Harnessing scandium chelation chemistry for the development of radiopharmaceuticals

美国食品和药物管理局最近批准的68Ga显影放射性药物及其177Lu辅助疗法 强调金属放射性同位素在诊断和治疗核方面的临床应用潜力 医药。68Ga、177Lu以上放射性金属加速器生产的改进 Stheranostic Pair已经开启了生产具有广泛半衰期和发射范围的放射性金属的机会 属性，扩大了可成像疾病目标的范围。然而，随后的临床发展 可应用的放射性药物由于对水的配位作用的认识存在很大差距而受到阻碍 相应的金属离子的化学。Sc(III)水化学就是一个很好的例子 难解之谜。43Sc(Eβ平均值=476keV，t1/2=3.9h)和44Sc(Eβ平均值=632keV，t1/2=4h)具有理想的 注射后24小时内进行正电子发射断层扫描(PET)。对于治疗应用，排放物 47Sc的性质(Eβ−平均值=162keV，t1/2=80.4h)与177Lu(Eβ−平均值=134keV，t1/2=159.6h)相当。这个 Sc(III)离子在离子半径和化学硬度方面与Lu(III)离子非常接近，因此 43Sc/44Sc也是已经广泛获得的177Lu疗法的理想诊断同位素合作伙伴 同位素，为放射治疗产生更直接的预测图像衍生的药代动力学和剂量学。 然而，明显的溶液化学知识的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。为了能够合成范围广泛的 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的策略，使高产、高摩尔活性、低温 治疗用放射性药物的放射化学方法。

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.