A suitable time point for quantifying the radiochemical purity of 225Ac-labeled radiopharmaceuticals

James M Kelly; Alejandro Amor-Coarasa; Elizabeth Sweeney; Justin J Wilson; Patrick W Causey; John W Babich

doi:10.1186/s41181-021-00151-y

A suitable time point for quantifying the radiochemical purity of ²²⁵Ac-labeled radiopharmaceuticals

EJNMMI Radiopharm Chem. 2021 Dec 20;6(1):38. doi: 10.1186/s41181-021-00151-y.

Authors

James M Kelly¹, Alejandro Amor-Coarasa², Elizabeth Sweeney³, Justin J Wilson⁴, Patrick W Causey⁵, John W Babich^{6

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Affiliations

¹ Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY, 10065, USA.
² Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
³ Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, 10065, USA.
⁴ Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 14853, USA.
⁵ Canadian Nuclear Laboratories, Chalk River, ON, K0J 1J0, Canada.
⁶ Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY, 10065, USA. jwbabich@gmail.com.
⁷ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA. jwbabich@gmail.com.
⁸ Department of Radiology, Citigroup Biomedical Imaging Center, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 E 69th St, New York, NY, 10021, USA. jwbabich@gmail.com.

Abstract

Background: As ²²⁵Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and QC testing. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an ²²⁵Ac-labeled radiopharmaceutical can be accurately quantified.

Results: Six ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP for any pre-equilibrium measurement taken at an early time point. The 585 TLC measurements span RCP values of 1.8-99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. A measurement of RCP > 90% at 2 h predicts a true RCP > 97% and guarantees that RCP will exceed 90% after secular equilibrium is reached. These findings were independently validated using NaI(Tl) scintillation counting and high resolution gamma spectroscopy on a smaller set of samples with 10% ≤ RCP ≤ 100%.

Conclusions: RCP of ²²⁵Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC using various methods of quantifying particle emissions. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.

Keywords: Ac-225; Quality control; Radiopharmacy; Targeted alpha therapy.