EJNMMI Radiopharmacy and Chemistry最新文献

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.

Background

The aim of this brief communication is to highlight the potential bacteriological risk linked to the processes control of radiopharmaceutical preparations made in a radiopharmacy laboratory. Survival rate of Pseudomonas aeruginosa (ATCC: 27853) or Staphylococcus aureus (ATCC: 25923) or Staphylococcus epidermidis (ATCC: 1228) in multidose technetium-99 m solution was studied.

Results

Depending on the nature and level of contamination by pathogenic bacteria, the lethal effect of radioactivity is not systematically observed. We found that P. aeruginosa was indeed affected by radioactivity. However, this was not the case for S. epidermidis, as the quantity of bacteria found in both solutions (radioactive and non-radioactive) was rapidly reduced, probably due to a lack of nutrients. Finally, the example of S. aureus is an intermediate case where we observed that high radioactivity affected the bacteria, as did the absence of nutrients in the reaction medium. The results were discussed in the light of current practices on the sterility test method, which recommends waiting for radioactivity to decay before carrying out the sterility test.

Conclusion

In terms of patient safety, the results run counter to current practice and the latest EANM recommendation of 2021 that radiopharmaceutical preparations should be decayed before sterility testing.

Background

Reduced expression or impaired signalling of tropomyosin receptor kinases (Trk receptors) are found in a vast spectrum of CNS disorders. [¹⁸F]TRACK is the first PET radioligand for TrkB/C with proven in vivo brain penetration and on-target specific signal. Here we report dosimetry data for [¹⁸F]TRACK in healthy humans. 6 healthy participants (age 22–61 y, 3 female) were scanned on a General Electric Discovery PET/CT 690 scanner. [¹⁸F]TRACK was synthesized with high molar activities (A_m = 250 ± 75 GBq/µmol), and a dynamic series of 12 whole-body scans were acquired after injection of 129 to 147 MBq of the tracer. Images were reconstructed with standard corrections using the manufacturer’s OSEM algorithm. Tracer concentration time-activity curves (TACs) were obtained using CT-derived volumes-of-interest. Organ-specific doses and the total effective dose were estimated using the Committee on Medical Internal Radiation Dose equation for adults and tabulated Source tissue values (S values).

Results

Average organ absorbed dose was highest for liver and gall bladder with 6.1E−2 (± 1.06E−2) mGy/MBq and 4.6 (± 1.18E−2) mGy/MBq, respectively. Total detriment weighted effective dose E_DW was 1.63E−2 ± 1.68E−3 mSv/MBq. Organ-specific TACs indicated predominantly hepatic tracer elimination.

Conclusion

Total and organ-specific effective doses for [¹⁸F]TRACK are low and the dosimetry profile is similar to other ¹⁸F-labelled radio tracers currently used in clinical settings.

Background

Despite the development of positron emission tomography (PET), single photon emission computed tomography (SPECT) still accounts for around 80% of all examinations performed in nuclear medicine departments. The search for new radiotracers or chelating agents for Technetium-99m is therefore still ongoing. O-TRENSOX and O-TRENOX two synthetic siderophores would be good candidates for this purpose as they are hexadentate ligands based on the very versatile and efficient 8-hydroxyquinoline chelating subunit. First, the radiolabeling of O-TRENOX and O-TRENSOX with ^99mTc was investigated. Different parameters such as the quantity of chelating agent, type of reducing agent, pH and temperature of the reaction mixture were adjusted in order to find the best radiolabeling conditions. Then an assessment of the partition coefficient by measuring the distribution of each radiosynthesized complex between octanol and phosphate-buffered saline was realized. The complex’s charge was evaluated on three different celluloses (neutral, negatively charged P81 and positively charged DE81), and finally in vivo studies with biodistribution and SPECT imaging of [^99mTc]Tc-O-TRENOX and [^99mTc]Tc-O-TRENSOX were performed.

Results

The radiolabeling studies showed a rapid and efficient complexation of ^99mTc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [^99mTc]Tc-O-TRENOX complex with a radiochemical purity of more than 98% and the [^99mTc]Tc-O-TRENSOX complex with one above 97% at room temperature within 5 min. [^99mTc]Tc-O-TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [^99mTc]Tc-O-TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice.

Conclusions

These encouraging results allow us to consider the O-TRENOX/^99mTc and O-TRENSOX/^99mTc complexes as serious candidates for SPECT imaging chelators. This study should be continued by conjugating these tris-oxine ligands to peptides or antibodies and comparing them with the other bifunctional agents used with Tc.