Anticalin proteins directed against the prostate-specific membrane antigen (PSMA), optionally having tailored plasma half-life using PASylation technology, show promise as radioligands for PET-imaging of xenograft tumors in mice. To investigate their suitability, the short-circulating unmodified Anticalin was labeled with 68Ga (τ1/2 = 68 min), using the NODAGA chelator, whereas the half-life extended PASylated Anticalin was labeled with 89Zr (τ1/2 = 78 h), using either the linear chelator deferoxamine (Dfo) or a cyclic derivative, fusarinine C (FsC). Different PSMA targeting Anticalin versions (optionally carrying the PASylation sequence) were produced carrying a single exposed N- or C-terminal Cys residue and site-specifically conjugated with the different radiochelators via maleimide chemistry. These protein conjugates were labeled with radioisotopes having distinct physical half-lives and, subsequently, applied for PET-imaging of subcutaneous LNCaP xenograft tumors in CB17 SCID mice. Uptake of the protein tracers into tumor versus healthy tissues was assessed by segmentation of PET data as well as biodistribution analyses. PET-imaging with both the 68Ga-labeled plain Anticalin and the 89Zr-labeled PASylated Anticalin allowed clear delineation of the xenograft tumor. The radioligand A3A5.1-PAS(200)-FsC·89Zr, having an extended plasma half-life, led to a higher tumor uptake 24 h p.i. compared to the 68Ga·NODAGA-Anticalin imaged 60 min p.i. (2.5% ID/g vs 1.2% ID/g). Pronounced demetallation was observed for the 89Zr·Dfo-labeled PASylated Anticalin, which was ∼50% lower in the case of the cyclic radiochelator FsC (p < 0.0001). Adjusting the plasma half-life of Anticalin radioligands using PASylation technology is a viable approach to increase radioisotope accumulation within the tumor. Furthermore, 89Zr-ImmunoPET-imaging using the FsC radiochelator is superior to that using Dfo. Our strategy for the half-life adjustment of a tumor-targeting Anticalin to match the physical half-life of the applied radioisotope illustrates the potential of small binding proteins as an alternative to antibodies for PET-imaging.

• Klíčová slova
• GCPII, GCPIII, N-acetyl-l-aspartyl-l-glutamate dipeptidase I, folate hydrolase 1, fusarinine, glutamate carboxypeptidase II, lipocalin,
• MeSH
• chelátory chemie   MeSH
• lidé MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory * MeSH
• pozitronová emisní tomografie metody   MeSH
• proteiny MeSH
• radioizotopy galia * MeSH
• radionuklidy chemie   MeSH
• tkáňová distribuce MeSH
• zirkonium chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane MeSH Prohlížeč
• chelátory MeSH
• fusigen MeSH Prohlížeč
• proteiny MeSH
• radioizotopy galia * MeSH
• radionuklidy MeSH
• zirkonium MeSH

Hybrid imaging combining the beneficial properties of radioactivity and optical imaging within one imaging probe has gained increasing interest in radiopharmaceutical research. In this study, we modified the macrocyclic gallium-68 chelator fusarinine C (FSC) by conjugating a fluorescent moiety and tetrazine (Tz) moieties. The resulting hybrid imaging agents were used for pretargeting applications utilizing click reactions with a trans-cyclooctene (TCO) tagged targeting vector for a proof of principle both in vitro and in vivo. Starting from FSC, the fluorophores Sulfocyanine-5, Sulfocyanine-7, or IRDye800CW were conjugated, followed by introduction of one or two Tz motifs, resulting in mono and dimeric Tz conjugates. Evaluation included fluorescence microscopy, binding studies, logD, protein binding, in vivo biodistribution, µPET (micro-positron emission tomography), and optical imaging (OI) studies. 68Ga-labeled conjugates showed suitable hydrophilicity, high stability, and specific targeting properties towards Rituximab-TCO pre-treated CD20 expressing Raji cells. Biodistribution studies showed fast clearance and low accumulation in non-targeted organs for both SulfoCy5- and IRDye800CW-conjugates. In an alendronate-TCO based bone targeting model the dimeric IRDye800CW-conjugate resulted in specific targeting using PET and OI, superior to the monomer. This proof of concept study showed that the preparation of FSC-Tz hybrid imaging agents for pretargeting applications is feasible, making such compounds suitable for hybrid imaging applications.

• Klíčová slova
• PET, click chemistry, fluorescence, fusarinine C, gallium-68, optical imaging,
• MeSH
• fluorescenční protilátková technika MeSH
• kyseliny hydroxamové * chemie   MeSH
• multimodální zobrazování * metody   MeSH
• optické zobrazování metody   MeSH
• ověření koncepční studie MeSH
• pozitronová emisní tomografie MeSH
• radiofarmaka * chemie   MeSH
• radioizotopy galia MeSH
• radionuklidy MeSH
• syntetická chemie okamžité shody MeSH
• tkáňová distribuce MeSH
• železité sloučeniny * chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fusigen MeSH Prohlížeč
• Gallium-68 MeSH Prohlížeč
• kyseliny hydroxamové * MeSH
• radiofarmaka * MeSH
• radioizotopy galia MeSH
• radionuklidy MeSH
• železité sloučeniny * 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.

• Klíčová slova
• PET, fluorescence microscopy, gallium-68, invasive pulmonary aspergillosis, near infrared, siderophores,
• 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
• Názvy látek
• fluorescenční barviva MeSH
• Gallium-68 MeSH Prohlížeč
• radioizotopy galia MeSH
• siderofory MeSH

PURPOSE: Aspergillus fumigatus produces the siderophore triacetylfusarinine C (TAFC) for iron acquisition which is essential for its virulence. Therefore, TAFC is a specific marker for invasive aspergillosis. We have shown previously that positron emission tomography (PET) imaging with [68Ga]TAFC exhibited excellent targeting properties in an A. fumigatus rat infection model. In this study, we aimed to prepare TAFC analogs modifying fusarinine C (FSC) by acylation with different carbon chain lengths as well as with charged substituents and investigated the influence of introduced substituents on preservation of TAFC characteristics in vitro and in vivo. PROCEDURES: Fifteen TAFC derivatives were prepared and labeled with gallium-68. In vitro uptake assays were carried out in A. fumigatus under iron-replete as well as iron-depleted conditions and distribution coefficient was determined. Based on these assays, three compounds, [68Ga]tripropanoyl(FSC) ([68Ga]TPFC), [68Ga]diacetylbutanoyl(FSC) ([68Ga]DABuFC), and [68Ga]trisuccinyl(FSC) ([68Ga]FSC(suc)3), with high, medium, and low in vitro uptake in fungal cultures, were selected for further evaluation. Stability and protein binding were evaluated and in vivo imaging performed in the A. fumigatus rat infection model. RESULTS: In vitro uptake studies using A. fumigatus revealed specific uptake of mono- and trisubstituted TAFC derivatives at RT. Lipophilicities as expressed by logD were 0.34 to - 3.80. The selected compounds displayed low protein binding and were stable in PBS and serum. Biodistribution and image contrast in PET/X-ray computed tomography of [68Ga]TPFC and [68Ga]DABuFC were comparable to [68Ga]TAFC, whereas no uptake in the infected region was observed with [68Ga]FSC(suc)3. CONCLUSIONS: Our studies show the possibility to modify TAFC without losing its properties and specific recognition by A. fumigatus. This opens also new ways for multimodality imaging or theranostics of fungal infection by introducing functionalities such as fluorescent dyes or antifungal moieties.

• Klíčová slova
• Aspergillus fumigatus, Gallium-68, Infection imaging, PET, Siderophores, Triacetylfusarinine C,
• MeSH
• Aspergillus fumigatus fyziologie   MeSH
• krevní proteiny metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyseliny hydroxamové chemie   MeSH
• lidé MeSH
• molekulární zobrazování * MeSH
• mutace genetika   MeSH
• mykózy diagnostické zobrazování   mikrobiologie   MeSH
• myši inbrední BALB C MeSH
• PET/CT MeSH
• plicní aspergilóza diagnostické zobrazování   mikrobiologie   MeSH
• radioizotopy galia chemie   MeSH
• siderofory chemická syntéza   chemie   MeSH
• tkáňová distribuce MeSH
• vazba proteinů MeSH
• železité sloučeniny chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Gallium-68 MeSH Prohlížeč
• krevní proteiny MeSH
• kyseliny hydroxamové MeSH
• N,N',N''-triacetylfusarinine C MeSH Prohlížeč
• radioizotopy galia MeSH
• siderofory MeSH
• železité sloučeniny MeSH

Cyclic pentapeptides containing the amino acid sequence arginine-glycine-aspartic (RGD) have been widely applied to target αvβ3 integrin, which is upregulated in various tumors during tumor-induced angiogenesis. Multimeric cyclic RGD peptides have been reported to be advantageous over monomeric counterparts for angiogenesis imaging. Here, we prepared mono-, di-, and trimeric cyclic arginine-glycine-aspartic-D-phenylalanine-lysine (c (RGDfK)) derivatives by conjugation with the natural chelator fusarinine C (FSC) using click chemistry based on copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC). The αvβ3 binding properties of 68Ga-labeled mono-, di-, and trimeric c(RGDfK) peptides were evaluated in vitro as well as in vivo and compared with the references monomeric [68Ga]GaNODAGA-c(RGDfK) and trimeric [68Ga]GaFSC(suc-c(RGDfK))3. All 68Ga-labeled c(RGDfK) peptides displayed hydrophilicity (logD = -2.96 to -3.80), low protein binding and were stable in phosphate buffered-saline (PBS) and serum up to 2 h. In vitro internalization assays with human melanoma M21 (αvβ3-positive) and M21-L (αvβ3-negative) cell lines showed specific uptake of all derivatives and increased in the series: mono- < di- < trimeric peptide. The highest tumor uptake, tumor-to-background ratios, and image contrast were found for the dimeric [68Ga]GaMAFC(c(RGDfK)aza)2. In conclusion, we developed a novel strategy for direct, straight forward preparation of mono-, di-, and trimeric c(RGDfK) conjugates based on the FSC scaffold. Interestingly, the best αvβ3 imaging properties were found for the dimeric [68Ga]GaMAFC(c(RGDfK)aza)2.

• Klíčová slova
• Angiogenesis, Gallium-68, PET, RGD, α(v)β(3) integrin,
• MeSH
• alkyny chemie   MeSH
• azidy chemie   MeSH
• cyklické peptidy chemie   farmakokinetika   MeSH
• izotopové značení MeSH
• měď chemie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• PET/CT MeSH
• polymerizace MeSH
• radioizotopy galia chemie   MeSH
• siderofory chemie   MeSH
• syntetická chemie okamžité shody MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• alkyny MeSH
• azidy MeSH
• cyclic arginine-glycine-aspartic acid peptide MeSH Prohlížeč
• cyklické peptidy MeSH
• Gallium-68 MeSH Prohlížeč
• měď MeSH
• radioizotopy galia MeSH
• siderofory 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.

• Klíčová slova
• Fusarinine C, PET, click chemistry, gallium-68, multimerization, pretargeting, rituximab,
• Publikační typ
• časopisecké články MeSH

Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting.

• MeSH
• chelátory chemie   farmakokinetika   MeSH
• heterografty MeSH
• integrin alfaVbeta3 metabolismus   MeSH
• kyseliny hydroxamové farmakokinetika   MeSH
• lidé MeSH
• molekulární sondy chemie   farmakokinetika   MeSH
• multimodální zobrazování metody   MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory diagnostické zobrazování   metabolismus   MeSH
• PET/CT MeSH
• radioizotopy galia farmakokinetika   MeSH
• receptor cholecystokininu B metabolismus   MeSH
• železité sloučeniny farmakokinetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• fusigen MeSH Prohlížeč
• integrin alfaVbeta3 MeSH
• kyseliny hydroxamové MeSH
• molekulární sondy MeSH
• radioizotopy galia MeSH
• receptor cholecystokininu B MeSH
• železité sloučeniny MeSH

PURPOSE: Multimeric arginine-glycine-aspartic acid (RGD) peptides have advantages for imaging integrin αvβ3 expression. Here, we compared the in vitro and in vivo behavior of three different Ga-68-labeled multimeric Fusarinine C-RGD (FSC-RGD) conjugates, whereby RGD was coupled directly, via a succinic acid or PEG linker (FSC(RGDfE)3, FSC(succ-RGD)3, FSC(Mal-RGD)3). The positron emission tomography/X-ray computed tomography (PET/CT) imaging properties were further compared using [(68)Ga]FSC(succ-RGD)3 with the monomeric [(68)Ga]NODAGA-RGD in a murine tumor model. PROCEDURE: FSC-RGD conjugates were labeled with Ga-68, and stability properties were studied. For in vitro characterization, the partition coefficient, integrin αvβ3 binding affinity, and cell uptake were determined. To characterize the in vivo properties, biodistribution studies and microPET/CT were carried out using mice bearing either human M21/M21-L melanoma or human U87MG glioblastoma tumor xenografts. RESULTS: All FSC-RGD conjugates were quantitatively labeled with Ga-68 within 10 min at RT. The [(68)Ga]FSC-RGD conjugates exhibited high stability and hydrophilic character, with only minor differences between the different conjugates. In vitro and in vivo studies showed enhanced integrin αvβ3 binding affinity, receptor-selective tumor uptake, and rapid renal excretion resulting in good imaging properties. CONCLUSIONS: The type of linker between FSC and RGD had no pronounced effect on targeting properties of [(68)Ga]FSC-RGD trimers. In particular, [(68)Ga]FSC(succ-RGD)3 exhibited improved properties compared to [(68)Ga]NODAGA-RGD, making it an alternative for imaging integrin αvβ3 expression.

• Klíčová slova
• Fusarinine C, Gallium-68, Integrins, Positron emission tomography (PET), RGD peptides,
• MeSH
• acetáty chemie   MeSH
• endocytóza MeSH
• heterocyklické sloučeniny monocyklické chemie   MeSH
• kyseliny hydroxamové chemie   MeSH
• lidé MeSH
• melanom diagnostické zobrazování   patologie   MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• oligopeptidy chemie   MeSH
• PET/CT * MeSH
• radiofarmaka chemie   MeSH
• radioizotopy galia MeSH
• tkáňová distribuce MeSH
• xenogenní modely - testy antitumorózní aktivity * MeSH
• železité sloučeniny chemie   MeSH
• zobrazování trojrozměrné MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane MeSH Prohlížeč
• acetáty MeSH
• arginyl-glycyl-aspartic acid MeSH Prohlížeč
• fusigen MeSH Prohlížeč
• heterocyklické sloučeniny monocyklické MeSH
• kyseliny hydroxamové MeSH
• oligopeptidy MeSH
• radiofarmaka MeSH
• radioizotopy galia MeSH
• železité sloučeniny MeSH

BACKGROUND: 6-[Bis(carboxymethyl)amino]-1,4-bis(carboxymethyl)-6-methyl-1,4-diazepane (AAZTA ) is a promising chelator with potential advantages over 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radiopharmaceutical applications. Its mesocyclic structure enables fast radiolabelling under mild conditions with trivalent metals including not only (68)Ga for positron emission tomography (PET) but also (177)Lu and (111)In for single-photon emission computed tomography (SPECT) and radionuclide therapy. Here, we describe the evaluation of a bifunctional AAZTA derivative conjugated to a model minigastrin derivative as a potential theranostic agent. METHODS: An AAZTA derivative with an aliphatic C9 chain as linker was coupled to a minigastrin, namely [AAZTA(0), D-Glu(1), desGlu(2-6)]-minigastrin (AAZTA-MG), and labelled with (68)Ga, (177)Lu and (111)In. The characterisation in vitro included stability studies in different media and determination of logD (octanol/PBS). Affinity determination (IC50) and cell uptake studies were performed in A431-CCK2R cells expressing the human CCK2 receptor. μPET/CT and ex vivo biodistribution studies were performed in CCK2 tumour xenograft-bearing nude mice and normal mice. RESULTS: AAZTA-MG showed high radiochemical yields for (68)Ga (>95 %), (177)Lu (>98 %) and (111)In (>98 %). The logD value of -3.7 for both [(68)Ga]- and [(177)Lu]-AAZTA-MG indicates a highly hydrophilic character. Stability tests showed overall high stability in solution with some degradation in human plasma for [(68)Ga]- and transchelation towards DTPA for and [(177)Lu]-AAZTA-MG. An IC50 value of 10.0 nM was determined, which indicates a high affinity for the CCK2 receptor. Specific cell uptake after 60 min was >7.5 % for [(68)Ga]-AAZTA-MG and >9.5 % for [(177)Lu]-AAZTA-MG, comparable to other DOTA-MG-analogues. μPET/CT studies in CCK2 receptor tumour xenografted mice not only revealed high selective accumulation in A431-CCK2R positive tumours of (68)Ga-labelled AAZTA-MG (1.5 % ID/g in 1 h post injection) but also higher blood levels as corresponding DOTA-analogues. The (111)In-labelled peptide had a tumour uptake of 1.7 % ID/g. Biodistribution in normal mice with the [(177)Lu]-AAZTA-MG showed a considerable uptake in intestine (7.3 % ID/g) and liver (1.5 % ID/g). CONCLUSION: Overall, AAZTA showed interesting properties as bifunctional chelator for peptides providing mild radiolabelling conditions for both (68)Ga and trivalent metals having advantages over the currently used chelator DOTA. Studies are ongoing to further investigate in vivo targeting properties and stability issues and the influence of spacer length on biodistribution of AAZTA.

• Publikační typ
• časopisecké články MeSH

Within the last years (89)Zr has attracted considerable attention as long-lived radionuclide for positron emission tomography (PET) applications. So far desferrioxamine B (DFO) has been mainly used as bifunctional chelating system. Fusarinine C (FSC), having complexing properties comparable to DFO, was expected to be an alternative with potentially higher stability due to its cyclic structure. In this study, as proof of principle, various FSC-RGD conjugates targeting αvß3 integrins were synthesized using different conjugation strategies and labeled with (89)Zr. In vitro stability, biodistribution, and microPET/CT imaging were evaluated using [(89)Zr]FSC-RGD conjugates or [(89)Zr]triacetylfusarinine C (TAFC). Quantitative (89)Zr labeling was achieved within 90 min at room temperature. The distribution coefficients of the different radioligands indicate hydrophilic character. Compared to [(89)Zr]DFO, [(89)Zr]FSC derivatives showed excellent in vitro stability and resistance against transchelation in phosphate buffered saline (PBS), ethylenediaminetetraacetic acid solution (EDTA), and human serum for up to 7 days. Cell binding studies and biodistribution as well as microPET/CT imaging experiments showed efficient receptor-specific targeting of [(89)Zr]FSC-RGD conjugates. No bone uptake was observed analyzing PET images indicating high in vivo stability. These findings indicate that FSC is a highly promising chelator for the development of (89)Zr-based PET imaging agents.

• Klíčová slova
• 89Zr, RGD peptide, fusarinine C, positron emission tomography (PET), triacetylfusarinine C,
• MeSH
• chelátory chemie   MeSH
• kyseliny hydroxamové chemie   MeSH
• lidé MeSH
• oligopeptidy chemie   MeSH
• pozitronová emisní tomografie MeSH
• radionuklidy chemie   MeSH
• železité sloučeniny chemie   MeSH
• zirkonium chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• arginyl-glycyl-aspartic acid MeSH Prohlížeč
• chelátory MeSH
• fusigen MeSH Prohlížeč
• kyseliny hydroxamové MeSH
• N,N',N''-triacetylfusarinine C MeSH Prohlížeč
• oligopeptidy MeSH
• radionuklidy MeSH
• železité sloučeniny MeSH
• zirkonium MeSH