EJNMMI Radiopharmacy and Chemistry最新文献

{"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":"8 1","pages":""},"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}

{"title":"Fully automated radiolabeling of [68Ga]Ga-EMP100 targeting c-MET for PET-CT clinical imaging","authors":"Timofei Rusu,&nbsp;Matthieu Delion,&nbsp;Charlotte Pirot,&nbsp;Amaury Blin,&nbsp;Anita Rodenas,&nbsp;Jean-Noël Talbot,&nbsp;Nicolas Veran,&nbsp;Christophe Portal,&nbsp;Françoise Montravers,&nbsp;Jacques Cadranel,&nbsp;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 [⁶⁸Ga]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 [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.</p><h3>Conclusions</h3><p>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.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"8 1","pages":""},"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}

{"title":"Fully automated radiosynthesis of [68Ga]Ga-FAPI-46 with cyclotron produced gallium","authors":"Adam J. Rosenberg,&nbsp;Yiu-Yin Cheung,&nbsp;Fei Liu,&nbsp;Carina Sollert,&nbsp;Todd E. Peterson,&nbsp;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 [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.</p><h3>Results</h3><p>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 &lt; 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 [⁶⁸Ga]GaCl₃, performs the labeling, formulates the product, and sterilizes the product while transferring to the final vial. Production of &gt; 40 mCi (&gt; 1480 MBq) of [⁶⁸Ga]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":"8 1","pages":""},"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}

{"title":"State of the art procedures towards reactive [18F]fluoride in PET tracer synthesis","authors":"Lizeth Y. F. Haveman,&nbsp;Danielle J. Vugts,&nbsp;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 ¹⁸F-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 [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.</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 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.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"8 1","pages":""},"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}

{"title":"Novel radionuclides for use in Nuclear Medicine in Europe: where do we stand and where do we go?","authors":"Maija Radzina,&nbsp;Laura Saule,&nbsp;Edgars Mamis,&nbsp;Ulli Koester,&nbsp;Thomas Elias Cocolios,&nbsp;Elina Pajuste,&nbsp;Marika Kalnina,&nbsp;Kristaps Palskis,&nbsp;Zoe Sawitzki,&nbsp;Zeynep Talip,&nbsp;Mikael Jensen,&nbsp;Charlotte Duchemin,&nbsp;Kirsten Leufgen,&nbsp;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: 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.</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":"8 1","pages":""},"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}

{"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,&nbsp;Kamil Wawrowicz,&nbsp;Agnieszka Majkowska-Pilip,&nbsp;Kinga Żelechowska-Matysiak,&nbsp;Mateusz Wierzbicki,&nbsp;Aleksander Bilewicz","doi":"10.1186/s41181-023-00212-4","DOIUrl":"10.1186/s41181-023-00212-4","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;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 &lt;sup&gt;109&lt;/sup&gt;Pd (T&lt;sub&gt;1/2&lt;/sub&gt; = 13.7 h) in the form of a &lt;sup&gt;109&lt;/sup&gt;Pd/&lt;sup&gt;109m&lt;/sup&gt;Ag in vivo generator. In this system, &lt;sup&gt;109&lt;/sup&gt;Pd emits beta particles of medium energy, while &lt;sup&gt;109m&lt;/sup&gt;Ag releases a cascade of conversion and Auger electrons. &lt;sup&gt;109&lt;/sup&gt;Pd was utilized in the form of 15 nm gold nanoparticles, which were coated with a monolayer of &lt;sup&gt;109&lt;/sup&gt;Pd. In this system, the &lt;sup&gt;109&lt;/sup&gt;Pd atoms are on the surface of the nanoparticle, while the &lt;sup&gt;109m&lt;/sup&gt;Ag atoms generated in the decay reaction possess the capability for unhindered emission of Auger electrons.&lt;/p&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;&lt;sup&gt;109&lt;/sup&gt;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 &lt;sup&gt;109m&lt;/sup&gt;Ag remains on the surface of gold nanoparticles after the decay of &lt;sup&gt;109&lt;/sup&gt;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@&lt;sup&gt;109&lt;/sup&gt;Pd-PEG-trastuzumab radiobioconjugate to the HER2 receptor on SKOV-3 cells, resulting in 90% internalization. Confocal images illustrated the accumulation of Au@&lt;sup&gt;109&lt;/sup&gt;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&lt;sup&gt;−&lt;/sup&gt; 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.&lt;/p&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;The obtained results show that trastuzumab-functionalized &lt;sup&gt;109&lt;/sup&gt;Pd-labeled nanoparticles can be suitable for the application in combined β&lt;sup&gt;−&lt;/sup&gt;&lt;b&gt;—&lt;/b&gt;Auger electron targeted radionuclide therapy. Due to both components decay (β&lt;sup&gt;−&lt;/sup&gt; and conversion/Auger electrons), the &lt;sup&gt;109&lt;/sup&gt;Pd/&lt;sup&gt;109m&lt;/sup&gt;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.&lt;/p&gt;&lt;","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"8 1","pages":""},"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}

{"title":"Good practices for the automated production of 18F-SiFA radiopharmaceuticals","authors":"Simon Blok,&nbsp;Carmen Wängler,&nbsp;Peter Bartenstein,&nbsp;Klaus Jurkschat,&nbsp;Ralf Schirrmacher,&nbsp;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 (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.</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 (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 (A_m). 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.</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":"8 1","pages":""},"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}

{"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,&nbsp;Zhongli Cai,&nbsp;Conrad Chan,&nbsp;Nubaira Forkan,&nbsp;Raymond M. Reilly","doi":"10.1186/s41181-023-00208-0","DOIUrl":"10.1186/s41181-023-00208-0","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;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, &lt;sup&gt;225&lt;/sup&gt;Ac may overcome this challenge by increasing the cytotoxic potency on HER2-positive BC cells. Our first aim was to synthesize and characterize [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab and [&lt;sup&gt;225&lt;/sup&gt;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 [&lt;sup&gt;225&lt;/sup&gt;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 [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab using [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab as a radiotracer in vivo in NRG mice with s.c. 164/8-1B/H2N.luc&lt;sup&gt;+&lt;/sup&gt; human BC tumours that metastasize to the brain.&lt;/p&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Trastuzumab was conjugated to 12.7 ± 1.2 DOTA chelators and labeled with &lt;sup&gt;111&lt;/sup&gt;In or &lt;sup&gt;225&lt;/sup&gt;Ac. [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab exhibited high affinity specific binding to HER2-positive SK-BR-3 human BC cells (K&lt;sub&gt;D&lt;/sub&gt; = 1.2 ± 0.3 × 10&lt;sup&gt;–8&lt;/sup&gt; mol/L). Treatment with [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab decreased the surviving fraction (SF) of SK-BR-3 cells dependent on the specific activity (SA) with SF &lt; 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 [&lt;sup&gt;225&lt;/sup&gt;Ac]Ac-DOTA-trastuzumab by γ-H2AX immunofluorescence microscopy. The time-integrated activity of [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab in SK-BR-3 cells was measured and used to estimate the absorbed doses from [&lt;sup&gt;225&lt;/sup&gt;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&lt;sub&gt;10&lt;/sub&gt;) was 1.10 Gy. Based on the D&lt;sub&gt;10&lt;/sub&gt; reported for γ-irradiation of SK-BR-3 cells, we estimate that the relative biological effectiveness of the α-particles emitted by &lt;sup&gt;225&lt;/sup&gt;Ac is 4.4. Biodistribution studies in NRG mice with s.c. 164/8-1B/H2N.luc&lt;sup&gt;+&lt;/sup&gt; human BC tumours at 48 h post-coinjection of [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab and [&lt;sup&gt;225&lt;/sup&gt;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 [&lt;sup&gt;111&lt;/sup&gt;In]In-DOTA-trastuzumab.&lt;/p&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;p&gt;We conclude that [&lt;sup&gt;225&lt;/sup&gt;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&lt;sup&gt;+&lt;/sup&gt; human BC tumours in NRG mice, and these tumours were imaged by SPECT/CT with [&lt;sup&gt;111&lt;/sup&gt;In]I","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"8 1","pages":""},"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}

{"title":"Imaging of fibrogenesis in the liver by [18F]TZ-Z09591, an Affibody molecule targeting platelet derived growth factor receptor β","authors":"Olivia Wegrzyniak,&nbsp;Bo Zhang,&nbsp;Johanna Rokka,&nbsp;Maria Rosestedt,&nbsp;Bogdan Mitran,&nbsp;Pierre Cheung,&nbsp;Emmi Puuvuori,&nbsp;Sofie Ingvast,&nbsp;Jonas Persson,&nbsp;Helena Nordström,&nbsp;John Löfblom,&nbsp;Fredrik Pontén,&nbsp;Fredrik Y. Frejd,&nbsp;Olle Korsgren,&nbsp;Jonas Eriksson,&nbsp;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 ([¹⁸F]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 [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.</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":"8 1","pages":""},"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}

{"title":"Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration","authors":"Ashleigh Hull,&nbsp;William Hsieh,&nbsp;Artem Borysenko,&nbsp;William Tieu,&nbsp;Dylan Bartholomeusz,&nbsp;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, [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.</p><h3>Results</h3><p>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.</p><h3>Conclusion</h3><p>[²²⁵Ac]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":"8 1","pages":""},"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}