EJNMMI Radiopharmacy and Chemistry最新文献

{"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}

{"title":"Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape","authors":"Raymond M. Reilly,&nbsp;Constantine J. Georgiou,&nbsp;Madeline K. Brown,&nbsp;Zhongli Cai","doi":"10.1186/s41181-024-00266-y","DOIUrl":"10.1186/s41181-024-00266-y","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups.&lt;/p&gt;&lt;h3&gt;Main body&lt;/h3&gt;&lt;p&gt;Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with &lt;sup&gt;111&lt;/sup&gt;In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [&lt;sup&gt;111&lt;/sup&gt;In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with β-particle emitting &lt;sup&gt;177&lt;/sup&gt;Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [&lt;sup&gt;90&lt;/sup&gt;Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [&lt;sup&gt;177&lt;/sup&gt;Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (&lt;sup&gt;111&lt;/sup&gt;In, &lt;sup&gt;99m&lt;/sup&gt;Tc, &lt;sup&gt;125&lt;/sup&gt;I, &lt;sup&gt;103&lt;/sup&gt;Pd, &lt;sup&gt;193m&lt;/sup&gt;Pt, &lt;sup&gt;195m&lt;/sup&gt;Pt), β-particles (&lt;sup&gt;177&lt;/sup&gt;Lu, &lt;sup&gt;186&lt;/sup&gt;Re, &lt;sup&gt;188&lt;/sup&gt;Re, &lt;sup&gt;90&lt;/sup&gt;Y, &lt;sup&gt;198&lt;/sup&gt;Au, &lt;sup&gt;131&lt;/sup&gt;I) or α-particles (&lt;sup&gt;225&lt;/sup&gt;Ac, &lt;sup&gt;213&lt;/sup&gt;Bi, &lt;sup&gt;212&lt;/sup&gt;Pb, &lt;sup&gt;211&lt;/sup&gt;At, &lt;sup&gt;223&lt;/sup&gt;Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity.&lt;/p&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;Radiation nanomedicines have shown great promise for treating canc","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00266-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140826087","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":"GMP production of [18F]FE-PE2I on a TRACERLab FX2 N synthesis module, a radiotracer for in vivo PET imaging of the dopamine transport","authors":"Mélodie Ferrat,&nbsp;Mohammad M. Moein,&nbsp;Carmen Cananau,&nbsp;Tetyana Tegnebratt,&nbsp;Paul Saliba,&nbsp;Fredrik Norman,&nbsp;Carsten Steiger,&nbsp;Klas Bratteby,&nbsp;Erik Samén,&nbsp;Kenneth Dahl,&nbsp;Thuy A. Tran","doi":"10.1186/s41181-024-00269-9","DOIUrl":"10.1186/s41181-024-00269-9","url":null,"abstract":"<div><h3>Background</h3><p>Parkinson's disease is a neurodegenerative disorder that is characterized by a degeneration of the dopaminergic system. Dopamine transporter (DAT) positron emission tomography (PET) imaging has emerged as a powerful and non-invasive method to quantify dopaminergic function in the living brain. The PET radioligand, [¹⁸F]FE-PE2I, a cocaine chemical derivative, has shown promising properties for in vivo PET imaging of DAT, including high affinity and selectivity for DAT, excellent brain permeability, and favorable metabolism. The aim of the current study was to scale up the production of [¹⁸F]FE-PE2I to fulfil the increasing clinical demand for this tracer.</p><h3>Results</h3><p>Thus, a fully automated and GMP-compliant production procedure has been developed using a commercially available radiosynthesis module GE TRACERLab FX2 N. [¹⁸F]FE-PE2I was produced with a radiochemical yield of 39 ± 8% (n = 4, relative [¹⁸F]F⁻ delivered to the module). The synthesis time was 70 min, and the molar activity was 925.3 ± 763 GBq/µmol (250 ± 20 Ci/µmol). The produced [¹⁸F]FE-PE2I was stable over 6 h at room temperature.</p><h3>Conclusion</h3><p>The protocol reliably provides a sterile and pyrogen–free GMP-compliant product.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00269-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140820449","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":"99mTc-labeled FAPI compounds for cancer and inflammation: from radiochemistry to the first clinical applications","authors":"Alessandra Boschi,&nbsp;Luca Urso,&nbsp;Licia Uccelli,&nbsp;Petra Martini,&nbsp;Luca Filippi","doi":"10.1186/s41181-024-00264-0","DOIUrl":"10.1186/s41181-024-00264-0","url":null,"abstract":"<div><h3>Background</h3><p>In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation. However, PET represents a high-cost technology, and its widespread adoption is still limited compared to the availability of gamma cameras. To address this issue, several efforts have been made to explore the potential of [^99mTc]Tc-FAPi tracers as molecular probes for imaging with gamma cameras and single photon emission computed tomography (SPECT).</p><h3>Main body</h3><p>Several approaches have been investigated for labeling FAPi-based compounds with ^99mTc. Specifically, the mono-oxo, tricarbonyl, isonitrile, and HYNIC strategies have been applied to produce [^99mTc]Tc-FAPi tracers, which have been tested in vitro and in animal models. Overall, these labeling approaches have demonstrated high efficiency and strong binding. The resulting [^99mTc]Tc-FAPi tracers have shown high specificity for FAP-positive cells and xenografts in both in vitro and animal model studies, respectively. However, the majority of [^99mTc]Tc-FAPi tracers have exhibited variable levels of lipophilicity, leading to preferential excretion through the hepatobiliary route and undesirable binding to lipoproteins. Consequently, efforts have been made to synthesize more hydrophilic FAPi-based compounds to improve pharmacokinetic properties and achieve a more favorable biodistribution, particularly in the abdominal region. SPECT imaging with [^99mTc]Tc-FAPi has yielded promising results in patients with gastrointestinal tumors, demonstrating comparable or superior diagnostic performance compared to other imaging modalities. Similarly, encouraging outcomes have been observed in subjects with gliomas, lung cancer, breast cancer, and cervical cancer. Beyond oncological applications, [^99mTc]Tc-FAPi-based imaging has been successfully employed in myocardial and idiopathic pulmonary fibrosis.</p><h3>Conclusions</h3><p>This overview focuses on the various radiochemical strategies for obtaining [^99mTc]Tc-FAPi tracers, highlighting the main challenges encountered and possible solutions when applying each distinct approach. Additionally, it covers the preclinical and initial clinical applications of [^99mTc]Tc-FAPi in cancer and inflammation.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00264-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140820450","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":"Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates","authors":"Severin Mairinger,&nbsp;Matthias Jackwerth,&nbsp;Ondřej Soukup,&nbsp;Matthias Blaickner,&nbsp;Clemens Decristoforo,&nbsp;Lukas Nics,&nbsp;Jens Pahnke,&nbsp;Marcus Hacker,&nbsp;Markus Zeitlinger,&nbsp;Oliver Langer","doi":"10.1186/s41181-024-00265-z","DOIUrl":"10.1186/s41181-024-00265-z","url":null,"abstract":"<div><h3>Background</h3><p>6-Bromo-7-[¹¹C]methylpurine ([¹¹C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [¹¹C]BMP afforded a mixture of 7- and 9-[¹¹C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [¹¹C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data.</p><h3>Results</h3><p>[¹¹C]BMP was synthesised by regioselective <i>N</i>^<i>7</i>-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [¹¹C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [¹¹C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [¹¹C]methyl iodide, with a radiochemical purity &gt; 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (<i>n</i> = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [¹¹C]BMP will deliver an effective dose in the typical range of ¹¹C-labelled radiotracers.</p><h3>Conclusions</h3><p>[¹¹C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [¹¹C]BMP will be safe and well tolerated in humans.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00265-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814115","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":"Small animal PET imaging with the 68Ga-labeled pH (low) insertion peptide-like peptide YJL-4 in a triple-negative breast cancer mouse model","authors":"YueHua Chen,&nbsp;ShuangShuang Song,&nbsp;YanQin Sun,&nbsp;FengYu Wu,&nbsp;GuangJie Yang,&nbsp;ZhenGuang Wang,&nbsp;MingMing Yu","doi":"10.1186/s41181-024-00267-x","DOIUrl":"10.1186/s41181-024-00267-x","url":null,"abstract":"<div><h3>Background</h3><p>The aim of this study was to prepare a novel ⁶⁸Ga-labeled pH (low) insertion peptide (pHLIP)-like peptide, YJL-4, and determine its value for the early diagnosis of triple-negative breast cancer (TNBC) via in vivo imaging of tumor-bearing nude mice. The novel peptide YJL-4 was designed using a template-assisted method and synthesized by solid-phase peptide synthesis. After modification with the chelator 1,4,7‑triazacyclononane-N,N′,N″-triacetic acid (NOTA), the peptide was labeled with ⁶⁸Ga. Then, the biodistribution of ⁶⁸Ga-YJL-4 in tumor-bearing nude mice was investigated, and the mice were imaged by small animal positron emission tomography (PET).</p><h3>Results</h3><p>The radiochemical yield and radiochemical purity of ⁶⁸Ga-YJL-4 were 89.5 ± 0.16% and 97.95 ± 0.06%, respectively. The biodistribution of ⁶⁸Ga-YJL-4 in tumors (5.94 ± 1.27% ID/g, 6.72 ± 1.69% ID/g and 4.54 ± 0.58% ID/g at 1, 2 and 4 h after injection, respectively) was significantly greater than that of the control peptide in tumors at the corresponding time points (<i>P</i> &lt; 0.01). Of the measured off-target organs, ⁶⁸Ga-YJL-4 was highly distributed in the liver and blood. The small animal PET imaging results were consistent with the biodistribution results. The tumors were visualized by PET at 2 and 4 h after the injection of ⁶⁸Ga-YJL-4. No tumors were observed in the control group.</p><h3>Conclusions</h3><p>The novel pHLIP family peptide YJL-4 can adopt an <i>α-</i>helical structure for easy insertion into the cell membrane in an acidic environment. ⁶⁸Ga-YJL-4 was produced in high radiochemical yield with good stability and can target TNBC tissue. Moreover, the strong concentration of radioactive ⁶⁸Ga-YJL-4 in the abdomen does not hinder the imaging of early TNBC.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00267-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140807309","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":"Radiolabeled 15-mer peptide internalization is mediated by megalin (LRP2 receptor) in a CRISPR/Cas9-based LRP2 knockout human kidney cell model","authors":"Anna Durinova,&nbsp;Lucie Smutna,&nbsp;Pavel Barta,&nbsp;Rajamanikkam Kamaraj,&nbsp;Tomas Smutny,&nbsp;Bernhard Schmierer,&nbsp;Petr Pavek,&nbsp;Frantisek Trejtnar","doi":"10.1186/s41181-024-00262-2","DOIUrl":"10.1186/s41181-024-00262-2","url":null,"abstract":"<div><h3>Background</h3><p>Megalin (LRP2 receptor) mediates the endocytosis of radiolabeled peptides into proximal tubular kidney cells, which may cause nephrotoxicity due to the accumulation of a radioactive tracer. The study aimed to develop a cellular model of human kidney HK2 cells with <i>LRP2</i> knockout (KO) using CRISPR/Cas9 technique. This model was employed for the determination of the megalin-mediated accumulation of ⁶⁸Ga- and ^99mTc-labeled 15-mer peptide developed to target the vascular endothelial growth factor (VEGF) receptor in oncology radiodiagnostics.</p><h3>Results</h3><p>The gene editing in the <i>LRP2</i> KO model was verified by testing two well-known megalin ligands when higher viability of KO cells was observed after gentamicin treatment at cytotoxic concentrations and lower FITC-albumin internalization by the KO cells was detected in accumulation studies. Fluorescent-activated cell sorting was used to separate genetically modified <i>LRP2</i> KO cell subpopulations. Moreover, flow cytometry with a specific antibody against megalin confirmed <i>LRP2</i> knockout. The verified KO model identified both ⁶⁸Ga- and ^99mTc-radiolabeled 15-mer peptides as megalin ligands in accumulation studies. We found that both radiolabeled 15-mers enter <i>LRP2</i> KO HK2 cells to a lesser extent compared to parent cells. Differences in megalin-mediated cellular uptake depending on the radiolabeling were not observed. Using biomolecular docking, the interaction site of the 15-mer with megalin was also described.</p><h3>Conclusion</h3><p>The CRISPR/Cas9 knockout of <i>LRP2</i> in human kidney HK2 cells is an effective approach for the determination of radiopeptide internalization mediated by megalin. This in vitro method provided direct molecular evidence for the cellular uptake of radiolabeled anti-VEGFR 15-mer peptides via megalin.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00262-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140619696","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}