Production of GMP-Compliant Clinical Amounts of Copper-61 Radiopharmaceuticals from Liquid Targets

Abstract

PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, Emax = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of 61Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [61Cu]Cu-DOTA-NOC, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based radiopharmaceuticals.

Antibody and Nanobody Radiolabeling with Copper-64: Solid vs. Liquid Target Approach

“…Copper-64 automatic purification was conducted following the previously published methodology [ 15 , 16 , 29 ] using the Synthera ® Extension module (IBA, Louvain-la-Neuve, Belgium) and a dedicated disposable cassette, without any manual intervention. The purification process was completed within a maximum of 60 min from the EOB.…”

“…The published protocol was followed with minor changes [29]. Briefly, 250 µL of the final purified solution containing each radiolabeled 64 Cu-conjugated compound under study was added to 500 µL of each medium (PBS, DTPA 50 mM, or mice serum), and the mixtures were incubated at 37 • C. At different time points, aliquots were taken and measured using the iTLC methods.…”

Recent Advances in 64Cu/67Cu-Based Radiopharmaceuticals

“…However, these theranostic couples have several disadvantages. The use of the 68 Ga/ 177 Lu theranostic pair is limited by the fact that gallium-68 generators are gradually being phased out by more cost-effective accelerator-based production, due to higher amounts of specific activity and no waiting required between productions, unlike the required 3-4 h interval between isotope elutions from portative generators [61]. 124 I, widely used in medical practice, has an accompanying positron gamma radiation, which complicates PET diagnosis due to false signal emerging and distortion of PET results [62,63].…”

“…Copper is a metal essential to human health, and it is a constituent of many enzymes [65]. Natural copper has two stable isotopes, 63 Cu and 65 Cu, and five radioisotopes, 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 Cu. Two of these isotopes, namely 64 Cu and 67 Cu, are considered therapeutic β-emitters for targeted radiation therapy.…”

Special Issue “In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research”

“…The utilization of the produced copper-61 was demonstrated by a fully automated GMP-compliant production of three radiopharmaceuticals labeled with gallium-68 in clinical practice. Copper-61 may serve as an alternative radionuclide to the widely used gallium-68 [ 16 ].…”