵敏度和更高的安全边际(纳米剂量)的放射性药物。该方法应导致快速生产超高比活度放射性碘标记的放射性药物，最终溶液中除注射载体外不含其他化学成分。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，这种制剂将增强靶向摄取，并避免过量活性感冒药的潜在药理和毒性影响。我们以前的努力支持使用固相放射性标记方法来实现这一纳米剂量概念。我们用于固相生产的目标分子是放射性标记的间碘苯甲基胍(MIBG)，这是一种用于儿童的放射性药物，用于检测和治疗源自心脏神经隆起和肾上腺素能张力的肿瘤。将使用两种合成方法来获得不同变化的固相MIBG前驱体。第一种方法是将定制的含有机锡的二乙烯基苯单体聚合，以生产一种硬质的高交联度树脂。第二种方法是将有机锡连接剂添加到预制的、多孔的、低交联度的聚合物珠子中。不同的工艺将产生具有不同三维物理性质的固相聚合物。每一个都将被评估放射化学和制药性能，重点是放射性标记方法和具体的监管考虑因素，因为它们与最终的GMP制造有关。选择具有最佳性能的最稳定、最坚固的固相树脂进行放射性标记是FDA最终批准的关键。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。必须建立聚合物前驱体的规格，以生产用于验证研究的大规模GMP质量材料。最终目标是实现一个高度稳健的过程，用于生产超高比活度的放射性碘药物。

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.