Harnessing scandium chelation chemistry for the development of radiopharmaceuticals

利用钪螯合化学来开发放射性药物

• 批准号: 10867016
• 负责人: Eszter Boros
• 金额: $ 34.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10867016
• 关键词: Acceleration; Albumins; Amides; Antigen Targeting; Binding; Biological Products; Chelating Agents; Chemicals; Chemistry; Clinical; Companions; Complex; Development; Diagnostic; Disadvantaged; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; FOLH1 gene; Fluorine; Generations; Goals; Half-Life; Hardness; Image; In Vitro; Injections; Ions; Isotope Therapy; Isotopes; Kinetics; Knowledge; Label; Libraries; Link; Lutetium; Metals; Methods; Mus; Nitrogen Dioxide; Patient-Focused Outcomes; Peptides; Performance; Plant Resins; Positron-Emission Tomography; Procedures; Production; Property; Proteins; Radial; Radiation therapy; Radiochemistry; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Saline; Scandium; Solid; System; Temperature; Therapeutic; Tracer; Validation; Xenograft Model; aqueous; chelation; chemotherapy; clinical application; clinical development; cohort; cold temperature; dosimetry; improved; in vivo; metallicity; novel; pre-clinical; radiochemical; rational design; small molecule; targeted imaging; theranostics; tumor; tumor growth

The recent FDA-approval of 68Ga-imaging radiopharmaceuticals and their 177Lu-based companion therapeutics underscores the potential of metallic radioisotopes for clinical applications in diagnostic and therapeutic nuclear medicine. The improvements made to accelerator-based production of radiometals beyond the 68Ga, 177Lu theranostic pair has opened opportunities to produce radiometals with a broad range of half-lifes and emission properties, expanding the scope of imageable disease targets. However, subsequent development of clinically applicable radiopharmaceuticals has been impeded by a significant gap in knowledge of aqueous coordination chemistry of the corresponding metal ions. Scandium(III) aqueous chemistry represents a prime example of this conundrum. 43Sc (Eβ+ avg = 476keV, t1/2= 3.9h) and 44Sc (Eβ+ avg = 632keV, t1/2= 4h) have ideal properties for positron emission tomography (PET) imaging up to 24h post injection. For therapy applications, the emission properties of 47Sc (Eβ− avg = 162keV, t1/2 = 80.4h) are comparable to 177Lu (Eβ− avg = 134keV, t1/2 = 159.6h). The Sc(III) ion is a close chemical match to Lu(III) with respect to ionic radius and chemical hardness; therefore 43Sc/44Sc also represents an ideal diagnostic isotope partner to the already widely accessible 177Lu therapy isotope, producing more directly predictive image-derived pharmacokinetics and dosimetry for radiotherapy. However, the pronounced solution chemistry knowledge deficiency has hampered efficient separation, isolation, and application of Sc(III) isotopes as clinical radiopharmaceuticals. To enable the synthesis of a broad range of diagnostic and therapeutic radiopharmaceuticals based on Sc and Lu isotopes, we propose three aims towards new chemical and in vivo validated strategies that enable high-yielding, high molar activity, low temperature radiochemistry approaches to theranostic radiopharmaceuticals.

最近FDA批准的68 Ga成像放射性药物及其基于177 Lu的伴随疗法 强调了金属放射性同位素在诊断和治疗核医学中的临床应用潜力 药对基于加速器的68 Ga，177 Lu以外的放射性金属生产的改进 治疗诊断对为生产具有广泛半衰期和发射范围的放射性金属提供了机会 性质，扩大了可成像疾病靶点的范围。然而，临床上的后续发展 水配位知识的巨大缺口阻碍了可应用的放射性药物 相应金属离子的化学性质。钪（III）水溶液化学就是一个很好的例子 难题~（43）Sc（Eβ+ avg = 476keV，t1/2= 3.9h）和~（44）Sc（Eβ+ avg = 632keV，t1/2= 4h 正电子发射断层扫描（PET）成像，直至注射后24小时。对于治疗应用， 47 Sc（Eβ− avg = 162 keV，t1/2 = 80.4h）的性质与177 Lu（Eβ− avg = 134 keV，t1/2 = 159.6h）相当。的 Sc（III）离子在离子半径和化学硬度方面与Lu（III）化学匹配;因此 43 Sc/44 Sc也是已经广泛使用的177 Lu治疗的理想诊断同位素伙伴 同位素，产生更直接的预测图像衍生的药物动力学和放射治疗的剂量测定。 然而，明显的溶液化学知识缺乏阻碍了有效的分离，分离， 以及Sc（III）同位素作为临床放射性药物的应用。为了能够合成广泛的 基于Sc和Lu同位素的诊断和治疗放射性药物，我们提出了三个目标， 新的化学和体内验证策略，可实现高产、高摩尔活性、低温 治疗诊断放射性药物的放射化学方法。