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

BACKGROUND: Cholecystokinin receptor subtype 2 (CCK-2) is overexpressed in various tumours like medullary thyroid carcinomas and small cell lung cancer. Radiolabelled peptides that bind with high affinity and specificity to CCK-2 receptors, thus hold great potential for visualizing such tumours. METHODS: We compared four 111In labelled gastrin analogues, called minigastrins (MG), namely MG11, MG45, MG47 and MG48 linked to metal chelating DOTA in preclinical experiments. The radiolabelled peptides were tested for peptide binding in CCK-2 receptor-bearing cell line AR42J and for their pharmacokinetics in normal rats. RESULTS: The experiments suggest that all gastrin analogues had similar and relatively rapid internalization into AR42J cells. Binding to CCK-2 receptors in AR42J cells was saturable for all agents but there were some differences in receptor affinity. This biodistribution study in rats showed a rapid decrease in blood radioactivity, predominantly renal clearance and saturable uptake of the radiopharmaceutical and/or its metabolites in the CCK-2 receptor-positive stomach. Higher kidney accumulation of radioactivity was only found for 111In-DOTA-minigastrin 48. CONCLUSIONS: The data suggest that the 111In-DOTA-minigastrin analogues studied are promising candidates for the scintigraphy of CCK-2 receptor-expressing tumours; 111In-DOTA-MG47 and 111In-DOTA-MG11 are the most promising.

• MeSH
• gastriny farmakokinetika   farmakologie   MeSH
• heterocyklické sloučeniny monocyklické MeSH
• komplexní sloučeniny MeSH
• krysa rodu Rattus MeSH
• nádorové buněčné linie MeSH
• peptidy MeSH
• radiofarmaka MeSH
• receptor cholecystokininu B metabolismus   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• gastriny MeSH
• heterocyklické sloučeniny monocyklické MeSH
• indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid MeSH Prohlížeč
• komplexní sloučeniny MeSH
• minigastrin MeSH Prohlížeč
• peptidy MeSH
• radiofarmaka MeSH
• receptor cholecystokininu B MeSH

Radiolabeled cholecystokinin/gastrin (CCK) receptor-targeting peptides are promising compounds for radiodiagnosis and radiotherapy of certain malignancies. This study evaluated the pharmacokinetic profile of a CCK-2 receptor-specific peptide, Demogastrin 1, labeled with technetium-99m ((99m)Tc-Demogastrin 1), in rats. To investigate the fate of (99m)Tc-Demogastrin 1 in the rat, biodistribution and elimination studies in vivo were performed, and elimination parameters in perfused rat liver and kidney were determined. Biodistribution studies showed that (99m)Tc-Demogastrin 1 was rapidly cleared from the blood and most organs. A significant amount of radioactivity was detected in the CCK-2 receptor-rich organs, such as the stomach. Low radioactivity was found in the CCK-1 receptor-rich organs. Radioactivity in bowels and stomach declined relatively slowly. High and long-term retention of radioactivity in the kidneys was observed. Elimination of (99m)Tc-Demogastrin 1 via the bile was negligible. A high and rapid renal excretion was observed in elimination experiments in vivo. In the perfused kidney, glomerular filtration was found to be the main renal excretion mechanism of (99m)Tc-Demogastrin 1. Demogastrin 1 was distributed preferentially to the organs expressing CCK-2 receptors. The decisive elimination route of (99m)Tc-Demogastrin 1 in rats was urinary excretion. A high and prolonged renal retention may limit potential clinical use of the compound.

• MeSH
• gastriny farmakokinetika   MeSH
• izotopové značení metody   MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny metabolismus   MeSH
• potkani Wistar MeSH
• radiofarmaka farmakokinetika   MeSH
• receptor cholecystokininu B metabolismus   MeSH
• technecium farmakokinetika   MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• gastriny MeSH
• radiofarmaka MeSH
• receptor cholecystokininu B MeSH
• technecium MeSH

BACKGROUND: CART (cocaine- and amphetamine-regulated transcript) peptide and cholecystokinin (CCK) are neuromodulators involved in feeding behavior. This study is based on previously found synergistic effect of leptin and CCK on food intake and our hypothesis on a co-operation of the CART peptide and CCK in food intake regulation and Fos activation in their common targets, the nucleus tractus solitarii of the brainstem (NTS), the paraventricular nucleus (PVN), and the dorsomedial nucleus (DMH) of the hypothalamus. RESULTS: In fasted C57BL/6 mice, the anorexigenic effect of CART(61-102) in the doses of 0.1 or 0.5 microg/mouse was significantly enhanced by low doses of CCK-8 of 0.4 or 4 microg/kg, while 1 mg/kg dose of CCK-A receptor antagonist devazepide blocked the effect of CART(61-102) on food intake. After simultaneous administration of 0.1 microg/mouse CART(61-102) and of 4 microg/kg of CCK-8, the number of Fos-positive neurons in NTS, PVN, and DMH was significantly higher than after administration of each particular peptide. Besides, CART(61-102) and CCK-8 showed an additive effect on inhibition of the locomotor activity of mice in an open field test. CONCLUSION: The synergistic and long-lasting effect of the CART peptide and CCK on food intake and their additive effect on Fos immunoreactivity in their common targets suggest a co-operative action of CART peptide and CCK which could be related to synergistic effect of leptin on CCK satiety.

• MeSH
• antagonisté hormonů farmakologie   MeSH
• benzodiazepinony farmakologie   MeSH
• devazepid farmakologie   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• hubenost * MeSH
• injekce intraperitoneální MeSH
• injekce intraventrikulární MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neurony účinky léků   metabolismus   MeSH
• nucleus dorsomedialis hypothalami účinky léků   fyziologie   MeSH
• nucleus paraventricularis hypothalami účinky léků   fyziologie   MeSH
• nucleus solitarius účinky léků   fyziologie   MeSH
• pátrací chování účinky léků   fyziologie   MeSH
• peptidové fragmenty farmakologie   MeSH
• proteiny nervové tkáně farmakologie   MeSH
• protoonkogenní proteiny c-fos metabolismus   MeSH
• receptor cholecystokininu A antagonisté a inhibitory   MeSH
• receptor cholecystokininu B antagonisté a inhibitory   MeSH
• regulace chuti k jídlu účinky léků   fyziologie   MeSH
• sinkalid farmakologie   MeSH
• synergismus léků MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté hormonů MeSH
• benzodiazepinony MeSH
• Cocaine- and Amphetamine-Regulated Transcript Protein MeSH
• devazepid MeSH
• fenylmočovinové sloučeniny MeSH
• L 365260 MeSH Prohlížeč
• peptidové fragmenty MeSH
• proteiny nervové tkáně MeSH
• protoonkogenní proteiny c-fos MeSH
• receptor cholecystokininu A MeSH
• receptor cholecystokininu B MeSH
• sinkalid MeSH

BACKGROUND: Due to their high CCK-2/gastrin receptor selectivity, high affinity, and rapid background clearance, radiolabeled minigastrins (MG) are emerging as promising new tools in the diagnosis and therapy of CCK-2/gastrin receptor-positive tumors. In this study, the pharmacokinetic profile, particularly the excretion mode, of two 111In-labeled minigastrins was compared in rats. The first tracer, 111In-MG-0 is based on (D)Glu1-MG, while the second, 111In-MG-11, is its des-(Glu)5-derivative, expected to be less retained in renal tissue. MATERIALS AND METHODS: The fate of 111In-MG-0 and 111In-MG-11 in the body of rats was investigated during biodistribution and bioelimination experiments, while the respective elimination parameters were determined in perfused rat liver and kidney models. RESULTS: During biodistribution both compounds were rapidly cleared from the blood and most non-target organs whereas activity levels in the bowel and stomach declined slowly. The overall contribution of hepatobiliary excretion of 111In-MG-0 and 111In-MG-11 was relatively small. In the perfused rat liver their elimination into the bile was negligible. In contrast, renal excretion was the major excretion pathway for both analogs, mainly via glomerular filtration. However, kidney levels were substantially higher and retention was more prolonged in the case of 111In-MG-0 as compared to 111In-MG-11. CONCLUSION: The presence of the (Glu)5-chain in 111Ln-MG-0 appears to be implicated in the prolonged radioactivity retention in the kidney of rats.

• MeSH
• cholecystokinin metabolismus   MeSH
• gastriny farmakokinetika   MeSH
• izotopové značení MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• ledviny metabolismus   MeSH
• oligopeptidy farmakokinetika   MeSH
• peptidové fragmenty metabolismus   MeSH
• perfuze MeSH
• potkani Wistar MeSH
• radiofarmaka farmakokinetika   MeSH
• radioizotopy india * MeSH
• receptor cholecystokininu B metabolismus   MeSH
• substrátová specifita MeSH
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholecystokinin 21 MeSH Prohlížeč
• cholecystokinin MeSH
• gastriny MeSH
• minigastrin MeSH Prohlížeč
• oligopeptidy MeSH
• peptidové fragmenty MeSH
• radiofarmaka MeSH
• radioizotopy india * MeSH
• receptor cholecystokininu B MeSH

Several analogs of Boc-protected C-terminal heptapeptide of cholecystokinin (Boc-CCK-7) with modified C-end Phe were pharmacologically characterized. The influence of the number of methyl groups on aromatic side chain of Phe was investigated in following tests: binding to pancreatic and brain membrane receptors, gall bladder contraction, amylase secretion, anorexia, sedation and analgesia. Two analogs seem to be promising selective anorectic agents with strongly protracted effect: Boc-[Phe(triMe)7]CCK-7 and Boc-[Phe(pentaMe)7]CCK-7. The first analog exhibits the same spectrum of activities as CCK-8, however partially decreased central effects, the second one shows partially decreased peripheral activities and totally suppressed central ones. Our study supports the idea that C-terminal residue of CCK is more important for biological potency than for binding to CCK receptors.

• MeSH
• amylasy metabolismus   MeSH
• centrální nervový systém účinky léků   MeSH
• cholecystokinin analogy a deriváty   metabolismus   farmakologie   MeSH
• hypnotika a sedativa farmakologie   MeSH
• krysa rodu Rattus MeSH
• morčata MeSH
• myši MeSH
• nechutenství chemicky indukované   MeSH
• neopioidní analgetika farmakologie   MeSH
• potkani Wistar MeSH
• práh bolesti účinky léků   MeSH
• přijímání potravy účinky léků   MeSH
• receptor cholecystokininu A MeSH
• receptor cholecystokininu B MeSH
• receptory cholecystokininu účinky léků   metabolismus   MeSH
• spánek účinky léků   MeSH
• žlučník účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• morčata MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amylasy MeSH
• cholecystokinin MeSH
• hypnotika a sedativa MeSH
• neopioidní analgetika MeSH
• receptor cholecystokininu A MeSH
• receptor cholecystokininu B MeSH
• receptory cholecystokininu MeSH