• MeSH
• galium MeSH
• nukleární lékařství MeSH
• teranostická nanomedicína MeSH
• Publikační typ
• abstrakty MeSH
• kongresy MeSH
• sborníky MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• radiologie, nukleární medicína a zobrazovací metody

BACKGROUND: Siderophores are small iron-binding molecules produced by microorganisms to facilitate iron acquisition from the environment. Radiolabelled siderophores offer a promising solution for infection imaging, as they can specifically target the pathophysiological mechanisms of pathogens. Gallium-68 can replace the iron in siderophores, enabling molecular imaging with positron emission tomography (PET). Stereospecific interactions play a crucial role in the recognition of receptors, transporters, and iron utilisation. Furthermore, these interactions have an impact on the host environment, affecting pharmacokinetics and biodistribution. This study examines the influence of siderophore stereoisomerism on imaging properties, with a focus on ferrirubin (FR) and ferrirhodin (FRH), two cis-trans isomeric siderophores of the ferrichrome type. RESULTS: Tested siderophores were labelled with gallium-68 with high radiochemical purity. The resulting complexes differed in their in vitro characteristics. [68Ga]Ga-FRH showed less hydrophilic properties and higher protein binding values than [68Ga]Ga-FR. The stability studies confirmed the high radiochemical stability of both [68Ga]Ga-siderophores in all examined media. Both siderophores were found to be taken up by S. aureus, K. pneumoniae and P. aeruginosa with similar efficacy. The biodistribution tested in normal mice showed rapid renal clearance with low blood pool retention and fast clearance from examined organs for [68Ga]Ga-FR, whereas [68Ga]Ga-FRH showed moderate retention in blood, resulting in slower pharmacokinetics. PET/CT imaging of mice injected with [68Ga]Ga-FR and [68Ga]Ga-FRH confirmed findings from ex vivo biodistribution studies. In a mouse model of S. aureus myositis, both radiolabeled siderophores showed radiotracer accumulation at the site of infection. CONCLUSIONS: The 68Ga-complexes of stereoisomers ferrirubin and ferrirhodin revealed different pharmacokinetic profiles. In vitro uptake was not affected by isomerism. Both compounds had uptake with the same bacterial culture with similar efficacy. PET/CT imaging showed that the [68Ga]Ga-complexes accumulate at the site of S. aureus infection, highlighting the potential of [68Ga]Ga-FR as a promising tool for infection imaging. In contrast, retention of the radioactivity in the blood was observed for [68Ga]Ga-FRH. In conclusion, the stereoisomerism of potential radiotracers should be considered, as even minor structural differences can influence their pharmacokinetics and, consequently, the results of PET imaging.

• Publikační typ
• časopisecké články MeSH

The inverse electron-demand Diels-Alder reaction between 1,2,4,5-tetrazine (Tz) and trans-cyclooct-2-ene (TCO) has gained increasing attraction among extensive studies on click chemistry due to its exceptionally fast reaction kinetics and high selectivity for in vivo pretargeting applications including PET imaging. The facile two-step approach utilizing TCO-modified antibodies as targeting structures has not made it into clinics yet. An increase in the blood volume of humans in comparison to mice seems to be the major limitation. This study aims to show if the design of multimeric Tz-ligands by chelator scaffolding can improve the binding capacity and may lead to enhanced PET imaging with gallium-68. We utilized for this purpose the macrocyclic siderophore Fusarinine C (FSC) which allows conjugation of up to three Tz-residues due to three primary amines available for site specific modification. The resulting mono- di- and trimeric conjugates were radiolabelled with gallium-68 and characterized in vitro (logD, protein binding, stability, binding towards TCO modified rituximab (RTX)) and in vivo (biodistribution- and imaging studies in normal BALB/c mice using a simplified RTX-TCO tumour surrogate). The 68Ga-labelled FSC-based Tz-ligands showed suitable hydrophilicity, high stability and high targeting specificity. The binding capacity to RTX-TCO was increased according to the grade of multimerization. Corresponding in vivo studies showed a multimerization typical profile but generally suitable pharmacokinetics with low accumulation in non-targeted tissue. Imaging studies in RTX-TCO tumour surrogate bearing BALB/c mice confirmed this trend and revealed improved targeting by multimerization as increased accumulation in RTX-TCO positive tissue was observed.

• Publikační typ
• časopisecké články MeSH

Cíl: Podrobnější přehled historie, současného stavu a nynějších trendů v získávání 68Ga, především z 68Ge/68Ga radionuklidového generátoru. Úvod: Pozitronová emisní tomografie (PET) je jednou z nejmodernějších metod nukleární medicíny. Stále nejhojněji využívaným radionuklidem při diagnostice pomocí PET je 18F, ale do popředí se dostávají i další pozitronové zářiče a velká pozornost je věnována právě 68Ga. Nespornou výhodou tohoto radionuklidu je způsob jeho získání. Oproti ostatním radionuklidům využívaným v PET diagnostice, které jsou připravovány téměř výhradně na cyklotronu, je 68Ga možné získat i pomocí radionuklidového generátoru, což výrazně zjednodušuje a urychluje další kroky jeho použití. Popis problematiky: Vývoj 68Ge/68Ga radionuklidových generátorů představoval komplexní výzkum separačních systémů, které jsou i dnes aktuálním tématem. V současnosti je dostupná řada separačních systémů, z nichž některé jsou již registrovány u Evropské agentury pro léčivé přípravky (EMA) či amerického Úřadu pro kontrolu potravin a léčiv (FDA) pro použití v humánní medicíně. Jiné jsou dostupné pouze pro výzkum a vývoj. S ohledem na technologické a legislativní těžkosti spojené s vývojem 68Ge/68Ga radionuklidového generátoru je navržení systému, který by poskytoval eluát 68Ga ve vhodné chemické formě a dostatečné radiochemické a radionuklidové čistotě, stále velkou výzvou a rozsáhlému studiu je věnována pozornost mnoha vědeckých týmů z celého světa. V České republice je dosud registrován jeden 68Ge/68Ga radionuklidový generátor a jeden kit pro značení 68Ga, SomaKit TOC pro diagnostiku neuroendokrinních tumorů (NET). Další kit, 68Ga-PSMA-11, je pak využíván pro diagnostiku karcinomu prostaty v rámci specifického léčebného programu. Ve světovém měřítku není však využití tohoto radionuklidu omezeno pouze na tyto aplikace a 68Ga je stále ve větší oblibě. Závěr: Rozsáhlé studie separačních systémů a cílících molekul by mohly v budoucnu vést u některých diagnostických procedur k nahrazení tradičního PET radionuklidu 18F právě 68Ga a to především díky možnosti eluce z radionuklidového generátoru.

Aim: Review of history, state of art and trends in gaining of 68Ga, especially from 68Ga/68Ge radionuclide generators. Introduction: Positron emission tomography (PET) is one of the most modern methods of nuclear medicine. Fluorine-18 is the most frequently used radionuclide for PET diagnostics, but there are other emerging radionuclides and the great attention is paid to 68Ga. The undeniable advantage of this radionuclide is its way of production. In contrast with other radionuclides for PET diagnostics almost exclusively prepared in the cyclotron, 68Ga can be gained also from a radionuclide generator which significantly simplifies and speeds up other steps of its use. Issue description: The development of 68Ge/68Ga radionuclide generators has been performed through the research of new separation systems which still remains a hot topic. Nowadays, the variety of separation systems is available. Some of them have a registration by European Medicines Agency (EMA) or American Food and Drug Administration (FDA) for use in human medicine. Others are suitable just for research and development. Regarding to technological and legislative difficulties connected with the development of 68Ge/68Ga radionuclide generator, the design of a system providing the eluate of 68Ga in convenient chemical form and sufficient radiochemical and radionuclide purity remains a great challenge and research teams around the world focus on the topic. Nowadays, there is one 68Ge/68Ga radionuclide generator and one kit for 68Ga labelling, SomaKit TOC, used for neuroendocrine tumours diagnostics registered in the Czech Republic. Other kit, 68Ga-PSMA-11, is used for diagnostics of prostate cancer in the specific treatment programme. However, the use of this radionuclide is not limited for these only applications and 68Ga enjoys the growing popularity in the world scale. Conclusion: Even though 18F remains the radionuclide of choice in PET, broad studies of separation systems and targeting molecules could lead to his replacement by 68Ga, mainly for the possibility of its elution from radionuclide generators.

• Klíčová slova
• gallium-68, germanium-68,
• MeSH
• pozitronová emisní tomografie * dějiny   metody   MeSH
• radioisotopové generátory * dějiny   přístrojové vybavení   MeSH
• radioizotopy galia * MeSH
• radionuklidy MeSH
• Publikační typ
• přehledy MeSH

Nukleární medicína je důležitým oborem moderní medicíny, zejména díky své roli v in vivo zobrazování důležitých procesů v lidském organizmu. Toto je možné prostřednictvím využití radiofarmak, specifických látek značených radioaktivním nuklidem, jejichž distribuci v těle lze vizualizovat pomocí speciálních skenerů a na základě fyziologických zákonitostí interpretovat dia­gnózu. Pozitronová emisní tomografie (PET) je moderní a v mnoha směrech nepostradatelná metoda nukleární medicíny. Spektrum radiofarmak pro tuto metodu dostupných se v posledních letech zvyšuje díky koordinované snaze výrobců syntézních zařízení, chemiků i potenciálních uživatelů – lékařů. Článek se formou přehledového článku zabývá vývojem na poli PET radiofarmak v posledních pěti letech s ohledem na onkologické aplikace PET.

Nuclear medicine is an important field of modern medicine, particularly thanks to its role in in vivo imaging of important processes in human organism. This is possible thanks to the use of radiopharmaceuticals, specific substances labeled by radioactive nuclide, its distribution in the body can be visualized by specialized scanners and, based on the knowledge of physiological patterns, dia­gnosis can be determined. Positron emission tomography (PET) is a modern and in many ways indispensable method of nuclear medicine. The spectrum of radiopharmaceuticals available in recent years is broadening thanks to a coordinated effort of manufacturers of synthesis equipment, chemists and potential users – physicians. This review focuses on the development in the PET radiopharmaceutical field in the last five years, with an emphasis on oncological applications of PET. Key words: nuclear medicine – positron-emission tomography – radiopharmaceuticals – gallium-68 – carbon-11 – fluorine-18 – zirconium-89 This work was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) and by MH CZ – DRO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 3. 2. 2014 Accepted: 3. 4. 2014

• Klíčová slova
• gallium-68, zirkonium-89, fluor-18, uhlík-11,
• MeSH
• fluorodeoxyglukosa F18 diagnostické užití   chemická syntéza   MeSH
• lidé MeSH
• nádory * MeSH
• pozitronová emisní tomografie * MeSH
• radiofarmaka * diagnostické užití   chemická syntéza   MeSH
• radioisotopové generátory přístrojové vybavení   MeSH
• radioizotopy fluoru diagnostické užití   MeSH
• radioizotopy galia diagnostické užití   MeSH
• radioizotopy uhlíku diagnostické užití   MeSH
• zirkonium diagnostické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Invasive pulmonary aspergillosis (IPA) is a life-threatening form of fungal infection, primarily in immunocompromised patients and associated with significant mortality. Diagnostic procedures are often invasive and/or time consuming and existing antifungals can be constrained by dose-limiting toxicity and drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced by the opportunistic pathogen Aspergillus fumigatus (A. fumigatus), with antifungal molecules to perform antifungal susceptibility tests and molecular imaging. A variation of small organic molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5) with antifungal activity were coupled to diacetylfusarinine C (DAFC), resulting in a "Trojan horse" to deliver antifungal compounds specifically into A. fumigatus hyphae by the major facilitator transporter MirB. Radioactive labeling with gallium-68 allowed us to perform in vitro characterization (distribution coefficient, stability, uptake assay) as well as biodistribution experiments and PET/CT imaging in an IPA rat infection model. Compounds chelated with stable gallium were used for antifungal susceptibility tests. [Ga]DAFC-fludioxonil, -FOA, and -Cy5 revealed a MirB-dependent active uptake with fungal growth inhibition at 16 µg/mL after 24 h. Visualization of an A. fumigatus infection in lungs of a rat was possible with gallium-68-labeled compounds using PET/CT. Heterogeneous biodistribution patterns revealed the immense influence of the antifungal moiety conjugated to DAFC. Overall, novel antifungal siderophore conjugates with promising fungal growth inhibition and the possibility to perform PET imaging combine both therapeutic and diagnostic potential in a theranostic compound for IPA caused by A. fumigatus.

• Publikační typ
• časopisecké články MeSH

Angiogenesis has a pivotal role in tumor growth and the metastatic process. Molecular imaging was shown to be useful for imaging of tumor-induced angiogenesis. A great variety of radiolabeled peptides have been developed to target αvβ3 integrin, a target structure involved in the tumor-induced angiogenic process. The presented study aimed to synthesize deferoxamine (DFO)-based c(RGD) peptide conjugate for radiolabeling with gallium-68 and perform its basic preclinical characterization including testing of its tumor-imaging potential. DFO-c(RGDyK) was labeled with gallium-68 with high radiochemical purity. In vitro characterization including stability, partition coefficient, protein binding determination, tumor cell uptake assays, and ex vivo biodistribution as well as PET/CT imaging was performed. [68Ga]Ga-DFO-c(RGDyK) showed hydrophilic properties, high stability in PBS and human serum, and specific uptake in U-87 MG and M21 tumor cell lines in vitro and in vivo. We have shown here that [68Ga]Ga-DFO-c(RGDyK) can be used for αvβ3 integrin targeting, allowing imaging of tumor-induced angiogenesis by positron emission tomography.

• MeSH
• deferoxamin analogy a deriváty   chemická syntéza   chemie   MeSH
• glioblastom diagnostické zobrazování   MeSH
• integrin alfaVbeta3 metabolismus   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• patologická angiogeneze diagnostické zobrazování   MeSH
• počítačová rentgenová tomografie metody   MeSH
• pozitronová emisní tomografie metody   MeSH
• radioizotopy galia chemie   MeSH
• tkáňová distribuce MeSH
• transplantace heterologní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Aspergillus fumigatus (A. fumigatus) is a human pathogen causing severe invasive fungal infections, lacking sensitive and selective diagnostic tools. A. fumigatus secretes the siderophore desferri-triacetylfusarinine C (TAFC) to acquire iron from the human host. TAFC can be labelled with gallium-68 to perform positron emission tomography (PET/CT) scans. Here, we aimed to chemically modify TAFC with fluorescent dyes to combine PET/CT with optical imaging for hybrid imaging applications. Starting from ferric diacetylfusarinine C ([Fe]DAFC), different fluorescent dyes were conjugated (Cy5, SulfoCy5, SulfoCy7, IRDye 800CW, ATTO700) and labelled with gallium-68 for in vitro and in vivo characterisation. Uptake assays, growth assays and live-cell imaging as well as biodistribution, PET/CT and ex vivo optical imaging in an infection model was performed. Novel fluorophore conjugates were recognized by the fungal TAFC transporter MirB and could be utilized as iron source. Fluorescence microscopy showed partial accumulation into hyphae. µPET/CT scans of an invasive pulmonary aspergillosis (IPA) rat model revealed diverse biodistribution patterns for each fluorophore. [68Ga]Ga-DAFC-Cy5/SufloCy7 and -IRDye 800CW lead to a visualization of the infected region of the lung. Optical imaging of ex vivo lungs corresponded to PET images with high contrast of infection versus non-infected areas. Although fluorophores had a decisive influence on targeting and pharmacokinetics, these siderophores have potential as a hybrid imaging compounds combining PET/CT with optical imaging applications.

• MeSH
• Aspergillus fumigatus MeSH
• fluorescenční barviva MeSH
• fluorescenční mikroskopie MeSH
• invazivní plicní aspergilóza diagnostické zobrazování   mikrobiologie   MeSH
• kompetitivní vazba MeSH
• koncentrace vodíkových iontů MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• PET/CT MeSH
• potkani inbrední LEW MeSH
• radioizotopy galia chemie   MeSH
• siderofory metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Indium-111 when formulated as indium-111 oxine remains the gold standard for long term cell tracking, whereas radiometals for improved PET applications still have to be established. We here describe the on-cartridge formation of gallium-68, zirconium-89 and copper-64 complexes in small volumes suitable for cell labelling, including labelling of red blood cells (RBC) and white blood cells (WBC) and their biological evaluation in vivo. METHODS: Small volumes (1-2 mL) of tracers (oxine, tropolone) were directly prepared on an anion exchange cartridge (Sep-Pak QMA). Cells were radiolabelled and the labelling efficiency and efflux were evaluated. The in vivo biodistribution of copper-64-labelled WBC using [64Cu][Cu(oxinate)2] and [64Cu][Cu(tropolonate)2] was monitored in an infection and inflammation animal model using BALB/c mice. RESULTS: On-cartridge concentration of gallium-68, zirconium-89 and copper-64 enabled formation of oxine and tropolone tracers in small volumes with good yields (≥50%) and quality (extraction ≥90%). Prepared tracers radiolabelled the RBC comparable to indium-111 tracers and in vivo biodistribution of copper-64 labelled WBC showed clear accumulation of cells at the site of infection and inflammation. CONCLUSIONS: This on-cartridge preparation method enables simple formation of various PET tracers for cell radiolabelling. Zirconium-89 and copper-64 tracers radiolabelled cells with sufficient stability. Due to their longer half-life this approach could be promising for routine applications where longer evaluation periods for cell tracking are needed. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This novel approach for on-cartridge concentration and preparation of oxine and tropolone precursors with different positron emitters, in small volume and suitable pH, offers a versatile tool towards cell labelling for preclinical and clinical PET applications.

• MeSH
• erytrocyty metabolismus   MeSH
• izotopové značení MeSH
• leukocyty metabolismus   MeSH
• myši MeSH
• PET/CT MeSH
• radiochemie přístrojové vybavení   MeSH
• radioizotopy galia chemie   metabolismus   MeSH
• radioizotopy mědi chemie   metabolismus   MeSH
• radionuklidy chemie   metabolismus   MeSH
• zirkonium chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Bacteria from the Burkholderia cepacia complex are generally considered to be non-pathogenic to the healthy population. However, some of these species may cause serious nosocomial infections in immunocompromised patients; as such, it is essential to diagnose these infections rapidly so that adequate treatment can be initiated. We report here the use of a radiolabeled siderophore, ornibactin (ORNB), for positron emission tomography imaging. We successfully radiolabeled ORNB with gallium-68 with high radiochemical purity and proved that the resulting complex has optimal in vitro characteristics. In mice, the complex did not show excessive accumulation in organs and was excreted in the urine. We demonstrated that the [68Ga]Ga-ORNB complex accumulates at the site of Burkholderia multivorans infection, including pneumonia, in two animal infection models. These results suggest that [68Ga]Ga-ORNB is a promising tool for the diagnosis, monitoring, and evaluation of the therapeutic response to B. cepacia complex infection.

• MeSH
• Burkholderia cepacia komplex * MeSH
• infekce bakteriemi rodu Burkholderia * diagnostické zobrazování   epidemiologie   MeSH
• myši MeSH
• pozitronová emisní tomografie MeSH
• radioizotopy galia MeSH
• siderofory MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH