Synthesis of [211At]4-astato-L-phenylalanine by dihydroxyboryl-astatine substitution reaction in aqueous solution

Abstract

Astatine-211 (211At)-labeled phenylalanine is expected to be a promising agent for targeted alpha-particle therapy for the treatment of patients with glioma. The existing reactions to prepare the labeled compound usually require organic solvents and metals that are toxic and hazardous to the environment. In this study, we developed a novel method wherein astatination was realized via the substitution of 211At for a dihydroxyboryl group coupled to phenylalanine. [211At]4-astato-L-phenylalanine was obtained as the carrier-free product in aqueous medium in high radiochemical yields (98.1 ± 1.9%, n = 5). The crude reaction mixture was purified by solid-phase extraction, and the radiochemical purity of the product was 99.3 ± 0.7% (n = 5). The high yield and purity were attributed to the formation of [211At]AtI and AtI2− as the reactive intermediates in the astatination reaction. The reaction did not require any organic solvents or toxic reagents, suggesting that this method is suitable for clinical applications.

Complexation of Astatine(III) with Ketones: Roles of NO3–Counterion and Exploration of Possible Binding Modes

“…Furthermore, our experimental results on D At in 3-octanone as a function of NO 3 – concentration suggest a 1:1 ratio of the astatine species with NO 3 – ; so, hydrolyzed At­(III) species such as AtO­(OH) should contribute very little to the extraction, and we expect AtO­(NO 3 ) to be the major astatine species being extracted. In addition, although astatine has been found to react with aromatic compounds, ,− the reaction is usually very slow, except for a phenyl ring with specific activating substituents. Additional evidence against a specific phenyl reaction or interaction comes from the observation that K ext values for 3-octanone (5.2) and acetophenone (8.3), which are of similar molecular weight, are in the same order of magnitude, suggesting that the extraction mechanism for aliphatic ketones and aromatic ketones should be similar.…”

Targeted α-therapy using astatine (211At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound

“…Precursor molecules of PSMA1, PSMA5, and PSMA6 were synthesized based on solid-phase peptide synthesis by Peptide Institute, Inc. (Osaka, Japan). 211 At was produced by a nuclear reaction of 209 Bi(α, 2n) 211 At using a cyclotron and purified by a dry distillation method, providing the aqueous solution of 211 At (0.1-1 MBq/μL) [20]. 211 At-labeled PSMA1, PSMA5, and PSMA6 were synthesized by the substitution reaction of 211 At with the dihydroxyboryl groups introduced to the corresponding precursor molecules, as described in a previous paper [20].…”

“…gov Identifier: NCT05275946) is in progress [19]. We also developed a novel labeling method using the substitution reaction of 211 At with dihydroxyboryl groups [20]. Moreover, we developed a newly designed precursor based on the structure of [ 18 F]PSMA-1007, which we believe is suitable for 211 At-labeling [21].…”

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

“…Nucleophilic halogen exchange (iodine for iodine) reactions are regularly used for the incorporation of radioiodine into organic molecules, with inorganic salts (ammonium sulfate) or copper (II) salts often being added to catalyze the iodine exchange. Notably, a naturally stable isotope of astatine does not exist, and, therefore, halogen exchange using astatine-211 would require the iodo- or bromo- derivatives [ 279 ]. However, this approach is unable to yield a pure, astatinated product since the unreacted iodo- or bromo-starting compounds cannot be removed.…”

“…However, this approach is unable to yield a pure, astatinated product since the unreacted iodo- or bromo-starting compounds cannot be removed. Therefore, astatination reactions generally occur through electrophilic substitution reactions in the presence of oxidants, with a new method developed using the substitution of a dihydroxyboryl group [ 279 , 280 ]. When radiohalogenating the abovementioned DDRi, the effect that the larger halogen will have on the modified molecule may also result in altered biological properties.…”