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.

最近对68GA成像的放射线药物及其177LU的公司理论的FDA批准 强调了金属放射性病的潜力用于诊断和治疗性核的临床应用 药品。对基于加速器的产生辐射量的改进超出了68GA，177LU TherAnotic对开放了生产具有一定范围和发射的辐射标准的机会 特性，扩大了可成像疾病靶标的范围。但是，随后在临床上发展 适用的放射性药物受到水性协调知识的显着差距的阻碍 相应金属离子的化学。 Scandium（iii）水性化学代表了这一点的一个主要例子 难题。 43SC（Eβ+ AVG = 476KeV，T1/2 = 3.9h）和44SC（Eβ+ AVG = 632KeV，T1/2 = 4H）具有理想的特性 注射后24小时成像的正电子发射断层扫描（PET）。对于治疗应用，排放 47SC（Eβ-AVG = 162KeV，T1/2 = 80.4H）的性质可与177lu（Eβ-AVG = 134KeV，T1/2 = 159.6H）相当。这 SC（III）离子是与离子半径和化学硬度相对于LU（III）的紧密化学匹配。所以 43SC/44SC还代表了已经广泛使用的177LU治疗的理想诊断同位素伴侣 同位素产生更直接的预测性图像衍生的药代动力学和放射疗法的剂量法。 但是，明显的溶液化学知识缺乏阻碍了有效的分离，隔离， SC（III）同位素作为临床放射性药物的应用。能够综合一系列 基于SC和LU同位素的诊断和治疗性放射性药物，我们提出三个目标 新的化学和体内验证的策略，可以使高产，高摩尔活性，低温 遗传性放射性药物的放射化学方法。