High Separation Factor, High Molar Activity, and Inexpensive Purification Method for the Production of Pure ¹⁶⁵Er.

Abstract

<b>Introduction</b>: Auger electron-emitting radionuclides with low (0.001-1 keV) energy, short-range (2-500 nm), and high linear energy transfer (4-26 keV/μm) can play an important role in the targeted radionuclide therapy (TRT) of cancer. ¹⁶⁵Er is a pure Auger electron-emitting radionuclide, making it a useful tool for the fundamental studies of the biological effects of Auger electrons. This work develops a simple, inexpensive, high separation factor, and high molar activity radiochemical isolation process for the production of ¹⁶⁵Er (<i>t</i>_1/2 10.36 h) suitable for TRT in vitro and in vivo studies using irradiated ^natHo solid targets. <b>Methods</b>: Small medical cyclotron proton-irradiation of ^natHo targets produced ¹⁶⁵Er in GBq scale quantities. ¹⁶⁵Er was isolated using cation exchange chromatographic resin (AG 50W-X8, 200-400 mesh, 20 mL, under atmospheric pressure) using α-hydroxyisobutyric acid (70 mM, pH 4.75) followed by extraction using TK212, TK211, and TK221 extraction chromatographic columns. Radio nuclidic and chemical purity of the final ¹⁶⁵Er were confirmed using HPGe Gamma spectrometry and induction coupled plasma-mass spectrometry analysis, respectively. The purified ¹⁶⁵Er was radiolabeled with two radiometal chelators (DOTA and Crown) and used to produce a new Auger electron-emitting radiopharmaceutical, [¹⁶⁵Er]Er-Crown-TATE. <b>Results</b>: Irradiation of 200 mg ^natHo targets with 20-30 μA of 12.8 MeV protons produced ¹⁶⁵Er at 25 ± 5 MBq·μA^-1·h^-1. The 4.5 ± 0.5 h radiochemical isolation yielded GBq scale of ¹⁶⁵Er in 0.05 M HCl (2 mL) with a radiochemical yield of 78.0 ± 5.6% decay corrected to the end of bombardment (EoB) and a Ho/¹⁶⁵Er separation factor of (1.14 ± 0.25) × 10⁶. The product showed high radio nuclidic purity and chemical purity. Concentration-dependent radiolabeling experiments with Crown and DOTA were performed resulting in the successful labeling of ¹⁶⁵Er with high (>90%) radiochemical yield. Radiolabeling experiments with Crown-TATE were performed 8 h after EoB and synthesized [¹⁶⁵Er]Er-Crown-TATE at molar activities of 202.4 MBq·nmol^-1 at the end of synthesis (EoS). <b>Conclusions</b>: A 3 h cyclotron irradiation and 4.5 h radiochemical separation produced GBq-scale ¹⁶⁵Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutic effects of Auger electron emissions. This will enable future fundamental radiation biology experiments of pure Auger electron-emitting therapeutic radiopharmaceuticals, such as [¹⁶⁵Er]Er-Crown-TATE, which will be used to understand the impact of Auger electrons in TRT.