EJNMMI Radiopharmacy and Chemistry最新文献

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 and application of radiopharmaceuticals.

Main body

This selection of highlights provides commentary on 24 different topics selected by each co-authoring 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

Prostate cancer (PC) has a 34% 5-year survival rate after progressing to metastatic castration-resistant prostate cancer (mCRPC), which occurs in 20–30% of cases. Treatments like chemotherapy, immunotherapy, and PSMA-targeted radioligand therapy (RLT) show promise, but challenges remain with tumor resistance, side effects, and dose-limiting toxicity in kidneys and bone marrow. This study investigated the hematotoxicity, treatment efficacy, and recovery after [¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617 treatment in a syngeneic PC mouse model.

Method

Twenty-five male C57BL/6 mice were inoculated with RM1-PGLS cells and monitored using [⁶⁸Ga]Ga-PSMA-11 PET/CT. The mice were divided into five groups as follows: (1) [²²⁵Ac]Ac-PSMA-617 treatment with tumors, (2) [¹⁷⁷Lu]Lu-PSMA-617 treatment with tumors, (3) control group with tumors, (4) [²²⁵Ac]Ac-PSMA-617 treatment without tumors, and (5) [¹⁷⁷Lu]Lu-PSMA-617 treatment without tumors. Tumor volume was measured weekly, and animals were sacrificed when tumors reached 1.5 cm³. Endpoint criteria included tumor size, survival, and body mass. Blood samples were collected at different time points to assess blood cell counts and liver and kidney function.

Results

Both treatments significantly slowed tumor progression and extended survival. [²²⁵Ac]Ac-PSMA-617-treated mice had a median survival of 70 days, compared to 58 days for [¹⁷⁷Lu]Lu-PSMA-617-treated mice and 30 days for the control group. Tumor volumes were significantly reduced in both treatment groups (P < 0.05). Hematological analysis showed that both treatments reduced WBCs, RBCs, and platelets, but values normalized within 35–42 days. Liver and kidney functions remained unaffected, and no significant renal or hepatic toxicity was observed.

Conclusion

Both [²²⁵Ac]Ac-PSMA-617 and [¹⁷⁷Lu]Lu-PSMA-617 caused transient hematotoxicity without prolonged effects. The data do not explicitly support the necessity of immunocompetent models for studying therapeutic outcomes in this context. Future studies incorporating immune profiling are warranted to investigate immune system interactions in radioligand therapy further.

Background

The use of radiopharmaceuticals labelled with fluorine-18 in non-invasive imaging, particularly in Positron Emission Tomography (PET), increased significantly during the last decade. However, traditional nucleophilic fluorination synthesis methods in most cases require azeotropic drying steps, leading to loss of activity and increased synthesis time. Microfluidic devices offer improvements with shorter reaction times, higher elution efficiency, and reduced reagent quantities.

Results

We developed a novel micro-cartridge for [¹⁸F]fluoride trapping and elution, etched in borosilicate optical glass (BK7) using ultrashort laser pulse machining. The micro-cartridge has a bead volume of 17 µL and a maximum capacity of 8.5 mg for anion exchange resin. The micro-cartridge, without the need for QMA preconditioning, exhibited an overall trapping efficiency and recovery efficiency (RE) of (94.09 ± 0.12)% using an activity exceeding 123 GBq of [¹⁸F]fluoride. This RE was obtained using 100 µL of a standard solution of anhydrous acetonitrile with Kryptofix 2.2.2, containing only 5 µL of water and 5.4 µmol of K₂CO₃ for [¹⁸F]fluoride elution. This solution was employed directly in the radiosynthesis of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO), resulting in a 100% radiochemical conversion (RCC) to THP-protected [¹⁸F]FMISO within 10 min at 110 °C.

Conclusions

The developed micro-cartridge provides a novel tool for integrating microfluidic chips into conventional cassettes, facilitating more efficient radiopharmaceutical preparation.

Background

The extracellular localisation of the Heat shock protein 90 (Hsp90) is associated with the diseased state and wound healing and presents a promising opportunity for cancer targeting using Positron Emission Tomography (PET) imaging and molecularly targeted radiotherapy. The aim of this work is to develop a radiotracer with low nanomolar binding affinity to target the extracellular and particularly membrane pool of Hsp90, evaluate it in vitro, and conduct preliminary PET studies in vivo in mouse tumour models. Variable Heavy domain of Heavy chain antibodies, often referred to as Nanobodies, are suitable targeting vectors for the extracellular targets due to their favourable pharmacokinetic properties and low nanomolar target affinities. The main objective of the study is to target tumours expressing extracellular and membrane Hsp90 phenotype with minimal tracer accumulation in the non-target organs, which limited the translation of previously studied small molecule cytosolic Hsp90 tracers suffering from high non-Hsp90 specific background in the abdominal area.

Results

Six nanobodies were obtained after llama immunization with recombinant Hsp90α and ELISA biopanning, produced in E. coli and screened for stability and affinity. We selected one nanobody, 4DAM26, with good thermal stability, no aggregation at elevated temperatures, and low nanomolar affinity towards Hsp90α and Hsp90β isoforms for translation as a PET radiotracer. The nanobody was bioconjugated to p-NCS-NODAGA and radiolabeled with gallium-68 with 75 ± 11% radiochemical yield and > 99% radiochemical purity and remained stable up to 3 h in phosphate buffered saline and mouse serum. Pilot in vivo evaluation using µPET/CT and ex vivo biodistribution demonstrated a favourable pharmacokinetic profile, but the tumour uptake was non-distinguishable from the background tissue.

Conclusion

Compared to the small molecule Hsp90 tracers, the studied Nb-based tracer has improved pharmacokinetics properties including renal clearance and almost no accumulation in the non-target organs. Tumour uptake, on the other hand, was minimal and could not be differentiated from the background in µPET/CT. Our experiments indicate that in the studied models, membrane and extracellular expression of Hsp90 is majorly an artifact of cellular death, as only dead/dying cells had accessible pools of Hsp90 by flow cytometry, a consequence of a leaky membrane. More fundamental research is required to reassess the role of extracellular Hsp90 in cancer, and our future efforts will be focused on improving our inventory of cytosolic Hsp90 tracers with proven Hsp90-specific tumour accumulation.

Background

Targeted alpha therapy with Ac-225 showed to be effective in treating metastatic cancers. However, the complex decay chain requires optimized radiolabeling and quality control. This study aims to determine critical parameters and establish optimal labeling and accurate measuring techniques for radiochemical yield and purity with DOTA-TATE as a model molecule. Ac-225 sources were analyzed for metals (ΣFe, Zn, Cu) and quantified by UPLC. Optimization of radiolabeling kinetics for clinical conditions was performed in regards to temperature (20–90 °C), heating time (5–60 min), pH (2.5–10, with/without excess of metal ions), buffers, quenchers, volume (0.1–10 mL) and molar activity (90–540 kBq/nmol). The quality control was investigated using radio-TLC/HPLC by changing gradient to evaluate peak separation, radiolysed peptide and impurity separation.

Results

Metal ingrowth was observed in Ac-225 stocks (n = 3), (time of arrival: 17.9, 36.8 and 101.4 nmol per 10 MBq). Optimal radiochemical yields were achieved with > 80 °C (20 min) at pH 8.5 (15 mM TRIS) up to 270 kBq. Labeling at a high pH showed a higher RCY, even in presence of an excess of metals. High stability (RCP > 90%) was achieved after addition of quenchers (cysteine, methionine, ascorbate, histidine, or gentisic acid (35 mM)) up to 24 h. For optimal determination of the radiochemical purity (indirect HPLC) fifty fractions are required.

Conclusion

The quality of Ac-225 labeled DOTA-radiopharmaceuticals is highly dependent on the pH and stabilization (buffer/quencher). Within this research it is demonstrated that optimized quality control methods and accurate measurement of the radiolabeling kinetics are crucial to ensure safe implementation for patient treatment.

Background

Sodium ¹⁸F-fluoride for injection can be easily cyclotron-produced and purified, as a simple inorganic salt, by adsorption/desorption onto an anion-exchange cartridge and then dispensed for clinical use. Since the clinical demand for this radiopharmaceutical is constantly increasing, this study aimed to design and develop a simple, fully automated method for the in-house, rapid, and efficient processing and dispensing of injectable solutions of Sodium ¹⁸F-fluoride without the need of a synthesis module and disposable kit, but using only the dispensing unit.

Results

A new simple method for the efficient routine production of injectable solutions of [¹⁸F]NaF was developed through a straightforward modification of the commercial dispenser Clio (Comecer S.p.A., Italy) and without the need of a synthesis module. The full production, processing and dispensing of [¹⁸F]NaF were entirely carried out on the same batch using only the dispensing module. Process validation was carried according to GMP guidelines to ensure consistency of [¹⁸F]NaF quality with international standards. The final radiopharmaceutical met all quality criteria specified by Ph. Eur. and chemical, radionuclidic and radiochemical impurities were significantly below the required limits.

Conclusion

A new simple and reliable procedure developed for the preparation and dispensing of injectable [¹⁸F]NaF in less than 10 min with a radiochemical yield > 97% (decay corrected) has been successfully developed. Notably, the proposed method also allows the preparation of [¹⁸F]NaF using the residual fluorine-18 activity remaining after a [¹⁸F]FDG production run, thus making it immediately accessible to patients for further PET imaging investigations.

Background

Through its central role in neurotransmission, the vesicular acetylcholine transporter (VAChT) is an increasingly valuable target for positron emission tomography (PET). VAChT ligands have been mostly derived from the vesamicol structure, but with limitations in available labelling methods and selectivity for VAChT against σ receptors being a common pitfall of such compounds, the development of selective VAChT tracers remains a challenge. Modern labelling techniques, in this case the [¹¹C]MeLi cross-coupling methodology, expands labelling opportunities, allowing to explore novel vesamicol-based structures as potential PET-tracers.

Results

A series of vesamicol derivatives was synthesized and their binding towards VAChT, σ1 and σ2 receptors assessed. Of all compound tested, (-)-2-methylspirobenzovesamicol ((-)-4) was the most promising with a 16 ± 4 nM affinity towards VAChT, a 29-fold weaker affinity for σ1 receptors and negligible binding (> 1 μM) towards σ2 receptors. The radiolabelling was performed from the corresponding bromide using a [¹¹C]MeLi cross-coupling protocol, yielding 2-[¹¹C]methylspirobenzovesamicol in 32–37% RCY. New in vitro binding data is also made available for (-)-FEOBV with human-sourced σ1 receptors, revealing a 300-fold stronger affinity for VAChT compared to σ receptors.

Conclusion

(-)-2-methylspirobenzovesamicol was identified as a potent and selective VAChT ligand, with moderate to low affinity for σ receptors, and its racemate was radiolabeled in good radiochemical yields with Carbon-11. At this stage, [¹¹C]-methyl-2-methylspirobenzovesamicol appears a promising ¹¹C-PET tracer for VAChT imaging.

Background

4-(4-Cyanophenyl)-2-(2-cyclopentylidenehydrazinyl)thiazole (remodelin) is a potent N-acetyltransferase 10 (NAT10) inhibitor. This compound inhibits tumors and weakens tumor resistance to antitumor drugs. Moreover, remodelin has been found to enhance healthspan in an animal model of the human accelerated ageing syndrome. In this study, we synthesized C-11-labelled remodelin ([¹¹C]remodelin) for the first time as a positron emission tomography (PET) probe and assessed its biodistribution in mice using PET.

Results

[¹¹C]Remodelin was synthesized by the reaction of a boron ester precursor (1) with hydrogen [¹¹C]cyanide, which was prepared from the cyclotron-produced [¹¹C]carbon dioxide via [¹¹C]methane. The decay-corrected radiochemical yield of [¹¹C]remodelin was 6.2 ± 2.3% (n = 20, based on [¹¹C]carbon dioxide) with a synthesis time of 45 min and radiochemical purity of > 90%. A PET study with [¹¹C]remodelin showed high uptake of radioactivity in the heart, liver, and small intestine of mice. The metabolite analysis indicated moderate metabolism of [¹¹C]remodelin in the heart.

Conclusions

In the present study, we successfully synthesized [¹¹C]remodelin and assessed its biodistribution of radioactivity in the mouse organs and tissues with PET. We are planning to prepare tumor and inflammatory models in which overexpression of NAT10 is possibly induced and conduct PET imaging for these animal models with [¹¹C]remodelin to elucidate the relationship between NAT10 and diseases.

Background

Cancer immunotherapy is a relatively new approach to cancer treatment. Peptides that target specific pathways and cells involved in immunomodulation can potentially improve the efficacy of cancer therapy. Recently, we reported iPD-L1 as a novel inhibitor peptide that specifically targets the cancer cell ligand PD-L1 (programmed death ligand 1). PD-L1 is responsible for inhibiting the immune checkpoint protein PD-1 expressed by regulatory T cells. On the other hand, anti-PD-L1 immunotherapy in combination with external beam radiotherapy has shown improved outcomes in the treatment of breast and lung cancer. The aim of this research was to prepare ¹⁷⁷Lu-labeled iPD-L1 and to preclinically evaluate its radiotherapeutic potential and role as a tumor immunomodulator by measuring macrophage activation, IL-10, TGFβ, and PD-L1 expression in 4T1 triple-negative breast cancer cells and murine 4T1 tumors after treatment with ¹⁷⁷Lu-iPD-L1.

Results

The iPD-L1 ligand, characterized by UPLC mass, UV-Vis, and FT-IR spectroscopies, showed a chemical purity of 99%. The ¹⁷⁷Lu-iPD-L1 radiochemical purity was 98.9 ± 1.1%. In vitro and in vivo studies demonstrated radiotracer stability in human serum (> 97% after 24 h evaluated by radio-HPLC), adequate affinity by the PDL1 protein (IC₅₀ = 4.21 nM), and specific detection for PD-L1 assessed in 4T1, HCT116, and AR42J cancer cells, in which PD-L1 expression was verified by immunofluorescence and Western Blot assays. After treatment with ¹⁷⁷Lu-iPD-L1 (0.4 Bq/cell), flow cytometry results showed a significant decrease in cell viability of 4T1 cells (dead 56.2%) compared to ¹⁷⁷LuCl₃ (dead 34.2%) and untreated cells (dead 9.4%). With high tumor uptake (6.97 ± 1.04%ID) and hepatobiliary and renal clearance, lutetium-177-labeled iPD-L1 delivered a tumor dose of 27 Gy/37 MBq and less than 0.36 Gy/37 MBq to non-source organs. PD-L1 positive tumors showed a significant increase in activated macrophages, PD-L1, IL-10, and TGFβ expression levels after ¹⁷⁷Lu-iPD-L1 treatment as evaluated by ELISA assay and immunohistochemistry.

Conclusions

Therefore, this study warrants further dosimetric and clinical studies to determine the immunomodulatory effect and therapeutic efficacy of ¹⁷⁷Lu-iPD-L1 in treating PD-L1-positive tumors in combination with anti-PD-1/PD-L1 immunotherapy protocols.

Background

Beyond the use of conventional short-lived PET radionuclides, there is a growing interest in tracking larger biomolecules and exploring radiotheranostic applications. One promising option for imaging medium-sized molecules and peptides is ⁵⁵Co (T₁/₂ = 17.5 h, β⁺ = 76%), which enables imaging of new and already established tracers with blood circulation of several hours. Additionally, ⁵⁵Co can be paired with the Auger-Meitner emitter ^58mCo (T₁/₂ = 9 h, 100% IC) for radiotheranostic applications. Here we report on ⁵⁵Co production via the ⁵⁸Ni(p,α)⁵⁵Co reaction channel using pressed ⁵⁸Ni and Mg matrix targets.

Results

This set up is capable to produce and isolate 240 ± 20 MBq [⁵⁵Co]Co^+ 2 (80% RCY) with 4 ml 0.25 M HEPES at 35 min post End Of Bombardment for 3 h, 25 µA protons irradiation. The RNP of the eluate is 99.98 ± 0.014% as measured 2 h & 17 h post EOB. AMA was determined to 1.5 ± 0.5 GBq/µmol [⁵⁵Co]Co-DOTA at EOB. Mg dissolves rapidly in the acid mixture, leaving behind a porous, sponge-like Ni matrix increasing the surface area of the Ni and therefore accelerating the dissolution.

Conclusion

We present a novel, simple, and rapid method to produce ⁵⁵Co with pressed ⁵⁸Ni/Mg matrix targets enabling faster target fabrication and dissolution. By using a simple hydraulic press, mechanically stable target coins useful for solid target irradiation are fabricated within 5 min and can be dissolved in 10 min at room temperature. The foils remain intact after irradiation and can endure irradiation conditions providing sufficient activity (> 200 MBq) for clinical doses. The method presented here using Mg as a support metal for fixation of the actual target material into target coins is applicable for other target combinations as well. Using Mg as a support metal is suitable due to its thermal conductivity, low activation, minimal impact on purification chemistry, softness, ductility, and rapid dissolution in acid.