A High Separation Factor for Er from Ho for Targeted Radionuclide Therapy.

Radionuclides emitting Auger electrons (AEs) with low (0.02-50 keV) energy, short (0.0007-40 µm) range, and high (1-10 keV/µm) linear energy transfer may have an important role in the targeted radionuclide therapy of metastatic and disseminated disease. Erbium-165 is a pure AE-emitting radionuclide that is chemically matched to clinical therapeutic radionuclide Lu, making it a useful tool for fundamental studies on the biological effects of AEs. This work develops new biomedical cyclotron irradiation and radiochemical isolation methods to produce Er suitable for targeted radionuclide therapeutic studies and characterizes a new such agent targeting prostate-specific membrane antigen. Biomedical cyclotrons proton-irradiated spot-welded Ho targets to produce Er, which was isolated via cation exchange chromatography (AG 50W-X8, 200-400 mesh, 20 mL) using alpha-hydroxyisobutyrate (70 mM, pH 4.7) followed by LN2 (20-50 µm, 1.3 mL) and bDGA (50-100 µm, 0.2 mL) extraction chromatography. The purified Er was radiolabeled with standard radiometal chelators and used to produce and characterize a new AE-emitting radiopharmaceutical, [Er]PSMA-617. Irradiation of 80-180 mg Ho targets with 40 µA of 11-12.5 MeV protons produced Er at 20-30 MBq·µA·h. The 4.9 ± 0.7 h radiochemical isolation yielded Er in 0.01 M HCl (400 µL) with decay-corrected (DC) yield of 64 ± 2% and a Ho/Er separation factor of (2.8 ± 1.1) · 10. Radiolabeling experiments synthesized [Er]PSMA-617 at DC molar activities of 37-130 GBq·µmol. A 2 h biomedical cyclotron irradiation and 5 h radiochemical separation produced GBq-scale Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutics. This will enable fundamental radiation biology experiments of pure AE-emitting therapeutic radiopharmaceuticals such as [Er]PSMA-617, which will be used to understand the impact of AEs in PSMA-targeted radionuclide therapy of prostate cancer.