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.