EJNMMI Radiopharmacy and Chemistry最新文献

Background

Transglutaminase 2 (TGase 2) is a multifunctional protein and has a prominent role in various (patho)physiological processes. In particular, its transamidase activity, which is rather latent under physiological conditions, gains importance in malignant cells. Thus, there is a great need of theranostic probes for targeting tumor-associated TGase 2, and targeted covalent inhibitors appear to be particularly attractive as vector molecules. Such an inhibitor, equipped with a radionuclide suitable for noninvasive imaging, would be supportive for answering the general question on the possibility for functional characterization of tumor-associated TGase 2. For this purpose, the recently developed ¹⁸F-labeled N^ε-acryloyllysine piperazide [¹⁸F]7b, which is a potent and selective irreversible inhibitor of TGase 2, was subject to a detailed radiopharmacological characterization herein.

Results

An alternative radiosynthesis of [¹⁸F]7b is presented, which demands less than 300 µg of the respective trimethylammonio precursor per synthesis and provides [¹⁸F]7b in good radiochemical yields (17 ± 7%) and high (radio)chemical purities (≥ 99%). Ex vivo biodistribution studies in healthy mice at 5 and 60 min p.i. revealed no permanent enrichment of ¹⁸F-activity in tissues with the exception of the bone tissue. In vivo pretreatment with ketoconazole and in vitro murine liver microsome studies complemented by mass spectrometric analysis demonstrated that bone uptake originates from metabolically released [¹⁸F]fluoride. Further metabolic transformations of [¹⁸F]7b include mono-hydroxylation and glucuronidation. Based on blood sampling data and liver microsome experiments, pharmacokinetic parameters such as plasma and intrinsic clearance were derived, which substantiated the apparently rapid distribution of [¹⁸F]7b in and elimination from the organisms. A TGase 2-mediated uptake of [¹⁸F]7b in different tumor cell lines could not be proven. Moreover, evaluation of [¹⁸F]7b in melanoma tumor xenograft models based on A375-hS100A4 (TGase 2 +) and MeWo (TGase 2 −) cells by ex vivo biodistribution and PET imaging studies were not indicative for a specific targeting.

Conclusion

[¹⁸F]7b is a valuable radiometric tool to study TGase 2 in vitro under various conditions. However, its suitability for targeting tumor-associated TGase 2 is strongly limited due its unfavorable pharmacokinetic properties as demonstrated in rodents. Consequently, from a radiochemical perspective [¹⁸F]7b requires appropriate structural modifications to overcome these limitations.

Background

Silver-111 is a promising β⁻-emitting radioisotope with ideal characteristics for targeted radionuclide therapy and associated single photon emission tomography imaging. Its decay properties closely resemble the clinically established lutetium-177, making it an attractive candidate for therapeutic applications. In addition, the clinical value of silver-111 is further enhanced by the existence of the positron-emitting counterpart silver-103, thus imparting a truly theranostic potential to this element. A so-fitting matching pair could potentially overcome the current limitations associated with the forced use of chemically different isotopes as imaging surrogates of lutetium-177, leading to more accurate and efficient diagnosis and treatment. However, the use of silver-111-based radiopharmaceuticals in vivo has faced obstacles due to the challenges related to its production and radiochemical separation from the target material. To address these issues, this study aims to implement a chromatographic separation methodology for the purification of reactor-produced silver-111. The ultimate goal is to achieve a ready-to-use formulation for the direct radiolabeling of tumour-seeking biomolecules.

Results

A two-step sequence chromatographic process was validated for cold Ag-Pd separation and then translated to the radioactive counterpart. Silver-111 was produced via the ¹¹⁰Pd(n,γ)¹¹¹Pd nuclear reaction on a natural palladium target and the subsequent β⁻-decay of palladium-111. Silver-111 was chemically separated from the metallic target via the implemented chromatographic process by using commercially available LN and TK200 resins. The effectiveness of the separations was assessed by inductively coupled plasma optical emission spectroscopy and γ-spectrometry, respectively, and the Ag⁺ retrieval was afforded in pure water. Recovery of silver-111 was > 90% with a radionuclidic purity > 99% and a separation factor of around 4.21·10⁻⁴.

Conclusions

The developed separation method was suitable to obtain silver-111 with high molar activity in a ready-to-use water-based formulation that can be directly employed for the labeling of radiotracers. By successfully establishing a robust and efficient production and purification method for silver-111, this research paves the way for its wider application in targeted radionuclide therapy and precision imaging.

Background

The demand for ⁶⁸Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, ⁶⁸Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([⁶⁸Ga]Ga-FAPI-46) in late-phase studies, whereas [⁶⁸Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.

Results

Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [⁶⁸Ga]Ga-FAPI-46 and 46 ± 7% for [⁶⁸Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including ⁶⁸Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.

Conclusions

The microfluidic-based approach enabled the implementation of radiosynthesis of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2–3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [⁶⁸Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.

Background

The Affibody molecule, ABY-025, has demonstrated utility to detect human epidermal growth factor receptor 2 (HER2) in vivo, either radiolabelled with indium-111 (¹¹¹In) or gallium-68 (⁶⁸Ga). Using the latter, ⁶⁸Ga, is preferred due to its use in positron emission tomography with superior resolution and quantifying capabilities in the clinical setting compared to ¹¹¹In. For an ongoing phase II study (NCT05619016) evaluating ABY-025 for detecting HER2-low lesions and selection of patients for HER2-targeted treatment, the aim was to optimize an automated and cGMP-compliant radiosynthesis of [⁶⁸Ga]Ga-ABY-025.

[⁶⁸Ga]Ga-ABY-025 was produced on a synthesis module, Modular-Lab PharmTracer (Eckert & Ziegler), commonly used for ⁶⁸Ga-labelings. The radiotracer has previously been radiolabeled on this module, but to streamline the production, the method was optimized. Steps requiring manual interactions to the radiolabeling procedure were minimized including a convenient and automated pre-concentration of the ⁶⁸Ga-eluate and a simplified automated final formulation procedure. Every part of the radiopharmaceutical production was carefully developed to gain robustness and to avoid any operator bound variations to the manufacturing. The optimized production method was successfully applied for ⁶⁸Ga-labeling of another radiotracer, verifying its versatility as a universal and robust method for radiosynthesis of Affibody-based peptides.

Results

A simplified and optimized automated cGMP-compliant radiosynthesis method of [⁶⁸Ga]Ga-ABY-025 was developed. With a decay corrected radiochemical yield of 44 ± 2%, a radiochemical purity (RCP) of 98 ± 1%, and with an RCP stability of 98 ± 1% at 2 h after production, the method was found highly reproducible. The production method also showed comparable results when implemented for radiolabeling another similar peptide.

Conclusion

The improvements made for the radiosynthesis of [⁶⁸Ga]Ga-ABY-025, including introducing a pre-concentration of the ⁶⁸Ga-eluate, aimed to utilize the full potential of the ⁶⁸Ge/⁶⁸Ga generator radioactivity output, thereby reducing radioactivity wastage. Furthermore, reducing the number of manually performed preparative steps prior to the radiosynthesis, not only minimized the risk of potential human/operator errors but also enhanced the process’ robustness. The successful application of this optimized radiosynthesis method to another similar peptide underscores its versatility, suggesting that our method can be adopted for ⁶⁸Ga-labeling radiotracers based on Affibody molecules in general.

Trial registration: NCT, NCT05619016, Registered 7 November 2022, https://clinicaltrials.gov/study/NCT05619016?term=HER2&cond=ABY025&rank=1

Background

Heterometallic gold metallacages are of great interest for the incorporation of several cations. Especially in nuclear medicine, those metallacages can serve as a platform for radionuclides relevant for imaging or therapy (e.g. ⁶⁸Ga or ¹⁷⁷Lu). Moreover, the radionuclide ¹⁹⁸Au is an attractive beta emitter, for potential application in nuclear medicine. Here, we aim to synthesize a new set of gold metallacages and to study their ability to coordinate to ⁶⁸Ga, ¹⁷⁷Lu and ¹⁹⁸Au.

Results

New heterometallic gold metallacages of composition [M{Au(L^morph-κS)}₃] (M = La³⁺, Tb³⁺, Lu³⁺ or Y³⁺) and [Ga{Au(L^morph-κS)}₂]NO₃ have been synthesized from 2,6-dipicolinoylbis(N,N-morpholinylthiourea) (H₂L^morph) with [AuCl(THT)] and the target M³⁺ metal ions in yields ranging from 33 (Lu) to 62% (Tb). The characterization of the compounds bases on ESI–MS, ¹H NMR, IR, EA and single-crystal X-ray diffraction techniques (all except the Ga derivative). Selected gold cages derived from H₂L^morph were compared to previously reported gold cages that were derived from 2,6-dipicolinoylbis(N,N-diethylthiourea) (H₂L^diethyl). The tested metallacages show similar IC₅₀ values close to that of auranofin in four different cancer cell lines (MCF-7, PC-3, U383, U343), e.g. 4.5 ± 0.7 µM for [Ga{Au(L^diethyl)}₂]NO₃ on PC-3. The radiolabeling experiments thereof show high radiochemical purities with ⁶⁸Ga and ¹⁹⁸Au and low radiochemical purity with ¹⁷⁷Lu.

Conclusions

The results indicate that these gold metallacages could serve as a novel platform for inclusion of different (radio)nuclides with potential theranostic applications in nuclear medicine.

Background

The alpha-emitter radium-223 (²²³Ra) is presently used in nuclear medicine for the palliative treatment of bone metastases from castration-resistant prostate cancer. This application arises from its advantageous decay properties and its intrinsic ability to accumulate in regions of high bone turnover when injected as a simple chloride salt. The commercial availability of [²²³Ra]RaCl₂ as a registered drug (Xofigo^®) is a further additional asset.

Main body

The prospect of extending the utility of ²²³Ra to targeted α-therapy of non-osseous cancers has garnered significant interest. Different methods, such as the use of bifunctional chelators and nanoparticles, have been explored to incorporate ²²³Ra in proper carriers designed to precisely target tumor sites. Nevertheless, the search for a suitable scaffold remains an ongoing challenge, impeding the diffusion of ²²³Ra-based radiopharmaceuticals.

Conclusion

This review offers a comprehensive overview of the current role of radium radioisotopes in nuclear medicine, with a specific focus on ²²³Ra. It also critically examines the endeavors conducted so far to develop constructs capable of incorporating ²²³Ra into cancer-targeting drugs. Particular emphasis is given to the chemical aspects aimed at providing molecular scaffolds for the bifunctional chelator approach.

The International Atomic Energy Agency (IAEA) held the 3rd International Symposium on Trends in Radiopharmaceuticals, (ISTR-2023) at IAEA Headquarters in Vienna, Austria, during the week of 16–21 April 2023. This procedural paper summarizes highlights from symposium presentations, posters, panel discussions and satellite meetings, and provides additional resources that may be useful to researchers working with diagnostic and therapeutic radiopharmaceuticals in the academic, government and industry setting amongst IAEA Member States and beyond. More than 550 participants in person from 88 Member States attended the ISTR-2023. Over 360 abstracts were presented from all over the world by a diverse group of global scientists working with radiopharmaceuticals. Given this group of international radiochemists is unique to ISTR (IAEA funding enabled many to attend), there was an invaluable wealth of knowledge on the global state of the radiopharmaceutical sciences present at the meeting. The intent of this Proceedings paper is to share this snapshot from our international colleagues with the broader radiopharmaceutical sciences community by highlighting presentations from the conference on the following topics: Isotope Production and Radiochemistry, Industrial Insights, Regional Trends, Training and Education, Women in the Radiopharmaceutical Sciences, and Future Perspectives and New Initiatives. The authors of this paper are employees of IAEA, members of the ISTR-2023 Organizing Committee and/or members of the EJNMMI Radiopharmacy and Chemistry Editorial Board who attended ISTR-2023. Overall, ISTR-2023 fostered the successful exchange of scientific ideas around every aspect of the radiopharmaceutical sciences. It was well attended by a diverse mix of radiopharmaceutical scientists from all over the world, and the oral and poster presentations provided a valuable update on the current state-of-the-art of the field amongst IAEA Member States. Presentations as well as networking amongst the attendees resulted in extensive knowledge transfer amongst the various stakeholders representing 88 IAEA Member States. This was considered particularly valuable for attendees from Member States where nuclear medicine and the radiopharmaceutical sciences are still relatively new. Since the goal is for the symposium series to be held every four years; the next one is anticipated to take place in 2027.

Background

The non-invasive imaging of leukocyte trafficking to assess inflammatory areas and monitor immunotherapy is currently generating great interest. There is a need to develop more robust cell labelling and imaging approaches to track living cells. Positron emission tomography (PET), a highly sensitive molecular imaging technique, allows precise signals to be produced from radiolabelled moieties. Here, we developed a novel leukocyte labelling approach with the PET radioisotope zirconium-89 (⁸⁹Zr, half-life of 78.4 h). Experiments were carried out using human leukocytes, freshly isolated from whole human blood.

Results

The ⁸⁹Zr-leukocyte labelling efficiency ranged from 46 to 87% after 30–60 min. Radioactivity concentrations of labelled cells were up to 0.28 MBq/1 million cells. Systemically administered ⁸⁹Zr-labelled leukocytes produced high-contrast murine PET images at 1 h–5 days post injection. Murine biodistribution data showed that cells primarily distributed to the lung, liver, and spleen at 1 h post injection, and are then gradually trafficked to liver and spleen over 5 days. Histological analysis demonstrated that exogenously ⁸⁹Zr-labelled human leukocytes were present in the lung, liver, and spleen at 1 h post injection. However, intravenously injected free [⁸⁹Zr]Zr⁴⁺ ion showed retention only in the bone with no radioactivity in the lung at 5 days post injection, which implied good stability of radiolabelled leukocytes in vivo.

Conclusions

Our study presents a stable and generic radiolabelling technique to track leukocytes with PET imaging and shows great potential for further applications in inflammatory cell and other types of cell trafficking studies.

Background

¹⁷⁷Lu-radiopharmaceuticals can contain the metastable impurity [^177mLu]lutetium with a physical half-life of 160.4 days, in varying concentrations depending on the route of production of the radionuclidic precursor [¹⁷⁷Lu]lutetium. Due to the long half-life of [^177mLu]lutetium, difficulties with waste disposal or sterility testing could arise. Here, we analyzed several ¹⁷⁷Lu-samples of different origins and suppliers regarding their ^177mLu-concentration.

Results

All samples tested showed a ^177mLu-concentration in the range that was stated on the certificate of analysis from the supplier which is in accordance with the European Pharmacopoeia.

Conclusions

Although all ^177mLu-concentrations were in accordance with the European Pharmacopoeia, we need to take into account the respective national legislation regarding radioactivity release limits. With regard to the German legislation, several probes for sterility testing in external laboratories could not be released for transport due to the concentration of [^177mLu]lutetium. Moreover, waste water tanks should specifically be monitored for ^177mLu-concentration, when e.g. Lutathera^® is administered in the clinic.

Background

The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Main body

This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals.

Conclusion

Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.