III-3. Radiochemistry & Nuclear Chemistry

RIKEN Accel. Prog. Rep. 55 (2022)

RIKEN Accel. Prog. Rep. 55 (2022)

Synthesis of [211 At]4-astato-L-phenylalanine bydihydroxyboryl-astatine substitution reaction in aqueous solution†
Y. Shirakami,∗1 T. Watabe,∗2 H. Obata,∗3 K. Kaneda,∗1 K. Ooe,∗2 Y. Liu,∗2 T. Teramoto,∗1 A. Toyoshima,∗1A. Shinohara,∗1 E. Shimosegawa,∗2 J. Hatazawa,∗1 and K. Fukase∗3
Radiopharmaceutical therapy, including targetedalpha-particle therapy (TAT), has recently emerged asa novel therapeutic modality for the treatment of tumor. We previously demonstrated the utility of [211 At]4astato-L-phenylalanine ([211 At]APA) for the treatmentof glioma in tumor-bearing mice by means of TAT.1)[211 At]APA speciﬁcally accumulates in tumor cells andare transported by the LAT1 transporters, which arepredominantly expressed on the surface of various tumor cells including the glioma cells. In a mouse model
xenografted with rat glioma cells, [211 At]APA signiﬁcantly decreased the tumor volume after a single injection of the agent (dose range: 0.1–1.0 MBq/mouse) inthe mouse.
Phenylalanine has been previously labeled with 211 At
using diﬀerent methods.2,3) However, most of the existing reactions for the synthesis of radiolabeled compounds either require the use of toxic and hazardous chemicals or are unable to yield a carrier-free ﬁnal product.
We have developed a new and improved methodfor the preparation of [211 At]APA using 4-boronoL-phenylalanine (BPA) as the starting molecule.
[211 At]APA was synthesized by the electrophilic substitution of 211 At for a dihydroxyboryl (or borono)group on an aromatic ring of the corresponding precursor molecule BPA using N-bromosuccinimde (NBS;NBS method) as an oxidant or KI (KI method) as
shown in Fig. 1. The radiochemical yield (RCY) andradiochemical purity (RCP) were better with the latter method. The reagents and compounds used forthe synthesis of [211 At]APA were commercially approved drugs and physiologically relevant for clinical use. The entire synthesis could be accomplishedin aqueous media; no organic solvents or toxic metals were required, suggesting that this method isrelevant for practical applications.
We also elucidated the diﬀerences between the chemical properties of iodine and astatine for the labeling reactions.
Based on our ﬁndings, the reaction scheme for the211
At labeling of arylboronic acids is depicted in Fig. 2.
In the NBS method, 211 At initially reacts with NBS toform the [211 At]astatosuccinimide intermediate (Fig. 2,top). Then, [211 At]astatosuccinimide reacts with thearylboronic acid to produce [211 At]arylastatide. In theKI method, 211 At reacts with KI to form the [211 At]AtIand/or AtI−Several
2 intermediate (Fig. 2, bottom).
†∗1∗2∗3Condensed from the article in Sci. Rep. 11, 12982 (2021)
Institute for Radiation Sciences, Osaka University
Department of Tracer Kinetics and Nuclear Medicine, Graduate school of Medicine, Osaka University
Department of Chemistry, Graduate School of Science, OsakaUniversity

OO
OH
HOB
OH

NH2

211At aq. soln.

KI or NBS, RTOH
211

At

NH2

[211At]APA

BPA

Fig. 1. Radioastatination reaction of boronophenylalanine.

NBS[211At]N-Astatosuccinimde

211At Aq. soln.

KI[211At]AtI orAtI2-Arylboronicacid
Ascorbic acid
Arylboronicacid[211At]Arylastatide[211At]Arylastatide

Fig. 2. Mechanism of astatination of arylboronic acids.

studies have suggested that astatine can react with iodide and produce inter-halogen compounds such as AtI4)
and AtI−
The AtI and/or AtI−
2.
2 intermediate reacts
with the arylboronic acid to give [211 At]arylastatide.
Compared to NBS, KI was found to be more eﬃcientfor the substitution of the dihydroxyboryl group by astatine in the aqueous media. KI can probably reduce
the hypervalent 211 At species present in the aqueous solution (∼10%), forming the reactive [211 At]AtI and/orAtI−
2 intermediate that allows higher RCYs comparedto that obtained using the NBS method.
KI was originally intended to be used as the carrier
atom of 211 At since there are no natural stable isotopesof astatine. Unexpectedly, the radiolabeling yield of[211 At]APA using KI was much higher than 95%, due
to the formation of [211 At]AtI and/or AtI−
2 as a reaction
intermediate in the aqueous solution.
It is well known that tyrosine can be labeled withradioactive iodine via an electrophilic substitution reaction in the presence of an oxidant, such as chloramine
T, Iodogen, N -chlorosuccinimde, NBS, or H2 O2 . Astatination of tyrosine, however, gave a low yield of [211 At]
astatotyrosine (<15%) with H2 O2 , and the product wasunstable under neutral and basic conditions. Additionally, the labeling yield was low. These results were suggestive of the diﬀerent chemical properties of astatine
and iodine.
In summary, we developed a novel method for the synthesis and puriﬁcation of [211 At]APA, which has potential clinical uses.
References
1) T. Watabe et al., Oncotarget 11, 1388 (2020).
2) G. J. Meyer et al., Appl. Radiat. Isot. 68, 1060 (2010).
3) N. Borrmann et al., Nuklearmedizin 52, 212 (2013).
4) G. W. Visser et al., Int. J. Appl. Radiat. Isot. 32, 905(1981).

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