EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"Trans-cyclooctene—a Swiss army knife for bioorthogonal chemistry: exploring the synthesis, reactivity, and applications in biomedical breakthroughs","authors":"Karuna Adhikari,&nbsp;Maarten Vanermen,&nbsp;Gustavo Da Silva,&nbsp;Tim Van den Wyngaert,&nbsp;Koen Augustyns,&nbsp;Filipe Elvas","doi":"10.1186/s41181-024-00275-x","DOIUrl":"10.1186/s41181-024-00275-x","url":null,"abstract":"<div><h3>Background</h3><p><i>Trans</i>-cyclooctenes (TCOs) are highly strained alkenes with remarkable reactivity towards tetrazines (Tzs) in inverse electron-demand Diels–Alder reactions. Since their discovery as bioorthogonal reaction partners, novel TCO derivatives have been developed to improve their reactivity, stability, and hydrophilicity, thus expanding their utility in diverse applications.</p><h3>Main body</h3><p>TCOs have garnered significant interest for their applications in biomedical settings. In chemical biology, TCOs serve as tools for bioconjugation, enabling the precise labeling and manipulation of biomolecules. Moreover, their role in nuclear medicine is substantial, with TCOs employed in the radiolabeling of peptides and other biomolecules. This has led to their utilization in pretargeted nuclear imaging and therapy, where they function as both bioorthogonal tags and radiotracers, facilitating targeted disease diagnosis and treatment. Beyond these applications, TCOs have been used in targeted cancer therapy through a \"click-to-release\" approach, in which they act as key components to selectively deliver therapeutic agents to cancer cells, thereby enhancing treatment efficacy while minimizing off-target effects. However, the search for a suitable TCO scaffold with an appropriate balance between stability and reactivity remains a challenge.</p><h3>Conclusions</h3><p>This review paper provides a comprehensive overview of the current state of knowledge regarding the synthesis of TCOs, and its challenges, and their development throughout the years. We describe their wide ranging applications as radiolabeled prosthetic groups for radiolabeling, as bioorthogonal tags for pretargeted imaging and therapy, and targeted drug delivery, with the aim of showcasing the versatility and potential of TCOs as valuable tools in advancing biomedical research and applications.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00275-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282653","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":"Synthesis and evaluation of [18F]FBNAF, a STAT3-targeting probe, for PET imaging of tumor microenvironment","authors":"Anna Miyazaki,&nbsp;Yasukazu Kanai,&nbsp;Keita Wakamori,&nbsp;Serina Mizuguchi,&nbsp;Mikiya Futatsugi,&nbsp;Fuko Hirano,&nbsp;Naoya Kondo,&nbsp;Takashi Temma","doi":"10.1186/s41181-024-00276-w","DOIUrl":"10.1186/s41181-024-00276-w","url":null,"abstract":"<div><h3>Background</h3><p>Signal transducer and activator of transcription 3 (STAT3) is a protein that regulates cell proliferation and differentiation, and it is attracting attention as a new index for evaluating cancer pathophysiology, as its activation has been highly correlated with the development and growth of tumors. With the development of STAT3 inhibitors, the demand for imaging probes will intensify. Noninvasive STAT3 imaging can help determine the cancer status and predict the efficacy of STAT3 inhibitors. In this study, we aimed to develop an imaging probe targeting STAT3 and synthesized [¹⁸F]FBNAF, which was derived from a STAT3-selective inhibitor as the lead compound, followed by in vitro and in vivo evaluations of [¹⁸F]FBNAF in positron emission tomography for STAT3.</p><h3>Results</h3><p>The results revealed that FBNAF concentration-dependently inhibited STAT3 phosphorylation, similar to the lead compound, thereby supporting radiosynthesis. [¹⁸F]FBNAF was easily synthesized from the pinacol boronate ester precursor with suitable radiochemical conversion (46%), radiochemical yield (6.0%), and radiochemical purity (&gt; 97%). [¹⁸F]FBNAF exhibited high stability in vitro and in vivo, and radioactivity accumulated in tumor tissues expressing STAT3 with an increasing tumor/blood ratio over time, peaking at 2.6 ± 0.8 at 120 min after injection in tumor-bearing mice. Tumor radioactivity was significantly reduced by the coinjection of a STAT3-selective inhibitor. Furthermore, the localization of radioactivity was almost consistent with STAT3 expression based on ex vivo autoradiography and immunohistochemistry using adjacent tumor sections.</p><h3>Conclusions</h3><p>Thus, [¹⁸F]FBNAF could be the first promising STAT3-targeting probe for PET imaging. A STAT3 imaging probe provides meaningful information on STAT3-associated cancer conditions and in tumor microenvironment.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00276-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246909","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":"Step-by-step optimisation of the radiosynthesis of the brain HDAC6 radioligand [18F]FSW-100 for clinical applications","authors":"Tetsuro Tago,&nbsp;Jun Toyohara","doi":"10.1186/s41181-024-00277-9","DOIUrl":"10.1186/s41181-024-00277-9","url":null,"abstract":"<div><h3>Background</h3><p>Histone deacetylase 6 (HDAC6) is an emerging target for the treatment and diagnosis of proteinopathies. [¹⁸F]FSW-100 was recently developed as a promising brain-penetrating radioligand for HDAC6 PET imaging and the process validation of [¹⁸F]FSW-100 radiosynthesis for clinical use is complete, but no detailed synthetic strategy nor process optimisation has been reported. Here, we describe the optimisation of several processes in [¹⁸F]FSW-100 radiosynthesis, including the ¹⁸F-fluorination reaction, semipurification of the ¹⁸F-intermediate, and purification of the product by high-performance liquid chromatography (HPLC), to achieve a radiochemical yield (RCY) adequate for clinical applications of the radioligand. Our findings will aid optimisation of radiosynthesis processes in general.</p><h3>Results</h3><p>In the ¹⁸F-fluorination reaction, the amount of copper reagent was reduced without reducing the nonisolated RCY of the intermediate (50%), thus reducing the risk of copper contamination in the product injection solution. Optimising the solid-phase extraction (SPE) conditions for semipurification of the intermediate improved its recovery efficiency. The addition of anti-radiolysis reagents to the mobile phase for the HPLC purification of [¹⁸F]FSW-100 increased its activity yield in radiosynthesis using a high [¹⁸F]fluoride radioactivity of approximately 50 GBq. The SPE-based formulation method and additives for the injection solution were optimised, and the resulting [¹⁸F]FSW-100 injection solution was stable for over 2 h with a radiochemical purity of greater than 95%.</p><h3>Conclusions</h3><p>Of all the reconsidered processes, we found that optimisation of the SPE-based semipurification of the intermediate and of the mobile phase for HPLC purification in particular improved the RCY of [¹⁸F]FSW-100, doubling it compared to that of the original protocol. The radioactivity of [¹⁸F]FSW-100 synthesized using the optimized protocol was sufficient for multiple doses for a clinical study.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00277-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236634","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":"eTFC-01: a dual-labeled chelate-bridged tracer for SSTR2-positive tumors","authors":"Dylan Chapeau,&nbsp;Savanne Beekman,&nbsp;Maryana Handula,&nbsp;Erika Murce,&nbsp;Corrina de Ridder,&nbsp;Debra Stuurman,&nbsp;Yann Seimbille","doi":"10.1186/s41181-024-00272-0","DOIUrl":"10.1186/s41181-024-00272-0","url":null,"abstract":"<div><h3>Background</h3><p>Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties. In our study, we designed a trifunctional chelate that facilitates the coupling of the targeting vector and fluorescent dye at opposite sites to avoid undesired steric hindrance effects. The synthesis of the trifunctional chelate N₃-Py-DOTAGA-(tBu)₃ (<b>7</b>) involved a five-step synthetic route, followed by conjugation to the linear peptidyl-resin <b>8</b> through solid-phase synthesis. After deprotection and cyclization, the near-infrared fluorescent dye sulfo-Cy.5 was introduced using copper free click chemistry, resulting in <b>eTFC-01</b>. Subsequently, <b>eTFC-01</b> was labeled with [¹¹¹In]InCl₃. In vitro assessments of eTFC-01 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex-vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice.</p><h3>Results</h3><p><b>eTFC-01</b> demonstrated a two-fold higher IC50 value for SSTR2 compared to the gold standard DOTA-TATE. Labeling of <b>eTFC-01</b> with [¹¹¹In]InCl₃ gave a high radiochemical yield and purity. The uptake of [¹¹¹In]In-<b>eTFC-01</b> in U2OS.SSTR2 cells was two-fold lower than the uptake of [¹¹¹In]In-DOTA-TATE, consistent with the binding affinity. Tumor uptake in H69-xenografted mice was lower for [¹¹¹In]In-<b>eTFC-01</b> at all-time points compared to [¹¹¹In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [¹¹¹In]In-<b>eTFC-01</b> in highly vascularized tissues, such as lungs, skin, and heart. Fluorescence measurements in different organs correlated with the radioactive signal distribution.</p><h3>Conclusion</h3><p>The successful synthesis and coupling of the trifunctional chelate to the peptide and fluorescent dye support the potential of this synthetic approach to generate dual labeled tracers. While promising in vitro, the in vivo results obtained with [¹¹¹In]In-<b>eTFC-01</b> suggest the need for adjustments to enhance tracer distribution.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00272-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074895","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 and in vivo evaluation of a tetrazine-conjugated poly-L-lysine effector molecule labeled with astatine-211","authors":"Chiara Timperanza,&nbsp;Holger Jensen,&nbsp;Ellinor Hansson,&nbsp;Tom Bäck,&nbsp;Sture Lindegren,&nbsp;Emma Aneheim","doi":"10.1186/s41181-024-00273-z","DOIUrl":"10.1186/s41181-024-00273-z","url":null,"abstract":"<div><h3>Background</h3><p>A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach for cancer treatment tackling disseminated cancer. As tumor size decreases, alpha-particles gain prominence due to their high Linear Energy Transfer (LET) and short path length. Among alpha-particle emitters, ²¹¹At stands out with its 7.2 hour half-life and 100% alpha emission decay. However, optimizing the pharmacokinetics of radiopharmaceuticals with short lived radionuclides such as ²¹¹At is pivotal, and in this regard, pretargeting is a valuable tool. This method involves priming the tumor with a modified monoclonal antibody capable of binding both the tumor antigen and the radiolabeled carrier, termed the “effector molecule. This smaller, faster-clearing molecule improves efficacy. Utilizing the Diels Alder click reaction between Tetrazine (Tz) and Trans-cyclooctene (TCO), the Tz-substituted effector molecule combines seamlessly with the TCO-modified antibody. This study aims to evaluate the in vivo biodistribution of two Poly-L-Lysine-based effector molecule sizes (10 and 21 kDa), labelled with ²¹¹At, and the in vitro binding of the most favorable polymer size, in order to optimize the pretargeted radioimmunotherapy with ²¹¹At.</p><h3>Results</h3><p>In vivo results favor the smaller polymer’s biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group.</p><h3>Conclusions</h3><p>Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00273-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141074846","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":"Highlight selection of radiochemistry and radiopharmacy developments by editorial board","authors":"Jun Toyohara,&nbsp;Danielle Vugts,&nbsp;Oliver C. Kiss,&nbsp;Sergio Todde,&nbsp;Xiang-Guo Li,&nbsp;Zhibo Liu,&nbsp;Zhi Yang,&nbsp;Nic Gillings,&nbsp;Emiliano Cazzola,&nbsp;Wiktor Szymanski,&nbsp;Nick van der Meulen,&nbsp;Raymond Reilly,&nbsp;Carlotta Taddei,&nbsp;Ralf Schirrmacher,&nbsp;Zijing Li,&nbsp;Yohannes Jorge Lagebo,&nbsp;Naoual Bentaleb,&nbsp;Marta de Souza Albernaz,&nbsp;Suzanne Lapi,&nbsp;Caterina Ramogida,&nbsp;Archana Mukherjee,&nbsp;Javier Ajenjo,&nbsp;Winnie Deuther-Conrad,&nbsp;Cécile Bourdeau","doi":"10.1186/s41181-024-00268-w","DOIUrl":"10.1186/s41181-024-00268-w","url":null,"abstract":"","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00268-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943751","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":"[68Ga]Ga-NODAGA-TriGalactan, a low molecular weight tracer for the non-invasive imaging of the functional liver reserve","authors":"Maximilian A. Zierke,&nbsp;Christine Rangger,&nbsp;Kimia Samadikhah,&nbsp;Marlene Panzer,&nbsp;Stefanie Dichtl,&nbsp;Nikolas Hörmann,&nbsp;Doris Wilflingseder,&nbsp;Andreas M. Schmid,&nbsp;Roland Haubner","doi":"10.1186/s41181-024-00271-1","DOIUrl":"10.1186/s41181-024-00271-1","url":null,"abstract":"<div><h3>Background</h3><p>Determination of the functional liver mass is important in a variety of clinical settings including liver surgery and transplantation. [^99mTc]Tc-diethylenetriamine-pentaacetic acid galactosyl human serum albumin (^99mTc-GSA) is a radiotracer targeting the asialoglycoprotein receptor (ASGR) and is routinely used in Japan for this purpose. Here we describe the development and evaluation of [⁶⁸Ga]Ga-NODAGA-TriGalactan a low molecular weight PET-tracer targeting this structure.</p><h3>Results</h3><p>For synthesis TRIS as branching unit and NODAGA as chelator for labelling with [⁶⁸Ga]Ga are included. Three galactose moieties are conjugated <i>via</i> a click chemistry approach resulting in the desired labelling precursor.⁶⁸Ga-labelling could be accomplished in high radiochemical yield and purity. [⁶⁸Ga]Ga-NODAGA-TriGalactan is very hydrophilic and revealed high plasma stability and low plasma protein binding. Fluorescence imaging showed binding on ASGR-positive organoids and the IC₅₀-value was in the nanomolar range. Most importantly, both biodistribution as well as animal imaging studies using normal mice demonstrated high liver uptake with rapid elimination from all other organs leading to even higher liver-to-background ratios as found for ^99mTc-GSA.</p><h3>Conclusion</h3><p>[⁶⁸Ga]Ga-NODAGA-TriGalactan shows high in vitro stability and selectively binds to the ASGR allowing imaging of the functional liver mass with high contrast. Thus, our first generation compound resulted already in an alternative to ^99mTc-GSA for imaging the functional liver reserve and might allow the broader use of this imaging technique.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00271-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943754","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 89Zr radiopharmaceutical production and quality control","authors":"Thomas Erik Wuensche,&nbsp;Serge Lyashchenko,&nbsp;Guus A. M. S. van Dongen,&nbsp;Danielle Vugts","doi":"10.1186/s41181-024-00258-y","DOIUrl":"10.1186/s41181-024-00258-y","url":null,"abstract":"<div><h3>Background</h3><p>During the previous two decades, PET imaging of biopharmaceuticals radiolabeled with zirconium-89 has become a consistent tool in preclinical and clinical drug development and patient selection, primarily due to its advantageous physical properties that allow straightforward radiolabeling of antibodies (⁸⁹Zr-immuno-PET). The extended half-life of 78.4 h permits flexibility with respect to the logistics of tracer production, transportation, and imaging and allows imaging at later points in time. Additionally, its relatively low positron energy contributes to high-sensitivity, high-resolution PET imaging. Considering the growing interest in radiolabeling antibodies, antibody derivatives, and other compound classes with ⁸⁹Zr in both clinical and pre-clinical settings, there is an urgent need to acquire valuable recommendations and guidelines towards standardization of labeling procedures.</p><h3>Main body</h3><p>This review provides an overview of the key aspects of ⁸⁹Zr-radiochemistry and radiopharmaceuticals. Production of ⁸⁹Zr, conjugation with the mostly used chelators and radiolabeling strategies, and quality control of the radiolabeled products are described in detail, together with discussions about alternative options and critical steps, as well as recommendations for troubleshooting. Moreover, some historical background on ⁸⁹Zr-immuno-PET, coordination chemistry of ⁸⁹Zr, and future perspectives are provided. This review aims to serve as a quick-start guide for scientists new to the field of ⁸⁹Zr-immuno-PET and to suggest approaches for harmonization and standardization of current procedures.</p><h3>Conclusion</h3><p>The favorable PET imaging characteristics of ⁸⁹Zr, its excellent availability due to relatively simple production and purification processes, and the development of suitable bifunctional chelators have led to the widespread use of ⁸⁹Zr. The combination of antibodies and ⁸⁹Zr, known as ⁸⁹Zr-immuno-PET, has become a cornerstone in drug development and patient selection in recent years. Despite the advanced state of ⁸⁹Zr-immuno-PET, new developments in chelator conjugation and radiolabeling procedures, application in novel compound classes, and improved PET scanner technology and quantification methods continue to reshape its landscape towards improving clinical outcomes.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00258-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140907930","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":"Automated synthesis of [89Zr]ZrCl4, [89Zr]ZrDFOSquaramide-bisPh(PSMA) and [89Zr]ZrDFOSquaramide-TATE","authors":"Asif Noor,&nbsp;Peter D. Roselt,&nbsp;Emily R. McGowan,&nbsp;Stan Poniger,&nbsp;Michael P. Wheatcroft,&nbsp;Paul S. Donnelly","doi":"10.1186/s41181-024-00270-2","DOIUrl":"10.1186/s41181-024-00270-2","url":null,"abstract":"<div><h3>Background</h3><p>Automated [⁸⁹Zr]Zr-radiolabeling processes have the potential to streamline the production of [⁸⁹Zr]Zr-labelled PET imaging agents. Most radiolabeling protocols use [⁸⁹Zr][Zr(ox)₄]⁴⁻ as the starting material and oxalate is removed after radiolabeling. In some instances, radiolabeling with [⁸⁹Zr]ZrCl₄ as starting material gives better radiochemical yields at lower reaction temperatures. In this work, a fully-automated process for production of [⁸⁹Zr]ZrCl₄ is reported and its use for the synthesis of [⁸⁹Zr]ZrDFOSq-bisPhPSMA and [⁸⁹Zr]ZrDFOSq-TATE.</p><h3>Results</h3><p>A simple automated process for the isolation of [⁸⁹Zr]ZrCl₄ by trapping [⁸⁹Zr][Zr(ox)₄]⁴⁻ on a bicarbonate-activated strong anion exchange cartridge followed by elution with 0.1 M HCl in 1 M NaCl was developed. [⁸⁹Zr]ZrCl₄ was routinely recovered from [⁸⁹Zr][Zr(ox)₄]⁴⁻ in &gt; 95% yield in mildly acidic solution of 0.1 M HCl in 1 M NaCl using a fully-automated process. The [⁸⁹Zr]ZrCl₄ was neutralized with sodium acetate buffer (0.25 M) removing the requirement for cumbersome manual neutralization with strong base. The mixture of [⁸⁹Zr]ZrCl₄ was used for direct automated radiolabeling reactions to produce [⁸⁹Zr]Zr-DFOSquaramide-bisPhPSMA and [⁸⁹Zr]ZrDFOSquaramide-TATE in 80–90% over all RCY in &gt; 95% RCP.</p><h3>Conclusions</h3><p>This method for the production of [⁸⁹Zr]ZrCl₄ does not require removal of HCl by evaporation making this process relatively fast and efficient. The fully automated procedures for the production of [⁸⁹Zr]ZrCl₄ and its use in radiolabeling are well suited to support the centralized and standardized manufacture of multiple dose preparations of zirconium-89 based radiopharmaceuticals.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00270-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140875495","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":"Bifunctional octadentate pseudopeptides as Zirconium-89 chelators for immuno-PET applications","authors":"Valentina Albanese,&nbsp;Chiara Roccatello,&nbsp;Salvatore Pacifico,&nbsp;Remo Guerrini,&nbsp;Delia Preti,&nbsp;Silvia Gentili,&nbsp;Matteo Tegoni,&nbsp;Maurizio Remelli,&nbsp;Denise Bellotti,&nbsp;Jonathan Amico,&nbsp;Giancarlo Gorgoni,&nbsp;Emiliano Cazzola","doi":"10.1186/s41181-024-00263-1","DOIUrl":"10.1186/s41181-024-00263-1","url":null,"abstract":"<div><h3>Background</h3><p>Positron emission tomography (PET) is a highly sensitive method that provides fine resolution images, useful in the field of clinical diagnostics. In this context, Zirconium-89 (⁸⁹Zr)-based imaging agents have represented a great challenge in molecular imaging with immuno-PET, which employs antibodies (mAbs) as biological vectors. Indeed, immuno-PET requires radionuclides that can be attached to the mAb to provide stable in vivo conjugates, and for this purpose, the radioactive element should have a decay half-life compatible with the time needed for the biodistribution of the immunoglobulin. In this regard, ⁸⁹Zr is an ideal radioisotope for immuno-PET because its half-life perfectly matches the in vivo pharmacokinetics of mAbs.</p><h3>Results</h3><p>The main objective of this work was the design and synthesis of a series of bifunctional octadentate pseudopeptides able to generate stable ⁸⁹Zr complexes. To achieve this, here we investigated hydroxamate, <i>N</i>-methylhydroxamate and catecholate chelating moieties in complexing radioactive zirconium. <i>N</i>-methylhydroxamate proved to be the most effective ⁸⁹Zr-chelating group. Furthermore, the increased flexibility and hydrophilicity obtained by using polyoxyethylene groups spacing the hydroxamate units led to chelators capable of rapidly forming (15 min) stable and water-soluble complexes with ⁸⁹Zr under mild reaction conditions (aqueous environment, room temperature, and physiological pH) that are mandatory for complexation reactions involving biomolecules. Additionally, we report challenge experiments with the competitor ligand EDTA and metal ions such as Fe³⁺, Zn²⁺ and Cu²⁺. In all examined conditions, the chelators demonstrated stability against transmetallation. Finally, a maleimide moiety was introduced to apply one of the most promising ligands in bioconjugation reactions through Thiol-Michael chemistry.</p><h3>Conclusion</h3><p>Combining solid phase and solution synthesis techniques, we identified novel ⁸⁹Zr-chelating molecules with a peptide scaffold. The adopted chemical design allowed modulation of molecular flexibility, hydrophilicity, as well as the decoration with different zirconium chelating groups. Best results in terms of ⁸⁹Zr-chelating properties were achieved with the N-methyl hydroxamate moiety. The Zirconium complexes obtained with the most effective compounds were water-soluble, stable to transmetallation, and resistant to peptidases for at least 6 days. Further studies are needed to assess the potential of this novel class of molecules as Zirconium-chelating agents for in vivo applications.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00263-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140842579","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}