Bryce J.B. Nelson , Samantha Leier , John Wilson , Melinda Wuest , Jonathan Doupe , Jan D. Andersson , Frank Wuest
{"title":"64Cu production via the 68Zn(p,nα)64Cu nuclear reaction: An untapped, cost-effective and high energy production route","authors":"Bryce J.B. Nelson , Samantha Leier , John Wilson , Melinda Wuest , Jonathan Doupe , Jan D. Andersson , Frank Wuest","doi":"10.1016/j.nucmedbio.2024.108875","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>Copper-64 (<sup>64</sup>Cu, t<sub>1/2</sub> = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting <sup>67</sup>Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of <sup>64</sup>Cu produced via the <sup>68</sup>Zn(p,nα)<sup>64</sup>Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified <sup>64</sup>Cu and tested for in vitro stability. [<sup>64</sup>Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using <sup>64</sup>Cu synthesized via the <sup>68</sup>Zn(p,nα)<sup>64</sup>Cu production route and its suitability as a theranostic imaging partner alongside <sup>67</sup>Cu therapy.</p></div><div><h3>Methods</h3><p><sup>64</sup>Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg <sup>68</sup>Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. <sup>64</sup>Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. <sup>64</sup>Cu incorporation was studied by radio-TLC. <sup>64</sup>Cu in vitro stability of [<sup>64</sup>Cu]Cu-NOTA, [<sup>64</sup>Cu]Cu-DOTA, [<sup>64</sup>Cu]Cu-TETA, and [<sup>64</sup>Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [<sup>64</sup>Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [<sup>68</sup>Ga]Ga-PSMA I&T.</p></div><div><h3>Results</h3><p>Maximum purified activity of 4.9 GBq [<sup>64</sup>Cu]CuCl<sub>2</sub> was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq <sup>64</sup>Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified <sup>64</sup>Cu detected <0.3 % co-produced <sup>67</sup>Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [<sup>64</sup>Cu]CuCl<sub>2</sub> product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with <sup>64</sup>Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUV<sub>mean</sub> = 1.65 ± 0.1) using [<sup>64</sup>Cu]Cu-PSMA I&T, while [<sup>68</sup>Ga]Ga-PSMA I&T yielded an SUV<sub>mean</sub> of 0.76 ± 0.14 after 60 min post-injection.</p></div><div><h3>Conclusions</h3><p><sup>64</sup>Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The <sup>64</sup>Cu production and purification process and the favourable PET imaging properties confirm the <sup>68</sup>Zn(p,nα)<sup>64</sup>Cu nuclear reaction as a viable <sup>64</sup>Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive <sup>64</sup>Ni target material and the <sup>64</sup>Ni(p,n)<sup>64</sup>Cu nuclear reaction.</p></div><div><h3>Advances in knowledge and implications for patient care</h3><p>Our <sup>64</sup>Cu production technique provides an alternative production route with the potential to improve <sup>64</sup>Cu availability for preclinical and clinical studies alongside <sup>67</sup>Cu therapy.</p></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"128 ","pages":"Article 108875"},"PeriodicalIF":3.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969805124000015/pdfft?md5=9350690548ff58e91789b923da52daf5&pid=1-s2.0-S0969805124000015-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nuclear medicine and biology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969805124000015","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
引用次数: 0
Abstract
Introduction
Copper-64 (64Cu, t1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy.
Methods
64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T.
Results
Maximum purified activity of 4.9 GBq [64Cu]CuCl2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUVmean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUVmean of 0.76 ± 0.14 after 60 min post-injection.
Conclusions
64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction.
Advances in knowledge and implications for patient care
Our 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy.
期刊介绍:
Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized.
These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field.
Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.