Abstract
2358
Introduction: Halodeboronation of borates is an integral part of radiohalide chemistry and allows for the synthesis of radiopharmaceuticals used for imaging and therapy. Several approaches have been developed for iodo-, bromo-, and chlorodeboronation, both metal-promoted and transition metal-free; using molecular halogens (X2) or their electrophilic cationic forms (X+). However, less research has been done to investigate astatodeboronation, especially transition metal-free processes. The short half-life (7.2 hours) of 211At and lack of stable isotopes hinders research and achieving different oxidation states of 211At is more complex - being heavily influenced by the purification methods used to obtain the astatine compared to the designer reagents available for other halogens.
Investigation of radiolabeling methods for 211At has practical purposes - with 211At having significant applications as a α-emitter for targeted α-therapy thanks to its high linear energy transfer and half-life allowing enough time to radiolabel small molecules or antibodies. Iodine is often employed as an analog for astatine - being its closest related halogen and having both: a stable isotope and long-lasting radioisotopes such as 125I (59.5 days) for radiolabeling comparisons. This method of investigating astatine has its limitations.
To elucidate the ideal conditions for astatodeboronation, we screened two previously reported radiolabeling methods: a metal-promoted labeling of boronic acids (BOH) and pinacol esters (Bpin) using 211At and 125I, and a transition metal-free labeling of boronic acids using 125I. Each feasible factor from the two methods was investigated using a two-level full-factorial screen to analyze their performance for astatodeboronation and iododeboronation using Bpin and BOH to determine which had the greatest impact on the radiolabeling.
Methods: 211At was produced onsite using a JSW BC3015 cyclotron - via the α-particle bombardment of 209Bi. 211At was separated from the irradiated targets by dry distillation and trapped in a solvent trap of pure acetonitrile. The transition metal-free and metal-promoted labeling methods were separated into 5 and 4 factors each respectively. Trifluoromethyl phenyl-BOH and Bpin were used as the aryl molecule to be labeled, with both the para- and meta- isomers being used to account for the substituents directing effects. The factors considered for the transition metal-free labeling were: reductant, oxidant, NaOH, KOAc, and heat. The metal-promoted labeling was performed with tetrakis(pyridine)copper(II) triflate, along with the factors: reductant, water, NaOH, and heat. The two levels for each factor were either absent or present in the reaction. Yields were calculated using high-performance liquid chromatography (HPLC) analysis.
Results:
Transition metal-free labeling with 125I required the presence of the oxidant to label the substrate; with the additional presence of the reductant improving the yield further. 211At was more flexible in regard to the conditions it could radiolabel under - with almost all conditions
resulting in product being formed. The astatodeboronation of para-BOH had the highest yield with the oxidant present and the reductant absent, while meta-BOH required the reductant present without the oxidant for its ideal labeling condition. Astatination overall benefited from heating the reactions in comparison to iodination which did not have a consistent effect when heated.
Transition metal-promoted labeling had a higher average yield for both isotopes compared to the metal-free conditions. Iodinations with a metal catalyst had favorable reactions across all conditions, with the presence of the reductant resulting in the highest yields. Astatine again benefited from heating reactions across all conditions and was hindered by the presence of the reductant. Astatinations were more successful when labeling the BOH reactants versus the Bpin.
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