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}
Pub Date : 2023-09-26DOI: 10.1186/s41181-023-00208-0
Misaki Kondo, Zhongli Cai, Conrad Chan, Nubaira Forkan, Raymond M. Reilly
Background
Trastuzumab (Herceptin) has improved the outcome for patients with HER2-positive breast cancer (BC) but brain metastases (BM) remain a challenge due to poor uptake of trastuzumab into the brain. Radioimmunotherapy (RIT) with trastuzumab labeled with α-particle emitting, 225Ac may overcome this challenge by increasing the cytotoxic potency on HER2-positive BC cells. Our first aim was to synthesize and characterize [111In]In-DOTA-trastuzumab and [225Ac]Ac-DOTA-trastuzumab as a theranostic pair for imaging and RIT of HER2-positive BC, respectively. A second aim was to estimate the cellular dosimetry of [225Ac]Ac-DOTA-trastuzumab and determine its cytotoxicity in vitro on HER2-positive BC cells. A third aim was to study the tumour and normal tissue uptake of [225Ac]Ac-DOTA-trastuzumab using [111In]In-DOTA-trastuzumab as a radiotracer in vivo in NRG mice with s.c. 164/8-1B/H2N.luc+ human BC tumours that metastasize to the brain.
Results
Trastuzumab was conjugated to 12.7 ± 1.2 DOTA chelators and labeled with 111In or 225Ac. [111In]In-DOTA-trastuzumab exhibited high affinity specific binding to HER2-positive SK-BR-3 human BC cells (KD = 1.2 ± 0.3 × 10–8 mol/L). Treatment with [225Ac]Ac-DOTA-trastuzumab decreased the surviving fraction (SF) of SK-BR-3 cells dependent on the specific activity (SA) with SF < 0.001 at SA = 0.74 kBq/µg. No surviving colonies were noted at SA = 1.10 kBq/µg or 1.665 kBq/µg. Multiple DNA double-strand breaks (DSBs) were detected in SK-BR-3 cells exposed to [225Ac]Ac-DOTA-trastuzumab by γ-H2AX immunofluorescence microscopy. The time-integrated activity of [111In]In-DOTA-trastuzumab in SK-BR-3 cells was measured and used to estimate the absorbed doses from [225Ac]Ac-DOTA-trastuzumab by Monte Carlo N-Particle simulation for correlation with the SF. The dose required to decrease the SF of SK-BR-3 cells to 0.10 (D10) was 1.10 Gy. Based on the D10 reported for γ-irradiation of SK-BR-3 cells, we estimate that the relative biological effectiveness of the α-particles emitted by 225Ac is 4.4. Biodistribution studies in NRG mice with s.c. 164/8-1B/H2N.luc+ human BC tumours at 48 h post-coinjection of [111In]In-DOTA-trastuzumab and [225Ac]Ac-DOTA-trastuzumab revealed HER2-specific tumour uptake (10.6 ± 0.6% ID/g) but spleen uptake was high (28.9 ± 7.4% ID/g). Tumours were well-visualized by SPECT/CT imaging using [111In]In-DOTA-trastuzumab.
Conclusion
We conclude that [225Ac]Ac-DOTA-trastuzumab exhibited potent and HER2-specific cytotoxicity on SK-BR-3 cells in vitro and HER2-specific uptake in s.c. 164/8-1B/H2N.luc+ human BC tumours in NRG mice, and these tumours were imaged by SPECT/CT with [111In]I
{"title":"[225Ac]Ac- and [111In]In-DOTA-trastuzumab theranostic pair: cellular dosimetry and cytotoxicity in vitro and tumour and normal tissue uptake in vivo in NRG mice with HER2-positive human breast cancer xenografts","authors":"Misaki Kondo, Zhongli Cai, Conrad Chan, Nubaira Forkan, Raymond M. Reilly","doi":"10.1186/s41181-023-00208-0","DOIUrl":"10.1186/s41181-023-00208-0","url":null,"abstract":"<div><h3>Background</h3><p>Trastuzumab (Herceptin) has improved the outcome for patients with HER2-positive breast cancer (BC) but brain metastases (BM) remain a challenge due to poor uptake of trastuzumab into the brain. Radioimmunotherapy (RIT) with trastuzumab labeled with α-particle emitting, <sup>225</sup>Ac may overcome this challenge by increasing the cytotoxic potency on HER2-positive BC cells. Our first aim was to synthesize and characterize [<sup>111</sup>In]In-DOTA-trastuzumab and [<sup>225</sup>Ac]Ac-DOTA-trastuzumab as a theranostic pair for imaging and RIT of HER2-positive BC, respectively. A second aim was to estimate the cellular dosimetry of [<sup>225</sup>Ac]Ac-DOTA-trastuzumab and determine its cytotoxicity in vitro on HER2-positive BC cells. A third aim was to study the tumour and normal tissue uptake of [<sup>225</sup>Ac]Ac-DOTA-trastuzumab using [<sup>111</sup>In]In-DOTA-trastuzumab as a radiotracer in vivo in NRG mice with s.c. 164/8-1B/H2N.luc<sup>+</sup> human BC tumours that metastasize to the brain.</p><h3>Results</h3><p>Trastuzumab was conjugated to 12.7 ± 1.2 DOTA chelators and labeled with <sup>111</sup>In or <sup>225</sup>Ac. [<sup>111</sup>In]In-DOTA-trastuzumab exhibited high affinity specific binding to HER2-positive SK-BR-3 human BC cells (K<sub>D</sub> = 1.2 ± 0.3 × 10<sup>–8</sup> mol/L). Treatment with [<sup>225</sup>Ac]Ac-DOTA-trastuzumab decreased the surviving fraction (SF) of SK-BR-3 cells dependent on the specific activity (SA) with SF < 0.001 at SA = 0.74 kBq/µg. No surviving colonies were noted at SA = 1.10 kBq/µg or 1.665 kBq/µg. Multiple DNA double-strand breaks (DSBs) were detected in SK-BR-3 cells exposed to [<sup>225</sup>Ac]Ac-DOTA-trastuzumab by γ-H2AX immunofluorescence microscopy. The time-integrated activity of [<sup>111</sup>In]In-DOTA-trastuzumab in SK-BR-3 cells was measured and used to estimate the absorbed doses from [<sup>225</sup>Ac]Ac-DOTA-trastuzumab by Monte Carlo N-Particle simulation for correlation with the SF. The dose required to decrease the SF of SK-BR-3 cells to 0.10 (D<sub>10</sub>) was 1.10 Gy. Based on the D<sub>10</sub> reported for γ-irradiation of SK-BR-3 cells, we estimate that the relative biological effectiveness of the α-particles emitted by <sup>225</sup>Ac is 4.4. Biodistribution studies in NRG mice with s.c. 164/8-1B/H2N.luc<sup>+</sup> human BC tumours at 48 h post-coinjection of [<sup>111</sup>In]In-DOTA-trastuzumab and [<sup>225</sup>Ac]Ac-DOTA-trastuzumab revealed HER2-specific tumour uptake (10.6 ± 0.6% ID/g) but spleen uptake was high (28.9 ± 7.4% ID/g). Tumours were well-visualized by SPECT/CT imaging using [<sup>111</sup>In]In-DOTA-trastuzumab.</p><h3>Conclusion</h3><p>We conclude that [<sup>225</sup>Ac]Ac-DOTA-trastuzumab exhibited potent and HER2-specific cytotoxicity on SK-BR-3 cells in vitro and HER2-specific uptake in s.c. 164/8-1B/H2N.luc<sup>+</sup> human BC tumours in NRG mice, and these tumours were imaged by SPECT/CT with [<sup>111</sup>In]I","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41097727","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 : 2023-09-21DOI: 10.1186/s41181-023-00210-6
Olivia Wegrzyniak, Bo Zhang, Johanna Rokka, Maria Rosestedt, Bogdan Mitran, Pierre Cheung, Emmi Puuvuori, Sofie Ingvast, Jonas Persson, Helena Nordström, John Löfblom, Fredrik Pontén, Fredrik Y. Frejd, Olle Korsgren, Jonas Eriksson, Olof Eriksson
Background
Platelet-derived growth factor receptor beta (PDGFRβ) is a receptor overexpressed on activated hepatic stellate cells (aHSCs). Positron emission tomography (PET) imaging of PDGFRβ could potentially allow the quantification of fibrogenesis in fibrotic livers. This study aims to evaluate a fluorine-18 radiolabeled Affibody molecule ([18F]TZ-Z09591) as a PET tracer for imaging liver fibrogenesis.
Results
In vitro specificity studies demonstrated that the trans-Cyclooctenes (TCO) conjugated Z09591 Affibody molecule had a picomolar affinity for human PDGFRβ. Biodistribution performed on healthy rats showed rapid clearance of [18F]TZ-Z09591 through the kidneys and low liver background uptake. Autoradiography (ARG) studies on fibrotic livers from mice or humans correlated with histopathology results. Ex vivo biodistribution and ARG revealed that [18F]TZ-Z09591 binding in the liver was increased in fibrotic livers (p = 0.02) and corresponded to binding in fibrotic scars.
Conclusions
Our study highlights [18F]TZ-Z09591 as a specific tracer for fibrogenic cells in the fibrotic liver, thus offering the potential to assess fibrogenesis clearly.
{"title":"Imaging of fibrogenesis in the liver by [18F]TZ-Z09591, an Affibody molecule targeting platelet derived growth factor receptor β","authors":"Olivia Wegrzyniak, Bo Zhang, Johanna Rokka, Maria Rosestedt, Bogdan Mitran, Pierre Cheung, Emmi Puuvuori, Sofie Ingvast, Jonas Persson, Helena Nordström, John Löfblom, Fredrik Pontén, Fredrik Y. Frejd, Olle Korsgren, Jonas Eriksson, Olof Eriksson","doi":"10.1186/s41181-023-00210-6","DOIUrl":"10.1186/s41181-023-00210-6","url":null,"abstract":"<div><h3>Background</h3><p>Platelet-derived growth factor receptor beta (PDGFRβ) is a receptor overexpressed on activated hepatic stellate cells (aHSCs). Positron emission tomography (PET) imaging of PDGFRβ could potentially allow the quantification of fibrogenesis in fibrotic livers. This study aims to evaluate a fluorine-18 radiolabeled Affibody molecule ([<sup>18</sup>F]TZ-Z09591) as a PET tracer for imaging liver fibrogenesis.</p><h3>Results</h3><p>In vitro specificity studies demonstrated that the trans-Cyclooctenes (TCO) conjugated Z09591 Affibody molecule had a picomolar affinity for human PDGFRβ. Biodistribution performed on healthy rats showed rapid clearance of [<sup>18</sup>F]TZ-Z09591 through the kidneys and low liver background uptake. Autoradiography (ARG) studies on fibrotic livers from mice or humans correlated with histopathology results. Ex vivo biodistribution and ARG revealed that [<sup>18</sup>F]TZ-Z09591 binding in the liver was increased in fibrotic livers (p = 0.02) and corresponded to binding in fibrotic scars.</p><h3>Conclusions</h3><p>Our study highlights [18F]TZ-Z09591 as a specific tracer for fibrogenic cells in the fibrotic liver, thus offering the potential to assess fibrogenesis clearly.</p><h3>Graphical abstract</h3>\u0000 <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\u0000 </div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41097728","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 : 2023-09-07DOI: 10.1186/s41181-023-00209-z
Ashleigh Hull, William Hsieh, Artem Borysenko, William Tieu, Dylan Bartholomeusz, Eva Bezak
Background
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [177Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [225Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.
Results
Cell binding and internalisation of [225Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [225Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [225Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [225Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [225Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.
Conclusion
[225Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.
{"title":"Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration","authors":"Ashleigh Hull, William Hsieh, Artem Borysenko, William Tieu, Dylan Bartholomeusz, Eva Bezak","doi":"10.1186/s41181-023-00209-z","DOIUrl":"10.1186/s41181-023-00209-z","url":null,"abstract":"<div><h3>Background</h3><p>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [<sup>177</sup>Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [<sup>225</sup>Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.</p><h3>Results</h3><p>Cell binding and internalisation of [<sup>225</sup>Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [<sup>225</sup>Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [<sup>225</sup>Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [<sup>225</sup>Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [<sup>225</sup>Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.</p><h3>Conclusion</h3><p>[<sup>225</sup>Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10484829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10252456","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 : 2023-09-04DOI: 10.1186/s41181-023-00206-2
Belinda Trachsel, Giulia Valpreda, Alexandra Lutz, Roger Schibli, Linjing Mu, Martin Béhé
Background
Peptidic radiotracers are preferentially excreted through the kidneys, which often results in high persistent renal retention of radioactivity, limiting or even preventing therapeutic clinical translation of these radiotracers. Exendin-4, which targets the glucagon-like-peptide 1 receptor (GLP-1R) overexpressed in insulinomas and in congenital hyperinsulinism, is an example thereof. The use of the tripeptide MVK, which is readily cleaved between methionine and valine by neprilysin at the renal brush border membrane, already showed promising results in reducing kidney uptake as reported in the literature. Based on our previous findings we were interested how linker variants with multiple copies of the MV-motive influence renal washout of radiolabelled exendin-4.
Results
Three exendin-4 derivatives, carrying either one MVK, a MV-MVK or a MVK-MVK linker were synthesized and compared to a reference compound lacking a cleavable linker. In vivo results of a biodistribution in GLP-1R overexpressing tumour bearing mice at 24 h post-injection demonstrated a significant reduction (at least 57%) of renal retention of all 111In-labeled exendin-4 compounds equipped with a cleavable linker compared to the reference compound. While the insertion of the single linker MVK led to a reduction in kidney uptake of 70%, the dual approach with the linker MV-MVK slightly, but not significantly enhanced this effect, with 77% reduction in kidney uptake compared to the reference. In vitro IC50 and cell uptake studies were conducted and demonstrated that though the cleavable linkers negatively influenced the affinity towards the GLP-1R, cell uptake remained largely unaffected, except for the MV-MVK cleavable linker conjugate, which displayed lower cell uptake than the other compounds. Importantly, the tumour uptake in the biodistribution study was not significantly affected with 2.9, 2.5, 3.2 and 1.5% iA/g for radiolabelled Ex4, MVK-Ex4, MV-MVK-Ex4 and MVK-MVK-Ex4, respectively.
Conclusion
Cleavable linkers are highly efficient in reducing the radioactivity burden in the kidney. Though the dual linker approach using the instillation of MV-MVK or MVK-MVK between exendin-4 and the radiometal chelator did not significantly outperform the single cleavable linker MVK, further structural optimization or the combination of different cleavable linkers could be a stepping stone in reducing radiation-induced nephrotoxicity.
{"title":"Reducing kidney uptake of radiolabelled exendin-4 using variants of the renally cleavable linker MVK","authors":"Belinda Trachsel, Giulia Valpreda, Alexandra Lutz, Roger Schibli, Linjing Mu, Martin Béhé","doi":"10.1186/s41181-023-00206-2","DOIUrl":"10.1186/s41181-023-00206-2","url":null,"abstract":"<div><h3>Background</h3><p>Peptidic radiotracers are preferentially excreted through the kidneys, which often results in high persistent renal retention of radioactivity, limiting or even preventing therapeutic clinical translation of these radiotracers. Exendin-4, which targets the glucagon-like-peptide 1 receptor (GLP-1R) overexpressed in insulinomas and in congenital hyperinsulinism, is an example thereof. The use of the tripeptide MVK, which is readily cleaved between methionine and valine by neprilysin at the renal brush border membrane, already showed promising results in reducing kidney uptake as reported in the literature. Based on our previous findings we were interested how linker variants with multiple copies of the MV-motive influence renal washout of radiolabelled exendin-4.</p><h3>Results</h3><p>Three exendin-4 derivatives, carrying either one MVK, a MV-MVK or a MVK-MVK linker were synthesized and compared to a reference compound lacking a cleavable linker. In vivo results of a biodistribution in GLP-1R overexpressing tumour bearing mice at 24 h post-injection demonstrated a significant reduction (at least 57%) of renal retention of all <sup>111</sup>In-labeled exendin-4 compounds equipped with a cleavable linker compared to the reference compound. While the insertion of the single linker MVK led to a reduction in kidney uptake of 70%, the dual approach with the linker MV-MVK slightly, but not significantly enhanced this effect, with 77% reduction in kidney uptake compared to the reference. In vitro IC<sub>50</sub> and cell uptake studies were conducted and demonstrated that though the cleavable linkers negatively influenced the affinity towards the GLP-1R, cell uptake remained largely unaffected, except for the MV-MVK cleavable linker conjugate, which displayed lower cell uptake than the other compounds. Importantly, the tumour uptake in the biodistribution study was not significantly affected with 2.9, 2.5, 3.2 and 1.5% iA/g for radiolabelled Ex4, MVK-Ex4, MV-MVK-Ex4 and MVK-MVK-Ex4, respectively.</p><h3>Conclusion</h3><p>Cleavable linkers are highly efficient in reducing the radioactivity burden in the kidney. Though the dual linker approach using the instillation of MV-MVK or MVK-MVK between exendin-4 and the radiometal chelator did not significantly outperform the single cleavable linker MVK, further structural optimization or the combination of different cleavable linkers could be a stepping stone in reducing radiation-induced nephrotoxicity.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159663","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 : 2023-08-30DOI: 10.1186/s41181-023-00207-1
Taco Metelerkamp Cappenberg, Stijn De Schepper, Christel Vangestel, Stef De Lombaerde, Leonie wyffels, Tim Van den Wyngaert, Jeffrey Mattis, Brian Gray, Koon Pak, Sigrid Stroobants, Filipe Elvas
Background
Imaging of cell death can provide an early indication of treatment response in cancer. [99mTc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [99mTc]Tc-Duramycin in healthy human volunteers.
Results
Six healthy volunteers (3 males, 3 females) were injected intravenously with [99mTc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [99mTc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo 99mTc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 μGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85–4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal.
Conclusion
[99mTc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [99mTc]Tc-Duramycin for clinical treatment response evaluation.
Trial registration: NCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640.
{"title":"First-in-human study of a novel cell death tracer [99mTc]Tc-Duramycin: safety, biodistribution and radiation dosimetry in healthy volunteers","authors":"Taco Metelerkamp Cappenberg, Stijn De Schepper, Christel Vangestel, Stef De Lombaerde, Leonie wyffels, Tim Van den Wyngaert, Jeffrey Mattis, Brian Gray, Koon Pak, Sigrid Stroobants, Filipe Elvas","doi":"10.1186/s41181-023-00207-1","DOIUrl":"10.1186/s41181-023-00207-1","url":null,"abstract":"<div><h3>Background</h3><p>Imaging of cell death can provide an early indication of treatment response in cancer. [<sup>99m</sup>Tc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [<sup>99m</sup>Tc]Tc-Duramycin in healthy human volunteers.</p><h3>Results</h3><p>Six healthy volunteers (3 males, 3 females) were injected intravenously with [<sup>99m</sup>Tc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [<sup>99m</sup>Tc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo <sup>99m</sup>Tc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 μGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85–4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal.</p><h3>Conclusion</h3><p>[<sup>99m</sup>Tc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [<sup>99m</sup>Tc]Tc-Duramycin for clinical treatment response evaluation.</p><p><i>Trial registration</i>: NCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10468453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10134138","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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