EJNMMI Radiopharmacy and Chemistry最新文献

{"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}

{"title":"Reducing kidney uptake of radiolabelled exendin-4 using variants of the renally cleavable linker MVK","authors":"Belinda Trachsel,&nbsp;Giulia Valpreda,&nbsp;Alexandra Lutz,&nbsp;Roger Schibli,&nbsp;Linjing Mu,&nbsp;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 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.</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":"8 1","pages":""},"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}

{"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,&nbsp;Stijn De Schepper,&nbsp;Christel Vangestel,&nbsp;Stef De Lombaerde,&nbsp;Leonie wyffels,&nbsp;Tim Van den Wyngaert,&nbsp;Jeffrey Mattis,&nbsp;Brian Gray,&nbsp;Koon Pak,&nbsp;Sigrid Stroobants,&nbsp;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. [^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.</p><h3>Results</h3><p>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 &lt; 5% free tracer 3 h PI. Excretion was almost exclusively renal.</p><h3>Conclusion</h3><p>[^99mTc]Tc-Duramycin demonstrated acceptable dosimetry (&lt; 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.</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":"8 1","pages":""},"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}

{"title":"Evaluation of the pharmacokinetics, dosimetry, and therapeutic efficacy for the α-particle-emitting transarterial radioembolization (αTARE) agent [225Ac]Ac-DOTA-TDA-Lipiodol® against hepatic tumors","authors":"Anders Josefsson,&nbsp;Angel G. Cortez,&nbsp;Harikrishnan Rajkumar,&nbsp;Joseph D. Latoche,&nbsp;Ambika P. Jaswal,&nbsp;Kathryn E. Day,&nbsp;Mohammadreza Zarisfi,&nbsp;Lora H. Rigatti,&nbsp;Ziyu Huang,&nbsp;Jessie R. Nedrow","doi":"10.1186/s41181-023-00205-3","DOIUrl":"10.1186/s41181-023-00205-3","url":null,"abstract":"<div><h3>Background</h3><p>The liver is a common site for metastatic disease for a variety of cancers, including colorectal cancer. Both primary and secondary liver tumors are supplied through the hepatic artery while the healthy liver is supplied by the portal vein. Transarterial radioembolization (TARE) using yttrium-90 glass or resin microspheres have shown promising results with reduced side-effects but have similar survival benefits as chemoembolization in patients with hepatocellular carcinoma (HCC). This highlights the need for new novel agents against HCC. Targeted alpha therapy (TAT) is highly potent treatment due to the short range (sparing adjacent normal tissue), and densely ionizing track (high linear energy transfer) of the emitted α-particles. The incorporation of α-particle-emitting radioisotopes into treatment of HCC has been extremely limited, with our recent publication pioneering the field of α-particle-emitting TARE (αTARE). This study focuses on an in-depth evaluation of the αTARE-agent [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® as an effective therapeutic agent against HCC regarding pharmacokinetics, dosimetry, stability, and therapeutic efficacy.</p><h3>Results</h3><p>[²²⁵Ac]Ac-DOTA-TDA was shown to be a highly stable with bench-top stability at ≥ 95% radiochemical purity (RCP) over a 3-day period and serum stability was ≥ 90% RCP over 5-days. The pharmacokinetic data showed retention in the tumor of [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® and clearance through the normal organs. In addition, the tumor and liver acted as suppliers of the free daughters, which accumulated in the kidneys supplied via the blood. The dose limiting organ was the liver, and the estimated maximum tolerable activity based on the rodents whole-body weight: 728–3641 Bq/g (male rat), 396–1982 Bq/g (male mouse), and 453–2263 Bq/g (female mouse), depending on an RBE-value (range 1–5). Furthermore, [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® showed significant improvement in survival for both the male and female mice (median survival 47-days) compared with controls (26-days untreated, and 33–35-days Lipiodol^® alone).</p><h3>Conclusions</h3><p>This study shows that [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® is a stable compound allowing for centralized manufacturing and distribution world-wide. Furthermore, the result of this study support the continue development of evaluation of the αTARE-agent [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® as a potential treatment option for treating hepatic tumors.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"8 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10012436","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":"In vitro characterisation of [177Lu]Lu-DOTA-C595 as a novel radioimmunotherapy for MUC1-CE positive pancreatic cancer","authors":"Ashleigh Hull,&nbsp;William Hsieh,&nbsp;William Tieu,&nbsp;Dylan Bartholomeusz,&nbsp;Yanrui Li,&nbsp;Eva Bezak","doi":"10.1186/s41181-023-00204-4","DOIUrl":"10.1186/s41181-023-00204-4","url":null,"abstract":"<div><h3>Background</h3><p>Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [¹⁷⁷Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [¹⁷⁷Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC.</p><h3>Results</h3><p>A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [¹⁷⁷Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [¹⁷⁷Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [¹⁷⁷Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [¹⁷⁷Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [¹⁷⁷Lu]Lu-DOTA-C595.</p><h3>Conclusion</h3><p>[¹⁷⁷Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [¹⁷⁷Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"8 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10012437","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}