Pub Date : 2025-02-04DOI: 10.1186/s41181-025-00329-8
Marija Atanasova Lazareva, Maja Chochevska, Katerina Kolevska, Maja Velickovska, Filip Jolevski, Paulina Apostolova, Ana Ugrinska, Emilija Janevik-Ivanovska
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.
{"title":"Development of an automated method for in-house production of sodium 18F-fluoride for injection: process validation as a step toward routine clinical application","authors":"Marija Atanasova Lazareva, Maja Chochevska, Katerina Kolevska, Maja Velickovska, Filip Jolevski, Paulina Apostolova, Ana Ugrinska, Emilija Janevik-Ivanovska","doi":"10.1186/s41181-025-00329-8","DOIUrl":"10.1186/s41181-025-00329-8","url":null,"abstract":"<div><h3>Background</h3><p>Sodium <sup>18</sup>F-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 <sup>18</sup>F-fluoride without the need of a synthesis module and disposable kit, but using only the dispensing unit.</p><h3>Results</h3><p>A new simple method for the efficient routine production of injectable solutions of [<sup>18</sup>F]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 [<sup>18</sup>F]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 [<sup>18</sup>F]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.</p><h3>Conclusion</h3><p>A new simple and reliable procedure developed for the preparation and dispensing of injectable [<sup>18</sup>F]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 [<sup>18</sup>F]NaF using the residual fluorine-18 activity remaining after a [<sup>18</sup>F]FDG production run, thus making it immediately accessible to patients for further PET imaging investigations.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00329-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143107978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-02DOI: 10.1186/s41181-025-00327-w
Hugo Helbert, Winnie Deuther-Conrad, Michel de Haan, Barbara Wenzel, Gert Luurtsema, Wiktor Szymanski, Peter Brust, Rudi A. J. O. Dierckx, Ben L. Feringa, Philip H. Elsinga
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.
{"title":"Synthesis and in vitro evaluation of spirobenzovesamicols as potential 11C-PET tracer alternatives to [18F]FEOBV for vesicular acetylcholine transporter (VAChT) imaging","authors":"Hugo Helbert, Winnie Deuther-Conrad, Michel de Haan, Barbara Wenzel, Gert Luurtsema, Wiktor Szymanski, Peter Brust, Rudi A. J. O. Dierckx, Ben L. Feringa, Philip H. Elsinga","doi":"10.1186/s41181-025-00327-w","DOIUrl":"10.1186/s41181-025-00327-w","url":null,"abstract":"<div><h3>Background</h3><p>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 [<sup>11</sup>C]MeLi cross-coupling methodology, expands labelling opportunities, allowing to explore novel vesamicol-based structures as potential PET-tracers.</p><h3>Results</h3><p>A series of vesamicol derivatives was synthesized and their binding towards VAChT, σ1 and σ2 receptors assessed. Of all compound tested, (-)-2-methylspirobenzovesamicol ((-)-<b>4</b>) 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 [<sup>11</sup>C]MeLi cross-coupling protocol, yielding 2-[<sup>11</sup>C]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.</p><h3>Conclusion</h3><p>(-)-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, [<sup>11</sup>C]-<i>methyl</i>-2-methylspirobenzovesamicol appears a promising <sup>11</sup>C-PET tracer for VAChT imaging.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-025-00327-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"The N-acetyltransferase 10 inhibitor [11C]remodelin: synthesis and preliminary positron emission tomography study in mice","authors":"Rui Luo, Yiding Zhang, Katsushi Kumata, Lin Xie, Yusuke Kurihara, Masanao Ogawa, Tomomi Kokufuta, Nobuki Nengaki, Feng Wang, Ming-Rong R. Zhang","doi":"10.1186/s41181-025-00330-1","DOIUrl":"10.1186/s41181-025-00330-1","url":null,"abstract":"<div><h3>Background</h3><p>4-(4-Cyanophenyl)-2-(2-cyclopentylidenehydrazinyl)thiazole (remodelin) is a potent <i>N</i>-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 ([<sup>11</sup>C]remodelin) for the first time as a positron emission tomography (PET) probe and assessed its biodistribution in mice using PET.</p><h3>Results</h3><p>[<sup>11</sup>C]Remodelin was synthesized by the reaction of a boron ester precursor (<b>1</b>) with hydrogen [<sup>11</sup>C]cyanide, which was prepared from the cyclotron-produced [<sup>11</sup>C]carbon dioxide via [<sup>11</sup>C]methane. The decay-corrected radiochemical yield of [<sup>11</sup>C]remodelin was 6.2 ± 2.3% (<i>n</i> = 20, based on [<sup>11</sup>C]carbon dioxide) with a synthesis time of 45 min and radiochemical purity of > 90%. A PET study with [<sup>11</sup>C]remodelin showed high uptake of radioactivity in the heart, liver, and small intestine of mice. The metabolite analysis indicated moderate metabolism of [<sup>11</sup>C]remodelin in the heart.</p><h3>Conclusions</h3><p>In the present study, we successfully synthesized [<sup>11</sup>C]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 [<sup>11</sup>C]remodelin to elucidate the relationship between NAT10 and diseases.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1186/s41181-025-00328-9
Myrna Luna-Gutiérrez, Erika Azorín-Vega, Rigoberto Oros-Pantoja, Blanca Ocampo-García, Pedro Cruz-Nova, Nallely Jiménez-Mancilla, Gerardo Bravo-Villegas, Clara Santos-Cuevas, Laura Meléndez-Alafort, Guillermina Ferro-Flores
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.
{"title":"Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy","authors":"Myrna Luna-Gutiérrez, Erika Azorín-Vega, Rigoberto Oros-Pantoja, Blanca Ocampo-García, Pedro Cruz-Nova, Nallely Jiménez-Mancilla, Gerardo Bravo-Villegas, Clara Santos-Cuevas, Laura Meléndez-Alafort, Guillermina Ferro-Flores","doi":"10.1186/s41181-025-00328-9","DOIUrl":"10.1186/s41181-025-00328-9","url":null,"abstract":"<div><h3>Background</h3><p>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 <sup>177</sup>Lu-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 <sup>177</sup>Lu-iPD-L1.</p><h3>Results</h3><p>The iPD-L1 ligand, characterized by UPLC mass, UV-Vis, and FT-IR spectroscopies, showed a chemical purity of 99%. The <sup>177</sup>Lu-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 (IC<sub>50</sub> = 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 <sup>177</sup>Lu-iPD-L1 (0.4 Bq/cell), flow cytometry results showed a significant decrease in cell viability of 4T1 cells (dead 56.2%) compared to <sup>177</sup>LuCl<sub>3</sub> (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 <sup>177</sup>Lu-iPD-L1 treatment as evaluated by ELISA assay and immunohistochemistry.</p><h3>Conclusions</h3><p>Therefore, this study warrants further dosimetric and clinical studies to determine the immunomodulatory effect and therapeutic efficacy of <sup>177</sup>Lu-iPD-L1 in treating PD-L1-positive tumors in combination with anti-PD-1/PD-L1 immunotherapy protocols.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-21DOI: 10.1186/s41181-024-00324-5
Jonathan Siikanen, Stefan Milton, Klas Bratteby, Wilson Lin, Jonathan W. Engle, Emma Jussing, Thuy A. Tran
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.
{"title":"Rapid fabrication and dissolution of pressed 58Ni/Mg matrix targets for 55Co production","authors":"Jonathan Siikanen, Stefan Milton, Klas Bratteby, Wilson Lin, Jonathan W. Engle, Emma Jussing, Thuy A. Tran","doi":"10.1186/s41181-024-00324-5","DOIUrl":"10.1186/s41181-024-00324-5","url":null,"abstract":"<div><h3>Background</h3><p>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 <sup>58m</sup>Co (T₁/₂ = 9 h, 100% IC) for radiotheranostic applications. Here we report on <sup>55</sup>Co production via the <sup>58</sup>Ni(p,α)<sup>55</sup>Co reaction channel using pressed <sup>58</sup>Ni and Mg matrix targets.</p><h3>Results</h3><p>This set up is capable to produce and isolate 240 ± 20 MBq [<sup>55</sup>Co]Co<sup>+ 2</sup> (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 [<sup>55</sup>Co]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.</p><h3>Conclusion</h3><p>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.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00324-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142995753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17DOI: 10.1186/s41181-024-00326-3
Panagiotis Kanellopoulos, Quanyi Yu, Abouzayed Abouzayed, Ekaterina Bezverkhniaia, Vladimir Tolmachev, Anna Orlova
Background
Gastrin releasing peptide receptor (GRPR)-directed radiopharmaceuticals for targeted radionuclide therapy may be a very promising addition in prostate and breast cancer patient management. Aiming to provide a GRPR-targeting theranostic pair, we have utilized the Tc-99m/Re-188 radiometal pair, in combination with two bombesin based antagonists, maSSS-PEG2-RM26 and maSES-PEG2-RM26. The two main aims of the current study were (i) to elucidate the influence of the radiometal-exchange on the biodistribution profile of the two peptides and (ii) to evaluate the feasibility of using the [99mTc]Tc labeled counterparts for the dosimetry estimation for the [188Re]Re-labeled conjugates.
Results
Both peptides were successfully labeled with Re-188 and evaluated both in vitro and in vivo. In GRPR expressing PC-3 cells, both [188Re]Re-labeled peptides displayed high cellular uptake (8.5 ± 0.1% and 5 ± 0.3% of added activity, respectively), heavily GRPR-driven, while retaining the radioantagonistic profile with slow internalization rates. Both agents demonstrated high receptor affinity when loaded with natRe (7.5 nM and 8 nM, respectively). When tested in vivo in GRPR expressing PC-3 xenografts, both radioantagonists demonstrated high tumor accumulation (6.3 ± 0.5%IA/g and 5 ± 1%IA/g at 1 h pi, respectively), with good retention over time (4 ± 2%IA/g and 3.1 ± 0.1%IA/g at 4 h pi, respectively). In addition, their biodistribution profiles were closely mimicking their [99mTc]Tc-labeled counterparts. Statistically significant lower tumor uptake was found for both conjugates labeled with Tc-99m, which may result in underestimation of the dose delivered to the tumor.
Conclusions
All the results indicate that Tc-99 m could be used for dosimetry evaluation for the two [188Re]Re-labeled radioligands, with minimal alterations in their biodistribution pattern and tumor targeting capabilities.
背景胃泌素释放肽受体（GRPR）导向的放射性药物靶向放射性核素治疗可能是前列腺癌和乳腺癌患者治疗中一个非常有前途的补充。为了提供grpr靶向治疗对，我们使用了Tc-99m/Re-188放射性金属对，结合两种基于bombesin的拮抗剂mass - peg2 - rm26和mas - peg2 - rm26。本研究的两个主要目的是：(i)阐明放射性金属交换对两种多肽生物分布的影响；（ii）评估使用[99mTc]Tc标记的对应物对[188Re] re标记的偶联物进行剂量学估计的可行性。结果两种多肽均被Re-188成功标记，并在体外和体内进行了评价。在表达GRPR的PC-3细胞中，两种[188Re] re标记的肽均表现出高细胞摄取（分别增加8.5±0.1%和5±0.3%的活性），高度由GRPR驱动，同时保留了缓慢内化率的放射拮抗剂特征。两种药物在负载natRe（分别为7.5 nM和8 nM）时均表现出较高的受体亲和力。在体内对表达GRPR的PC-3异种移植物进行测试时，两种放射拮抗剂均表现出高的肿瘤积累（分别为6.3±0.5%IA/g和5±1%IA/g，分别为1 h pi），并随时间保持良好（分别为4±2%IA/g和3.1±0.1%IA/g，分别为4 h pi）。此外，它们的生物分布特征与[99mTc] tc标记的对偶物非常相似。用Tc-99m标记的两种缀合物的肿瘤摄取在统计学上显著降低，这可能导致给肿瘤的剂量被低估。结论tc - 99m可用于两种[188Re] re -标记放射配体的剂量学评价，其生物分布模式和肿瘤靶向能力变化极小。
{"title":"Evaluation of maSSS/maSES-PEG2-RM26 for their potential therapeutic use after labeling with Re-188. Could their [99mTc]Tc-labeled counterparts be used to estimate dosimetry?","authors":"Panagiotis Kanellopoulos, Quanyi Yu, Abouzayed Abouzayed, Ekaterina Bezverkhniaia, Vladimir Tolmachev, Anna Orlova","doi":"10.1186/s41181-024-00326-3","DOIUrl":"10.1186/s41181-024-00326-3","url":null,"abstract":"<div><h3>Background</h3><p>Gastrin releasing peptide receptor (GRPR)-directed radiopharmaceuticals for targeted radionuclide therapy may be a very promising addition in prostate and breast cancer patient management. Aiming to provide a GRPR-targeting theranostic pair, we have utilized the Tc-99m/Re-188 radiometal pair, in combination with two bombesin based antagonists, maSSS-PEG2-RM26 and maSES-PEG2-RM26. The two main aims of the current study were (i) to elucidate the influence of the radiometal-exchange on the biodistribution profile of the two peptides and (ii) to evaluate the feasibility of using the [<sup>99m</sup>Tc]Tc labeled counterparts for the dosimetry estimation for the [<sup>188</sup>Re]Re-labeled conjugates.</p><h3>Results</h3><p>Both peptides were successfully labeled with Re-188 and evaluated both in vitro and in vivo. In GRPR expressing PC-3 cells, both [<sup>188</sup>Re]Re-labeled peptides displayed high cellular uptake (8.5 ± 0.1% and 5 ± 0.3% of added activity, respectively), heavily GRPR-driven, while retaining the radioantagonistic profile with slow internalization rates. Both agents demonstrated high receptor affinity when loaded with <sup>nat</sup>Re (7.5 nM and 8 nM, respectively). When tested in vivo in GRPR expressing PC-3 xenografts, both radioantagonists demonstrated high tumor accumulation (6.3 ± 0.5%IA/g and 5 ± 1%IA/g at 1 h pi, respectively), with good retention over time (4 ± 2%IA/g and 3.1 ± 0.1%IA/g at 4 h pi, respectively). In addition, their biodistribution profiles were closely mimicking their [<sup>99m</sup>Tc]Tc-labeled counterparts. Statistically significant lower tumor uptake was found for both conjugates labeled with Tc-99m, which may result in underestimation of the dose delivered to the tumor.</p><h3>Conclusions</h3><p>All the results indicate that Tc-99 m could be used for dosimetry evaluation for the two [<sup>188</sup>Re]Re-labeled radioligands, with minimal alterations in their biodistribution pattern and tumor targeting capabilities.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00326-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142994956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17DOI: 10.1186/s41181-024-00322-7
Rizwan Farooq, Thibault Gendron, Richard S. Edwards, Timothy H. Witney
Background
(S)-4-(3-18F-Fluoropropyl)-ʟ-glutamic acid ([18F]FSPG) is a positron emission tomography radiotracer used to image system xc−, an antiporter that is upregulated in several cancers. Not only does imaging system xc− with [18F]FSPG identify tumours, but it can also provide an early readout of response and resistance to therapy. Unfortunately, the clinical production of [18F]FSPG has been hampered by a lack of robust, cGMP-compliant methods. Here, we report the automated synthesis of [18F]FSPG on the Trasis AllinOne™, overcoming previous limitations to provide a user-friendly method ready for clinical adoption.
Results
The optimised method provided [18F]FSPG in 33.5 ± 4.9% radiochemical yield in just 35 min when starting with 18–25 GBq. Importantly, this method could be scaled up to > 100 GBq starting activity with only a modest reduction in radiochemical yield, providing [18F]FSPG with a molar activity of 372 ± 65 GBq/µmol and excellent radiochemical purity (96.8 ± 1.1%). The formulated product was stable when produced with these high starting activities.
Conclusions
We have developed the first automated synthesis of [18F]FSPG on the Trasis AllinOne™. The method produces [18F]FSPG with excellent radiochemical purity and in high amounts suitable for large clinical trials and off-site distribution. The method expands the number of synthesis modules capable of producing [18F]FSPG and has been carefully designed for cGMP compliance to simplify regulatory approval for clinical production. The methods developed for the purification of high-activity [18F]FSPG are transferrable and should aid the development of clinical [18F]FSPG productions on other synthesis modules.
{"title":"Compact and cGMP-compliant automated synthesis of [18F]FSPG on the Trasis AllinOne™","authors":"Rizwan Farooq, Thibault Gendron, Richard S. Edwards, Timothy H. Witney","doi":"10.1186/s41181-024-00322-7","DOIUrl":"10.1186/s41181-024-00322-7","url":null,"abstract":"<div><h3>Background</h3><p>(<i>S</i>)-4-(3-<sup>18</sup>F-Fluoropropyl)-ʟ-glutamic acid ([<sup>18</sup>F]FSPG) is a positron emission tomography radiotracer used to image system x<sub>c</sub><sup>−</sup>, an antiporter that is upregulated in several cancers. Not only does imaging system x<sub>c</sub><sup>−</sup> with [<sup>18</sup>F]FSPG identify tumours, but it can also provide an early readout of response and resistance to therapy. Unfortunately, the clinical production of [<sup>18</sup>F]FSPG has been hampered by a lack of robust, cGMP-compliant methods. Here, we report the automated synthesis of [<sup>18</sup>F]FSPG on the Trasis AllinOne™, overcoming previous limitations to provide a user-friendly method ready for clinical adoption.</p><h3>Results</h3><p>The optimised method provided [<sup>18</sup>F]FSPG in 33.5 ± 4.9% radiochemical yield in just 35 min when starting with 18–25 GBq. Importantly, this method could be scaled up to > 100 GBq starting activity with only a modest reduction in radiochemical yield, providing [<sup>18</sup>F]FSPG with a molar activity of 372 ± 65 GBq/µmol and excellent radiochemical purity (96.8 ± 1.1%). The formulated product was stable when produced with these high starting activities.</p><h3>Conclusions</h3><p>We have developed the first automated synthesis of [<sup>18</sup>F]FSPG on the Trasis AllinOne™. The method produces [<sup>18</sup>F]FSPG with excellent radiochemical purity and in high amounts suitable for large clinical trials and off-site distribution. The method expands the number of synthesis modules capable of producing [<sup>18</sup>F]FSPG and has been carefully designed for cGMP compliance to simplify regulatory approval for clinical production. The methods developed for the purification of high-activity [<sup>18</sup>F]FSPG are transferrable and should aid the development of clinical [<sup>18</sup>F]FSPG productions on other synthesis modules.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00322-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142994839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-10DOI: 10.1186/s41181-024-00323-6
Katarína Benčurová, Theresa Balber, Victoria Weissenböck, Lukas Kogler, Joachim Friske, Verena Pichler, Markus Mitterhauser, Marcus Hacker, Cécile Philippe, Marius Ozenil
Background
Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi.
Results
[carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection.
Conclusions
Although [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated.
{"title":"Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ","authors":"Katarína Benčurová, Theresa Balber, Victoria Weissenböck, Lukas Kogler, Joachim Friske, Verena Pichler, Markus Mitterhauser, Marcus Hacker, Cécile Philippe, Marius Ozenil","doi":"10.1186/s41181-024-00323-6","DOIUrl":"10.1186/s41181-024-00323-6","url":null,"abstract":"<div><h3>Background</h3><p>Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [<i>carbonyl</i>-<sup>11</sup>C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [<sup>18</sup>F]FluorThanatrace and [<sup>18</sup>F]PARPi.</p><h3>Results</h3><p>[<i>carbonyl</i>-<sup>11</sup>C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [<i>carbonyl</i>-<sup>11</sup>C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection.</p><h3>Conclusions</h3><p>Although [<i>carbonyl</i>-<sup>11</sup>C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"10 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00323-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1186/s41181-024-00309-4
Emanuel Sporer, Claire Deville, Natan J. W. Straathof, Linda M. Bruun, Ulli Köster, Mikael Jensen, Thomas L. Andresen, Paul J. Kempen, Jonas R. Henriksen, Andreas I. Jensen
Background
Brachytherapy (BT) is routinely used in the treatment of various cancers. Current BT relies on the placement of large sources of radioactivity at the tumor site, requiring applicators that may cause local traumas and lesions. Further, they suffer from inflexibility in where they can be placed and some sources reside permanently in the body, causing potential long-term discomfort. These issues can be circumvented through injectable sources, prepared as biodegradable materials containing radionuclides that form solid seeds after administration. The level of radioactivity contained in such seeds must be sufficient to achieve substantial local irradiation. In this report, we investigate two different strategies for biodegradable BT seeds.
Results
The first strategy entails injectable seeds based on 103Pd-labeled palladium-gold alloy nanoparticles ([103Pd]PdAuNPs). These were prepared by combining [103Pd]PdH2Cl4 and AuHCl4, followed by lipophilic surface coating and dispersed in lactose octaisobutyrate and ethanol (LOIB:EtOH), in overall radiochemical yield (RCY) of 83%. With the second strategy, [103Pd]Pd-SSIB was prepared by conjugating the [16]aneS4 chelator with lipophilic sucrose septaisobutyrate (SSIB) followed by complexation with [103Pd]PdH2Cl4 (RCY = 99%) and mixed with LOIB:EtOH. [103Pd]Pd-SSIB was likewise formulated as injectable liquid forming seeds by mixing with LOIB. Both formulations reached activities of 1.0–1.5 GBq/mL and negligible release of radioactivity after injection of 100 µL (100–150 MBq) into aqueous buffer or mouse serum of less than 1% over one month.
Conclusion
Both strategies for forming injectable BT seeds containing high 103Pd activity resulted in high radiolabeling yields, high activity per seed, and high activity retention. We consider both strategies suitable for BT, with the preferable strategy using a [16]aneS4 chelator due to its higher biodegradability.
{"title":"Optimized chelator and nanoparticle strategies for high-activity 103Pd-loaded biodegradable brachytherapy seeds","authors":"Emanuel Sporer, Claire Deville, Natan J. W. Straathof, Linda M. Bruun, Ulli Köster, Mikael Jensen, Thomas L. Andresen, Paul J. Kempen, Jonas R. Henriksen, Andreas I. Jensen","doi":"10.1186/s41181-024-00309-4","DOIUrl":"10.1186/s41181-024-00309-4","url":null,"abstract":"<div><h3>Background</h3><p>Brachytherapy (BT) is routinely used in the treatment of various cancers. Current BT relies on the placement of large sources of radioactivity at the tumor site, requiring applicators that may cause local traumas and lesions. Further, they suffer from inflexibility in where they can be placed and some sources reside permanently in the body, causing potential long-term discomfort. These issues can be circumvented through injectable sources, prepared as biodegradable materials containing radionuclides that form solid seeds after administration. The level of radioactivity contained in such seeds must be sufficient to achieve substantial local irradiation. In this report, we investigate two different strategies for biodegradable BT seeds.</p><h3>Results</h3><p>The first strategy entails injectable seeds based on <sup>103</sup>Pd-labeled palladium-gold alloy nanoparticles ([<sup>103</sup>Pd]PdAuNPs). These were prepared by combining [<sup>103</sup>Pd]PdH<sub>2</sub>Cl<sub>4</sub> and AuHCl<sub>4</sub>, followed by lipophilic surface coating and dispersed in lactose octaisobutyrate and ethanol (LOIB:EtOH), in overall radiochemical yield (RCY) of 83%. With the second strategy, [<sup>103</sup>Pd]Pd-SSIB was prepared by conjugating the [16]aneS<sub>4</sub> chelator with lipophilic sucrose septaisobutyrate (SSIB) followed by complexation with [<sup>103</sup>Pd]PdH<sub>2</sub>Cl<sub>4</sub> (RCY = 99%) and mixed with LOIB:EtOH. [<sup>103</sup>Pd]Pd-SSIB was likewise formulated as injectable liquid forming seeds by mixing with LOIB. Both formulations reached activities of 1.0–1.5 GBq/mL and negligible release of radioactivity after injection of 100 µL (100–150 MBq) into aqueous buffer or mouse serum of less than 1% over one month.</p><h3>Conclusion</h3><p>Both strategies for forming injectable BT seeds containing high <sup>103</sup>Pd activity resulted in high radiolabeling yields, high activity per seed, and high activity retention. We consider both strategies suitable for BT, with the preferable strategy using a [16]aneS<sub>4</sub> chelator due to its higher biodegradability.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00309-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-23DOI: 10.1186/s41181-024-00319-2
Daniel Gündel, Mudasir Maqbool, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Anne Heerklotz, Magali Toussaint, Winnie Deuther-Conrad, Guy Bormans, Peter Brust, Klaus Kopka, Rareş-Petru Moldovan
Background
The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [18F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood–brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -d4 and -d8 deuterated isotopologues of [18F]JHU94620.
Results
The deuterated [18F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with KD values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [18F]JHU94620-d8 in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats.
Conclusion
These results support further investigations of [18F]JHU94620-d8 in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.
{"title":"Development and evaluation of deuterated [18F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain","authors":"Daniel Gündel, Mudasir Maqbool, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Anne Heerklotz, Magali Toussaint, Winnie Deuther-Conrad, Guy Bormans, Peter Brust, Klaus Kopka, Rareş-Petru Moldovan","doi":"10.1186/s41181-024-00319-2","DOIUrl":"10.1186/s41181-024-00319-2","url":null,"abstract":"<div><h3>Background</h3><p>The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [<sup>18</sup>F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood–brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -<i>d</i><sub>4</sub> and -<i>d</i><sub>8</sub> deuterated isotopologues of [<sup>18</sup>F]JHU94620.</p><h3>Results</h3><p>The deuterated [<sup>18</sup>F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with <i>K</i><sub>D</sub> values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [<sup>18</sup>F]JHU94620-<i>d</i><sub>8</sub> in the spleen and to a local <i>h</i>CB2R(D80N) protein overexpression in the striatal region in rats.</p><h3>Conclusion</h3><p>These results support further investigations of [<sup>18</sup>F]JHU94620-<i>d</i><sub>8</sub> in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00319-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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