Facilitating PET Imaging: Eco-Friendly Purification Using Solid-Phase Material for Labeling Metal-Based Radiopharmaceuticals

Abstract

Radiopharmaceuticals rely on radioactive isotopes for diagnosis and therapy, particularly in positron emission tomography (PET), but removing excess radiometals to ensure biosafety and imaging quality is a time-consuming process that causes radiotracer decay, while organic eluents might cause health hazards. In this study, we present a solid-phase material, NOTA-resin, which enables efficient radiometal removal (clearance rate >97% in 4 min) in a single step, at room temperature, and without organic solvents. Furthermore, we have validated the practicability of NOTA-resin in tumor-bearing mice models, demonstrating its compatibility with commercial radiotracers without adverse effects on tumor targeting and PET imaging quality while significantly shortening processing times, saving resources, and reducing waste.

Keywords: green chemistry; positron emission tomography; postradiolabeling purification; radiopharmaceuticals; solid phase extraction.

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Concept of NOTA-resin purification compared to conventional SPE.

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(A) Schematic diagram of postlabeling purification using the conventional SPE method (top) and the NOTA-resin treatment method (bottom). (B) Synthetic route of NOTA-resin, i. BrCH₂COOH, DIC, DMF, r.t., 1 h; ii. TACN, DCM, 18 h; iii. tert-butyl chloroacetate, DIPEA, DMF, r.t., 36 h; iv. 95% TFA, 2.5% TIPS, 2.5% H₂O. (C) Molecular structure of the solid support (resin). (D) SEM images of the NOTA-resin.

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(A) Physical appearance of NOTA-resin and unmodified resin during treatment of 25 mM CuSO₄ solution. (B) FTIR spectra of unmodified resin, NOTA-resin, and Ga-NOTA-resin. i: N–H stretching; ii: carbonyl stretching; iii: amide III vibration. (C) Absorption spectra of 25 mM CuSO₄ solution treated by NOTA-resin and unmodified resin. Compatibility of NOTA-resin with (D) a Ga-NOTA derivative and (E) a Ga-DOTA derivative was evaluated by the amount of recovered complexes after NOTA-resin treatment followed by water washing. Quantification was performed on the recovery of the respective complexes and monitored by HPLC. (D: red line, recovery of Ga-NOTA-YRGD; orange line, cumulative recovery of Ga-NOTA-YRGD. E: Blue line, recovery of Ga-DOTATATE-amide; green line, cumulative recovery of Ga-DOTATATE-amide.)

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Radio-HPLC chromatograms of the postradiolabeling solution: (A) unpurified and (B) purified by mixing with NOTA-resin for 3 min. (C) Tumor-to-background PET signal intensity ratios calculated from the corresponding PET/CT images. PET/CT images of AR42J-tumor-bearing mice 1 h postinjection of ⁶⁸Ga-DOTA-NOC radiotracer, which was purified using (D) NOTA-resin, (E) C18 SPE column, or (F) C18 SPE column with additional ⁶⁸GaCl₃ added to simulate unpurified solution.