Pozzi Oscar R, Zalutsky Michael R
Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA.
J Nucl Med. 2005 Aug;46(8):1393-400.
A variety of promising targeted radiotherapeutics labeled with alpha-emitters have been developed. Clinical investigation of these radiopharmaceuticals requires the production of high activity levels, which can be hindered by alpha-particle-mediated radiolytic effects on labeling chemistry. The purpose of this study was to investigate the effects of radiation dose on the synthesis of N-succinimidyl 3-(211)At-astatobenzoate (SAB), a compound used in our clinical trials for labeling antibodies with alpha-particle-emitting (211)At.
Yields for the synthesis of SAB as a function of the radiation dose received by the reaction medium were determined. The variables studied included the radiohalogenation precursors N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB) and N-succinimidyl 3-(trimethylstannyl)benzoate (MeSTB); the solvents chloroform, benzene, and methanol; and the addition of acetic acid and the oxidant N-chlorosuccinimide. The (211)At product spectra were determined from high-performance liquid chromatograms and then plotted against radiation dose.
SAB production declined rapidly with increasing dose, consistent with the documented radiolytic decomposition of BuSTB and MeSTB in chloroform. Even though these tin precursors were not appreciably degraded in benzene, SAB could not be produced in this solvent; instead, highly lipophilic (211)At-labeled species were generated in nearly quantitative yields. Although a dose-dependent decline in SAB yield also was observed in methanol, both in the presence and in the absence of an oxidant, the results were better than those obtained with the other solvents. An unexpected observation was that SAB could be obtained at a yield of greater than 30% when the reaction was run in methanol without the addition of acetic acid or an oxidant; these 2 components previously were considered essential for astatodestannylation.
Radiolytic factors can play an important role in the synthesis of clinical-level activities of (211)At-labeled radiopharmaceuticals, necessitating the development of reaction conditions different from those that are used successfully at lower activity levels.
已经开发出多种用α发射体标记的有前景的靶向放射治疗剂。这些放射性药物的临床研究需要产生高活性水平，而α粒子介导的对标记化学的辐射分解作用可能会阻碍这一点。本研究的目的是研究辐射剂量对N-琥珀酰亚胺基3-（211）砹-苯甲酸酯（SAB）合成的影响，SAB是我们临床试验中用于用发射α粒子的（211）砹标记抗体的化合物。
测定SAB合成产率与反应介质所接受辐射剂量的函数关系。研究的变量包括放射性卤化前体N-琥珀酰亚胺基3-（三正丁基锡基）苯甲酸酯（BuSTB）和N-琥珀酰亚胺基3-（三甲基锡基）苯甲酸酯（MeSTB）；溶剂氯仿、苯和甲醇；以及乙酸和氧化剂N-氯代琥珀酰亚胺的添加。从高效液相色谱图确定（211）砹产物光谱，然后绘制其与辐射剂量的关系图。
随着剂量增加，SAB产量迅速下降，这与文献报道的BuSTB和MeSTB在氯仿中的辐射分解一致。尽管这些锡前体在苯中没有明显降解，但在这种溶剂中无法产生SAB；相反，产生了几乎定量产率的高亲脂性（211）砹标记物种。尽管在甲醇中，无论有无氧化剂，都观察到SAB产率随剂量下降，但结果优于其他溶剂。一个意外的发现是，当反应在甲醇中进行而不添加乙酸或氧化剂时，可以获得产率大于30%的SAB；这两种成分以前被认为是脱锡反应所必需的。
辐射分解因素在（211）砹标记放射性药物临床水平活性的合成中可能起重要作用，因此需要开发不同于在较低活性水平下成功使用的反应条件。
