Pub Date : 2023-10-26DOI: 10.1186/s41181-023-00221-3
Julien Leenhardt, Luc Choisnard, Maelle Plasse, Valérie Ardisson, Nicolas de Leiris, Loic Djaileb, Pierrick Bedouch, Marie-Dominique Brunet
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.
{"title":"Bacterial survival in radiopharmaceutical solutions: a critical impact on current practices","authors":"Julien Leenhardt, Luc Choisnard, Maelle Plasse, Valérie Ardisson, Nicolas de Leiris, Loic Djaileb, Pierrick Bedouch, Marie-Dominique Brunet","doi":"10.1186/s41181-023-00221-3","DOIUrl":"10.1186/s41181-023-00221-3","url":null,"abstract":"<div><h3>Background</h3><p>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 <i>Pseudomonas aeruginosa</i> (<i>ATCC: 27853</i>) or <i>Staphylococcus aureus (ATCC: 25923)</i> or <i>Staphylococcus epidermidis (ATCC: 1228)</i> in multidose technetium-99 m solution was studied.</p><h3>Results</h3><p>Depending on the nature and level of contamination by pathogenic bacteria, the lethal effect of radioactivity is not systematically observed. We found that <i>P. aeruginosa</i> was indeed affected by radioactivity. However, this was not the case for <i>S. epidermidis</i>, 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 <i>S. aureus</i> 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.</p><h3>Conclusion</h3><p>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.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50160261","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 : 2023-10-23DOI: 10.1186/s41181-023-00219-x
Alexander Thiel, Alexey Kostikov, Hailey Ahn, Youstina Daoud, Jean-Paul Soucy, Stephan Blinder, Carolin Jaworski, Carmen Wängler, Björn Wängler, Freimut Juengling, Shirin A. Enger, Ralf Schirrmacher
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 (Am = 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 EDW 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.
{"title":"Dosimetry of [18F]TRACK, the first PET tracer for imaging of TrkB/C receptors in humans","authors":"Alexander Thiel, Alexey Kostikov, Hailey Ahn, Youstina Daoud, Jean-Paul Soucy, Stephan Blinder, Carolin Jaworski, Carmen Wängler, Björn Wängler, Freimut Juengling, Shirin A. Enger, Ralf Schirrmacher","doi":"10.1186/s41181-023-00219-x","DOIUrl":"10.1186/s41181-023-00219-x","url":null,"abstract":"<div><h3>Background</h3><p>Reduced expression or impaired signalling of tropomyosin receptor kinases (Trk receptors) are found in a vast spectrum of CNS disorders. [<sup>18</sup>F]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 [<sup>18</sup>F]TRACK in healthy humans. 6 healthy participants (age 22–61 y, 3 female) were scanned on a General Electric Discovery PET/CT 690 scanner. [<sup>18</sup>F]TRACK was synthesized with high molar activities (A<sub>m</sub> = 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).</p><h3>Results</h3><p>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<sub>DW</sub> was 1.63E−2 ± 1.68E−3 mSv/MBq. Organ-specific TACs indicated predominantly hepatic tracer elimination.</p><h3>Conclusion</h3><p>Total and organ-specific effective doses for [<sup>18</sup>F]TRACK are low and the dosimetry profile is similar to other <sup>18</sup>F-labelled radio tracers currently used in clinical settings.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49688222","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 : 2023-10-19DOI: 10.1186/s41181-023-00214-2
Julien Leenhardt, Alexandre Biguet Petit Jean, Florian Raes, Emilien N’Guessan, Marlène Debiossat, Clémence André, Sandrine Bacot, Mitra Ahmadi, Nicolas de Leiris, Loïc Djaileb, Catherine Ghezzi, Marie-Dominique Brunet, Alexis Broisat, Pascale Perret, Amaury du Moulinet d’Hardemare
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.
{"title":"TrisOxine abiotic siderophores for technetium complexation: radiolabeling and biodistribution studies","authors":"Julien Leenhardt, Alexandre Biguet Petit Jean, Florian Raes, Emilien N’Guessan, Marlène Debiossat, Clémence André, Sandrine Bacot, Mitra Ahmadi, Nicolas de Leiris, Loïc Djaileb, Catherine Ghezzi, Marie-Dominique Brunet, Alexis Broisat, Pascale Perret, Amaury du Moulinet d’Hardemare","doi":"10.1186/s41181-023-00214-2","DOIUrl":"10.1186/s41181-023-00214-2","url":null,"abstract":"<div><h3>Background</h3><p>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. <i>O-</i>TRENSOX and <i>O-</i>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 <i>O-</i>TRENOX and <i>O</i>-TRENSOX with <sup>99m</sup>Tc 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 [<sup>99m</sup>Tc]Tc-<i>O-</i>TRENOX and [<sup>99m</sup>Tc]Tc-<i>O-</i>TRENSOX were performed.</p><h3>Results</h3><p>The radiolabeling studies showed a rapid and efficient complexation of <sup>99m</sup>Tc with both chelating agents. Using tin pyrophosphate as the reducing agent and a minimum of 100 nmol of ligand, we obtained the [<sup>99m</sup>Tc]Tc-<i>O-</i>TRENOX complex with a radiochemical purity of more than 98% and the [<sup>99m</sup>Tc]Tc-<i>O-</i>TRENSOX complex with one above 97% at room temperature within 5 min. [<sup>99m</sup>Tc]Tc-<i>O-</i>TRENOX complex was lipophilic and neutral, leading to a hepatobiliary elimination in mice. On the contrary, the [<sup>99m</sup>Tc]Tc-<i>O-</i>TRENSOX complex was found to be hydrophilic and negatively charged. This was confirmed by a predominantly renal elimination in mice.</p><h3>Conclusions</h3><p>These encouraging results allow us to consider the <i>O-</i>TRENOX/<sup>99m</sup>Tc and <i>O-</i>TRENSOX/<sup>99m</sup>Tc 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.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10587049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49672881","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}
Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer’s disease (AD) has been reported; RIPK1 is involved in microglia’s phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1.
Results
(S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK’963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK’963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK’963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK’963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47–115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively.
Conclusions
We synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK’963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to
{"title":"Synthesis and evaluation of a novel PET ligand, a GSK’963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain","authors":"Hiroshi Ikenuma, Aya Ogata, Hiroko Koyama, Bin Ji, Hideki Ishii, Takashi Yamada, Junichiro Abe, Chie Seki, Yuji Nagai, Masanori Ichise, Takafumi Minamimoto, Makoto Higuchi, Ming-Rong Zhang, Takashi Kato, Kengo Ito, Masaaki Suzuki, Yasuyuki Kimura","doi":"10.1186/s41181-023-00217-z","DOIUrl":"10.1186/s41181-023-00217-z","url":null,"abstract":"<div><h3>Background</h3><p>Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer’s disease (AD) has been reported; RIPK1 is involved in microglia’s phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1.</p><h3>Results</h3><p>(<i>S</i>)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1<i>H</i>-pyrazol-1-yl)propan-1-one (GSK’963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since <sup>11</sup>C-labeling (half-life: 20.4 min) GSK’963 retaining its structure requiring the Grignard reaction of <i>tert</i>-butylmagnesium halides and [<sup>11</sup>C]carbon dioxide was anticipated to give a low yield, we decided instead to <sup>11</sup>C-label a GSK’963 analog ((<i>S</i>)-2,2-dimethyl-1-(5-(<i>m</i>-tolyl)-4,5-dihydro-1<i>H</i>-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK’963. Thus, we successfully <sup>11</sup>C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47–115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [<sup>11</sup>C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [<sup>11</sup>C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [<sup>11</sup>C]GG502. On brain PET imaging in acute inflammation model rats, [<sup>11</sup>C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [<sup>11</sup>C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [<sup>11</sup>C]GG502 in the brain and the plasma, respectively.</p><h3>Conclusions</h3><p>We synthesized and evaluated a <sup>11</sup>C-labeled PET ligand based on the methylated analog of GSK’963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [<sup>11</sup>C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49672880","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 : 2023-10-16DOI: 10.1186/s41181-023-00213-3
Timofei Rusu, Matthieu Delion, Charlotte Pirot, Amaury Blin, Anita Rodenas, Jean-Noël Talbot, Nicolas Veran, Christophe Portal, Françoise Montravers, Jacques Cadranel, Aurélie Prignon
Background
c-MET is a transmembrane receptor involved in many biological processes and contributes to cell proliferation and migration during cancer invasion process. Its expression is measured by immunehistochemistry on tissue biopsy in clinic, although this technique has its limitations. PET-CT could allow in vivo mapping of lesions expressing c-MET, providing whole-body detection. A number of radiopharmaceuticals are under development for this purpose but are not yet in routine clinical use. EMP100 is a cyclic oligopeptide bound to a DOTA chelator, with nanomolar affinity for c-MET. The aim of this project was to develop an automated method for radiolabelling the radiopharmaceutical [68Ga]Ga-EMP100.
Results
The main results showed an optimal pH range between 3.25 and 3.75 for the complexation reaction and a stabilisation of the temperature at 90 °C, resulting in an almost complete incorporation of gallium-68 after 10 min of heating. In these experiments, 90 µg of EMP-100 peptide were initially used and then lower amounts (30, 50, 75 µg) were explored to determine the minimum required for sufficient synthesis yield. Radiolysis impurities were identified by radio-HPLC and ascorbic acid and ethanol were used to improve the purity of the compound. Three batches of [68Ga]Ga-EMP100 were then prepared according to the optimised parameters and all met the established specifications. Finally, the stability of [68Ga]Ga-EMP100 was assessed at room temperature over 3 h with satisfactory results in terms of appearance, pH, radiochemical purity and sterility.
Conclusions
For the automated synthesis of [68Ga]Ga-EMP100, the parameters of pH, temperature, precursor peptide content and the use of adjuvants for impurity management were efficiently optimised, resulting in the production of three compliant and stable batches according to the principles of good manufacturing practice. [68Ga]Ga-EMP100 was successfully synthesised and is now available for clinical development in PET-CT imaging.
{"title":"Fully automated radiolabeling of [68Ga]Ga-EMP100 targeting c-MET for PET-CT clinical imaging","authors":"Timofei Rusu, Matthieu Delion, Charlotte Pirot, Amaury Blin, Anita Rodenas, Jean-Noël Talbot, Nicolas Veran, Christophe Portal, Françoise Montravers, Jacques Cadranel, Aurélie Prignon","doi":"10.1186/s41181-023-00213-3","DOIUrl":"10.1186/s41181-023-00213-3","url":null,"abstract":"<div><h3>Background</h3><p>c-MET is a transmembrane receptor involved in many biological processes and contributes to cell proliferation and migration during cancer invasion process. Its expression is measured by immunehistochemistry on tissue biopsy in clinic, although this technique has its limitations. PET-CT could allow in vivo mapping of lesions expressing c-MET, providing whole-body detection. A number of radiopharmaceuticals are under development for this purpose but are not yet in routine clinical use. EMP100 is a cyclic oligopeptide bound to a DOTA chelator, with nanomolar affinity for c-MET. The aim of this project was to develop an automated method for radiolabelling the radiopharmaceutical [<sup>68</sup>Ga]Ga-EMP100.</p><h3>Results</h3><p>The main results showed an optimal pH range between 3.25 and 3.75 for the complexation reaction and a stabilisation of the temperature at 90 °C, resulting in an almost complete incorporation of gallium-68 after 10 min of heating. In these experiments, 90 µg of EMP-100 peptide were initially used and then lower amounts (30, 50, 75 µg) were explored to determine the minimum required for sufficient synthesis yield. Radiolysis impurities were identified by radio-HPLC and ascorbic acid and ethanol were used to improve the purity of the compound. Three batches of [<sup>68</sup>Ga]Ga-EMP100 were then prepared according to the optimised parameters and all met the established specifications. Finally, the stability of [<sup>68</sup>Ga]Ga-EMP100 was assessed at room temperature over 3 h with satisfactory results in terms of appearance, pH, radiochemical purity and sterility.</p><h3>Conclusions</h3><p>For the automated synthesis of [<sup>68</sup>Ga]Ga-EMP100, the parameters of pH, temperature, precursor peptide content and the use of adjuvants for impurity management were efficiently optimised, resulting in the production of three compliant and stable batches according to the principles of good manufacturing practice. [<sup>68</sup>Ga]Ga-EMP100 was successfully synthesised and is now available for clinical development in PET-CT imaging.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41231396","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 : 2023-10-16DOI: 10.1186/s41181-023-00216-0
Adam J. Rosenberg, Yiu-Yin Cheung, Fei Liu, Carina Sollert, Todd E. Peterson, Jonathan A. Kropski
Background
Radiopharmaceuticals capable of targeting the fibroblast activation protein have become widely utilized in the research realm as well as show great promise to be commercialized; with [68Ga]Ga-FAPI-46 being one of the most widely utilized. Until now the synthesis has relied on generator-produced gallium-68. Here we present a developed method to utilize liquid-target cyclotron-produced gallium-68 to prepare [68Ga]Ga-FAPI-46.
Results
A fully-automated manufacturing process for [68Ga]Ga-FAPI-46 was developed starting with the 68Zn[p,n]68Ga cyclotron bombardment to provide [68Ga]GaCl3, automated purification of the [68Ga]GaCl3, chelation with the precursor, and final formulation/purification. The activity levels produced were sufficient for multiple clinical research doses, and the final product met all release criteria. Furthermore, the process consistently provides < 2% of Ga-66 and Ga-67 at the 4-h expiry, meeting the Ph. Eur. standards.
Conclusions
The automated radiosynthesis on the GE FASTlab 2 module purifies the cyclotron output into [68Ga]GaCl3, performs the labeling, formulates the product, and sterilizes the product while transferring to the final vial. Production of > 40 mCi (> 1480 MBq) of [68Ga]Ga-FAPI-46 in excellent radiochemical yield was achieved with all batches meeting release criteria.
{"title":"Fully automated radiosynthesis of [68Ga]Ga-FAPI-46 with cyclotron produced gallium","authors":"Adam J. Rosenberg, Yiu-Yin Cheung, Fei Liu, Carina Sollert, Todd E. Peterson, Jonathan A. Kropski","doi":"10.1186/s41181-023-00216-0","DOIUrl":"10.1186/s41181-023-00216-0","url":null,"abstract":"<div><h3>Background</h3><p>Radiopharmaceuticals capable of targeting the fibroblast activation protein have become widely utilized in the research realm as well as show great promise to be commercialized; with [<sup>68</sup>Ga]Ga-FAPI-46 being one of the most widely utilized. Until now the synthesis has relied on generator-produced gallium-68. Here we present a developed method to utilize liquid-target cyclotron-produced gallium-68 to prepare [<sup>68</sup>Ga]Ga-FAPI-46.</p><h3>Results</h3><p>A fully-automated manufacturing process for [<sup>68</sup>Ga]Ga-FAPI-46 was developed starting with the <sup>68</sup>Zn[p,n]<sup>68</sup>Ga cyclotron bombardment to provide [<sup>68</sup>Ga]GaCl<sub>3</sub>, automated purification of the [<sup>68</sup>Ga]GaCl<sub>3</sub>, chelation with the precursor, and final formulation/purification. The activity levels produced were sufficient for multiple clinical research doses, and the final product met all release criteria. Furthermore, the process consistently provides < 2% of Ga-66 and Ga-67 at the 4-h expiry, meeting the Ph. Eur. standards.</p><h3>Conclusions</h3><p>The automated radiosynthesis on the GE FASTlab 2 module purifies the cyclotron output into [<sup>68</sup>Ga]GaCl<sub>3</sub>, performs the labeling, formulates the product, and sterilizes the product while transferring to the final vial. Production of > 40 mCi (> 1480 MBq) of [<sup>68</sup>Ga]Ga-FAPI-46 in excellent radiochemical yield was achieved with all batches meeting release criteria.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10579206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41231397","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 : 2023-10-12DOI: 10.1186/s41181-023-00203-5
Lizeth Y. F. Haveman, Danielle J. Vugts, Albert D. Windhorst
Background
Positron emission tomography (PET) is a powerful, non-invasive preclinical and clinical nuclear imaging technique used in disease diagnosis and therapy assessment. Fluorine-18 is the predominant radionuclide used for PET tracer synthesis. An impressive variety of new ‘late-stage’ radiolabeling methodologies for the preparation of 18F-labeled tracers has appeared in order to improve the efficiency of the labeling reaction.
Main body
Despite these developments, one outstanding challenge into the early key steps of the process remains: the preparation of reactive [18F]fluoride from oxygen-18 enriched water ([18O]H2O). In the last decade, significant changes into the trapping, elution and drying stages have been introduced. This review provides an overview of the strategies and recent developments in the production of reactive [18F]fluoride and its use for radiolabeling.
Conclusion
Improved, modified or even completely new fluorine-18 work-up procedures have been developed in the last decade with widespread use in base-sensitive nucleophilic 18F-fluorination reactions. The many promising developments may lead to a few standardized drying methodologies for the routine production of a broad scale of PET tracers.
{"title":"State of the art procedures towards reactive [18F]fluoride in PET tracer synthesis","authors":"Lizeth Y. F. Haveman, Danielle J. Vugts, Albert D. Windhorst","doi":"10.1186/s41181-023-00203-5","DOIUrl":"10.1186/s41181-023-00203-5","url":null,"abstract":"<div><h3>Background</h3><p>Positron emission tomography (PET) is a powerful, non-invasive preclinical and clinical nuclear imaging technique used in disease diagnosis and therapy assessment. Fluorine-18 is the predominant radionuclide used for PET tracer synthesis. An impressive variety of new ‘late-stage’ radiolabeling methodologies for the preparation of <sup>18</sup>F-labeled tracers has appeared in order to improve the efficiency of the labeling reaction.</p><h3>Main body</h3><p>Despite these developments, one outstanding challenge into the early key steps of the process remains: the preparation of reactive [<sup>18</sup>F]fluoride from oxygen-18 enriched water ([<sup>18</sup>O]H<sub>2</sub>O). In the last decade, significant changes into the trapping, elution and drying stages have been introduced. This review provides an overview of the strategies and recent developments in the production of reactive [<sup>18</sup>F]fluoride and its use for radiolabeling.</p><h3>Conclusion</h3><p>Improved, modified or even completely new fluorine-18 work-up procedures have been developed in the last decade with widespread use in base-sensitive nucleophilic <sup>18</sup>F-fluorination reactions. The many promising developments may lead to a few standardized drying methodologies for the routine production of a broad scale of PET tracers.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41187530","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 : 2023-10-12DOI: 10.1186/s41181-023-00211-5
Maija Radzina, Laura Saule, Edgars Mamis, Ulli Koester, Thomas Elias Cocolios, Elina Pajuste, Marika Kalnina, Kristaps Palskis, Zoe Sawitzki, Zeynep Talip, Mikael Jensen, Charlotte Duchemin, Kirsten Leufgen, Thierry Stora
Background
In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research. The aim of this article is to introduce readers with current status of novel radionuclides in Europe.
Main body
A consortium questionnaire was disseminated through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end-users in nuclear medicine were identified. A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: 177Lu, 68 Ga, 111In, 90Y, other alpha emitters, 225Ac, 64Cu and Terbium isotopes. Radionuclides that would be of interest for users within the next 2–5 years are 64Cu, Terbium radionuclide “family” and alpha emitters, such as 225Ac.
Conclusions
Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified.
{"title":"Novel radionuclides for use in Nuclear Medicine in Europe: where do we stand and where do we go?","authors":"Maija Radzina, Laura Saule, Edgars Mamis, Ulli Koester, Thomas Elias Cocolios, Elina Pajuste, Marika Kalnina, Kristaps Palskis, Zoe Sawitzki, Zeynep Talip, Mikael Jensen, Charlotte Duchemin, Kirsten Leufgen, Thierry Stora","doi":"10.1186/s41181-023-00211-5","DOIUrl":"10.1186/s41181-023-00211-5","url":null,"abstract":"<div><h3>Background</h3><p>In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research. The aim of this article is to introduce readers with current status of novel radionuclides in Europe.</p><h3>Main body</h3><p>A consortium questionnaire was disseminated through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end-users in nuclear medicine were identified. A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: <sup>177</sup>Lu, <sup>68</sup> Ga, <sup>111</sup>In, <sup>90</sup>Y, other alpha emitters, <sup>225</sup>Ac, <sup>64</sup>Cu and Terbium isotopes. Radionuclides that would be of interest for users within the next 2–5 years are <sup>64</sup>Cu, Terbium radionuclide “family” and alpha emitters, such as <sup>225</sup>Ac.</p><h3>Conclusions</h3><p>Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41187529","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}
In radionuclide therapy, to enhance therapeutic efficacy, an intriguing alternative is to ensure the simultaneous implementation of low- and high-LET radiation emitted from a one radionuclide. In the present study, we introduce the concept of utilizing 109Pd (T1/2 = 13.7 h) in the form of a 109Pd/109mAg in vivo generator. In this system, 109Pd emits beta particles of medium energy, while 109mAg releases a cascade of conversion and Auger electrons. 109Pd was utilized in the form of 15 nm gold nanoparticles, which were coated with a monolayer of 109Pd. In this system, the 109Pd atoms are on the surface of the nanoparticle, while the 109mAg atoms generated in the decay reaction possess the capability for unhindered emission of Auger electrons.
Results
109Pd, obtained through neutron irradiation of natural palladium, was deposited onto 15-nm gold nanoparticles, exceeding a efficiency rate of 95%. In contrast to previously published data on in vivo generators based on chelators, where the daughter radionuclide diffuses away from the molecules, daughter radionuclide 109mAg remains on the surface of gold nanoparticles after the decay of 109Pd. To obtain a radiobioconjugate with an affinity for HER2 receptors, polyethylene glycol chains and the monoclonal antibody trastuzumab were attached to the Au@Pd nanoparticles. The synthesized bioconjugate contained an average of 9.5 trastuzumab molecules per one nanoparticle. In vitro cell studies indicated specific binding of the Au@109Pd-PEG-trastuzumab radiobioconjugate to the HER2 receptor on SKOV-3 cells, resulting in 90% internalization. Confocal images illustrated the accumulation of Au@109Pd-PEG-trastuzumab in the perinuclear area surrounding the cell nucleus. Despite the lack of nuclear localization, which is necessary to achieve an effective cytotoxic effect of Auger electrons, a substantial cytotoxic effect, significantly greater than that of pure β− and pure Auger electron emitters was observed. We hypothesize that in the studied system, the cytotoxic effect of the Auger electrons could have also occurred through the damage to the cell’s nuclear membrane by Auger electrons emitted from nanoparticles accumulated in the perinuclear area.
Conclusion
The obtained results show that trastuzumab-functionalized 109Pd-labeled nanoparticles can be suitable for the application in combined β−—Auger electron targeted radionuclide therapy. Due to both components decay (β− and conversion/Auger electrons), the 109Pd/109mAg in vivo generator presents unique potential in this field. Despite the lack of nuclear localization, which is highly required for efficient Auger electron therapy, an adequate cytotoxic effect was attained.
{"title":"Au@109Pd core–shell nanoparticle conjugated to trastuzumab for the therapy of HER2+ cancers: studies on the applicability of 109Pd/109mAg in vivo generator in combined β− auger electron therapy","authors":"Nasrin Abbasi Gharibkandi, Kamil Wawrowicz, Agnieszka Majkowska-Pilip, Kinga Żelechowska-Matysiak, Mateusz Wierzbicki, Aleksander Bilewicz","doi":"10.1186/s41181-023-00212-4","DOIUrl":"10.1186/s41181-023-00212-4","url":null,"abstract":"<div><h3>Background</h3><p>In radionuclide therapy, to enhance therapeutic efficacy, an intriguing alternative is to ensure the simultaneous implementation of low- and high-LET radiation emitted from a one radionuclide. In the present study, we introduce the concept of utilizing <sup>109</sup>Pd (T<sub>1/2</sub> = 13.7 h) in the form of a <sup>109</sup>Pd/<sup>109m</sup>Ag in vivo generator. In this system, <sup>109</sup>Pd emits beta particles of medium energy, while <sup>109m</sup>Ag releases a cascade of conversion and Auger electrons. <sup>109</sup>Pd was utilized in the form of 15 nm gold nanoparticles, which were coated with a monolayer of <sup>109</sup>Pd. In this system, the <sup>109</sup>Pd atoms are on the surface of the nanoparticle, while the <sup>109m</sup>Ag atoms generated in the decay reaction possess the capability for unhindered emission of Auger electrons.</p><h3>Results</h3><p><sup>109</sup>Pd, obtained through neutron irradiation of natural palladium, was deposited onto 15-nm gold nanoparticles, exceeding a efficiency rate of 95%. In contrast to previously published data on in vivo generators based on chelators, where the daughter radionuclide diffuses away from the molecules, daughter radionuclide <sup>109m</sup>Ag remains on the surface of gold nanoparticles after the decay of <sup>109</sup>Pd. To obtain a radiobioconjugate with an affinity for HER2 receptors, polyethylene glycol chains and the monoclonal antibody trastuzumab were attached to the Au@Pd nanoparticles. The synthesized bioconjugate contained an average of 9.5 trastuzumab molecules per one nanoparticle. In vitro cell studies indicated specific binding of the Au@<sup>109</sup>Pd-PEG-trastuzumab radiobioconjugate to the HER2 receptor on SKOV-3 cells, resulting in 90% internalization. Confocal images illustrated the accumulation of Au@<sup>109</sup>Pd-PEG-trastuzumab in the perinuclear area surrounding the cell nucleus. Despite the lack of nuclear localization, which is necessary to achieve an effective cytotoxic effect of Auger electrons, a substantial cytotoxic effect, significantly greater than that of pure β<sup>−</sup> and pure Auger electron emitters was observed. We hypothesize that in the studied system, the cytotoxic effect of the Auger electrons could have also occurred through the damage to the cell’s nuclear membrane by Auger electrons emitted from nanoparticles accumulated in the perinuclear area.</p><h3>Conclusion</h3><p>The obtained results show that trastuzumab-functionalized <sup>109</sup>Pd-labeled nanoparticles can be suitable for the application in combined β<sup>−</sup><b>—</b>Auger electron targeted radionuclide therapy. Due to both components decay (β<sup>−</sup> and conversion/Auger electrons), the <sup>109</sup>Pd/<sup>109m</sup>Ag in vivo generator presents unique potential in this field. Despite the lack of nuclear localization, which is highly required for efficient Auger electron therapy, an adequate cytotoxic effect was attained.</p><","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41187527","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 : 2023-10-11DOI: 10.1186/s41181-023-00215-1
Simon Blok, Carmen Wängler, Peter Bartenstein, Klaus Jurkschat, Ralf Schirrmacher, Simon Lindner
Background
The positron emitting isotope fluorine-18 (18F) possesses almost ideal physicochemical properties for the development of radiotracers for diagnostic molecular imaging employing positron emission tomography (PET). 18F in its nucleophilic anionic 18F− form is usually prepared by bombarding an enriched 18O water target with protons of various energies between 5 and 20 MeV depending on the technical specifications of the cyclotron. Large thick-target yields between 5 and 14 GBq/µA can be obtained, enough to prepare large batches of radiotracers capable to serve a considerable contingent of patients (50 + per clinical batch). The overall yield of the radiotracer however depends on the efficiency of the 18F labeling chemistry. The Silicon Fluoride Acceptor chemistry (SiFA) has introduced a convenient and highly efficient way to provide clinical peptide-based 18F-radiotracers in a kit-like procedure matching the convenience of 99mTc radiopharmaceuticals.
Main body
A radiotracer’s clinical success primarily hinges on whether its synthesis can be automated. Due to its simplicity, the SiFA chemistry, which is based on isotopic exchange (18F for 19F), does not only work in a manual setup but has been proven to be automatable, yielding large batches of 18F-radiotracers of high molar activity (Am). The production of SiFA radiotracer can be centralized and the radiopharmaceutical be distributed via the “satellite” principle, where one production facility economically serves multiple clinical application sites. Clinically validated tracers such as [18F]SiTATE and [18F]Ga-rhPSMA-7/-7.3 have been synthesized in an automated synthesis unit under good manufacturing practice conditions and used in large patient cohorts. Communication of common guidelines and practices is warranted to further the dissemination of SiFA radiopharmaceuticals and to give easy access to this technology.
Conclusion
This current review highlights the most recent achievements in SiFA radiopharmaceutical automation geared towards large batch production for clinical application. Best practice advice and guidance towards a facilitated implementation of the SiFA technology into new and already operating PET tracer production facilities is provided. A brief outlook spotlights the future potential of SiFA radiochemistry within the landscape of non-canonical labeling chemistries.
{"title":"Good practices for the automated production of 18F-SiFA radiopharmaceuticals","authors":"Simon Blok, Carmen Wängler, Peter Bartenstein, Klaus Jurkschat, Ralf Schirrmacher, Simon Lindner","doi":"10.1186/s41181-023-00215-1","DOIUrl":"10.1186/s41181-023-00215-1","url":null,"abstract":"<div><h3>Background</h3><p>The positron emitting isotope fluorine-18 (<sup>18</sup>F) possesses almost ideal physicochemical properties for the development of radiotracers for diagnostic molecular imaging employing positron emission tomography (PET). <sup>18</sup>F in its nucleophilic anionic <sup>18</sup>F<sup>−</sup> form is usually prepared by bombarding an enriched <sup>18</sup>O water target with protons of various energies between 5 and 20 MeV depending on the technical specifications of the cyclotron. Large thick-target yields between 5 and 14 GBq/µA can be obtained, enough to prepare large batches of radiotracers capable to serve a considerable contingent of patients (50 + per clinical batch). The overall yield of the radiotracer however depends on the efficiency of the <sup>18</sup>F labeling chemistry. The Silicon Fluoride Acceptor chemistry (SiFA) has introduced a convenient and highly efficient way to provide clinical peptide-based <sup>18</sup>F-radiotracers in a kit-like procedure matching the convenience of <sup>99m</sup>Tc radiopharmaceuticals.</p><h3>Main body</h3><p>A radiotracer’s clinical success primarily hinges on whether its synthesis can be automated. Due to its simplicity, the SiFA chemistry, which is based on isotopic exchange (<sup>18</sup>F for <sup>19</sup>F), does not only work in a manual setup but has been proven to be automatable, yielding large batches of <sup>18</sup>F-radiotracers of high molar activity (A<sub>m</sub>). The production of SiFA radiotracer can be centralized and the radiopharmaceutical be distributed via the “satellite” principle, where one production facility economically serves multiple clinical application sites. Clinically validated tracers such as [<sup>18</sup>F]SiTATE and [<sup>18</sup>F]Ga-rhPSMA-7/-7.3 have been synthesized in an automated synthesis unit under good manufacturing practice conditions and used in large patient cohorts. Communication of common guidelines and practices is warranted to further the dissemination of SiFA radiopharmaceuticals and to give easy access to this technology.</p><h3>Conclusion</h3><p>This current review highlights the most recent achievements in SiFA radiopharmaceutical automation geared towards large batch production for clinical application. Best practice advice and guidance towards a facilitated implementation of the SiFA technology into new and already operating PET tracer production facilities is provided. A brief outlook spotlights the future potential of SiFA radiochemistry within the landscape of non-canonical labeling chemistries.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10567618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41187528","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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