Bifunctional derivatives of bis(phosphinate)-bearing cyclam (BPC) chelators bearing a carboxylate, amine, isothiocyanate, azide, or cyclooctyne in the BP side chain were synthesized. Conjugations required no protection of phosphinate or ring secondary amine groups. The ring amines were not reactive (proton protected) at pH < ∼8. For isothiocyanate coupling, oligopeptide N-terminal α-amines were more suitable than alkyl amines, e.g., Lys ω-amine (p Ka ∼7.5-8.5 and ∼10-11, respectively) due to lower basicity. The Cu-64 labeling was efficient at room temperature (specific activity ∼100 GBq/μmol; 25 °C, pH 6.2, ∼100 ligand equiv, 10 min). A representative Cu-64-BPC was tested in vivo showing fast clearance and no nonspecific radioactivity deposition. The monoclonal anti-PSCA antibody 7F5 conjugates with thiocyanate BPC derivative or NODAGA were radiolabeled and studied in PC3-PSCA tumor bearing mice by PET. The radiolabeled BPC conjugate was accumulated in the prostate tumor with a low off-target uptake, unlike Cu-64-labeled NODAGA-antibody conjugate. The BPC chelators have a great potential for theranostic applications of the Cu-64/Cu-67 matched pair.

• MeSH
• chelátory chemie   farmakokinetika   MeSH
• imunokonjugáty chemie   farmakokinetika   MeSH
• izotopové značení MeSH
• kyseliny fosfinové chemie   MeSH
• ligandy MeSH
• makrocyklické laktamy chemie   farmakokinetika   MeSH
• monoklonální protilátky chemie   farmakokinetika   MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory prostaty diagnóza   diagnostické zobrazování   metabolismus   MeSH
• potkani nazí MeSH
• potkani Wistar MeSH
• pozitronová emisní tomografie MeSH
• radiofarmaka chemie   farmakokinetika   MeSH
• radioizotopy mědi chemie   farmakokinetika   MeSH
• stabilita léku MeSH
• tkáňová distribuce MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• Copper-64 MeSH Prohlížeč
• imunokonjugáty MeSH
• kyseliny fosfinové MeSH
• ligandy MeSH
• makrocyklické laktamy MeSH
• monoklonální protilátky MeSH
• radiofarmaka MeSH
• radioizotopy mědi MeSH

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

• Klíčová slova
• 223Ra, actinium, alpha particle, astatine, bismuth, decay, in vivo generators, nuclear recoil, radium, targeted alpha therapy,
• MeSH
• aktinium chemie   terapeutické užití   MeSH
• alfa částice terapeutické užití   MeSH
• astat chemie   terapeutické užití   MeSH
• bismut chemie   terapeutické užití   MeSH
• chelátory chemie   farmakokinetika   MeSH
• dávka záření MeSH
• heterocyklické sloučeniny monocyklické chemie   farmakokinetika   MeSH
• heterocyklické sloučeniny chemie   farmakokinetika   MeSH
• knihovny malých molekul chemie   farmakokinetika   MeSH
• lidé MeSH
• nádory patologie   radioterapie   MeSH
• nosiče léků aplikace a dávkování   chemie   MeSH
• radiofarmaka chemie   terapeutické užití   MeSH
• radionuklidy chemie   terapeutické užití   MeSH
• radium chemie   terapeutické užití   MeSH
• vztah dávky záření a odpovědi MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• 1,4,7-triazacyclononane-N,N',N''-triacetic acid MeSH Prohlížeč
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid MeSH Prohlížeč
• Actinium-225 MeSH Prohlížeč
• aktinium MeSH
• astat MeSH
• Astatine-211 MeSH Prohlížeč
• bismut MeSH
• Bismuth-213 MeSH Prohlížeč
• chelátory MeSH
• heterocyklické sloučeniny monocyklické MeSH
• heterocyklické sloučeniny MeSH
• knihovny malých molekul MeSH
• nosiče léků MeSH
• radiofarmaka MeSH
• radionuklidy MeSH
• Radium-223 MeSH Prohlížeč
• radium 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

The effect of replacement of the N,N-chelating ligand 1,10-phenanthroline (phen) in the Ir(III) pentamethylcyclopentadienyl (Cp*) complex [(η(5)-Cp*)(Ir)(phen)Cl](+) (2) with the C,N-chelating ligand 7,8-benzoquinoline (bq) to give [(η(5)-Cp*)(Ir)(bq)Cl] (1) on the cytotoxicity of these Cp*Ir(III) complexes toward cancer cell lines was investigated. Complex 2 is inactive, similar to other Cp*Ir(III) complexes containing the N,N-chelating ligands. In contrast, a single atom change (C(-) for N) in the chelating N,N ligand resulted in potency in human ovarian carcinoma cisplatin-sensitive A2780 cells, and, strikingly, 1 is active in the cisplatin-resistant human breast cancer MCF-7 and A2780/cisR cells. Replacement of the N,N-chelating ligand with the C,N-chelating ligand gives rise to increased hydrophobicity, leading to higher cellular accumulation, higher DNA-bound iridium in cells and higher cytotoxicity. The pathways involved in cellular accumulation of 1 have been further explored and compared with conventional cisplatin. The results show that both energy-independent passive diffusion and energy-dependent transport play a role in accumulation of 1. Further results were consistent with involvement of p-glycoprotein, multidrug resistance-associated protein 1 and glutathione metabolism in the efflux of 1. In contrast, the internalization of 1 mediated by the endocytotic uptake pathway(s) seems less likely. Understanding the factors which contribute to the mechanism of cellular accumulation of this Ir(III) complex can now lead to the design of structurally similar metal complexes for antitumor chemotherapy.

• MeSH
• antitumorózní látky chemie   farmakokinetika   farmakologie   MeSH
• chelátory chemie   farmakokinetika   farmakologie   MeSH
• chemorezistence MeSH
• cisplatina farmakologie   MeSH
• iridium chemie   farmakokinetika   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakokinetika   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   metabolismus   MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• chelátory MeSH
• cisplatina MeSH
• iridium MeSH
• komplexní sloučeniny MeSH
• multidrug resistance-associated protein 1 MeSH Prohlížeč
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH

The distribution and elimination of 99Tcm-complexes with methylene-diphosphonate (MDP) and with the calcium salt of diethylene-triamine-penta(methylene phosphonate) (DTPMP) were compared in rats. Both compounds exhibited high bone uptake and long-term retention of radioactivity in the skeleton. No significant accumulation of the complexes in non-osseous tissues was found. The pharmacokinetics of both chelates were similar, small differences in their distribution and elimination probably being due to different binding to plasma proteins. Two processes, namely bone uptake and kidney elimination, contributed to the disappearance of the complexes from the blood. The higher protein binding of 99Tcm-MDP probably caused its slower rate of urine elimination and insignificantly higher bone uptake compared with 99Tcm-DTPMP. On the other hand, the more rapid reduction in blood and muscle radioactivity with 99Tcm-DTPMP resulted in accelerated non-osseous tissue clearance compared with 99Tcm-MDP. This suggests that the time between administration and imaging may be shorter for 99Tcm-DTPMP than for 99Tcm-MDP. Furthermore, the much greater stability of 99Tcm-DTPMP may also reduce degradation of the complex and 99Tcm liberation in the body. For a general evaluation of both compounds, it will be necessary to determine lesion-to-bone ratios.

• MeSH
• chelátory farmakokinetika   MeSH
• kosti a kostní tkáň diagnostické zobrazování   MeSH
• krevní proteiny metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• organofosforové sloučeniny * farmakokinetika   MeSH
• organotechneciové sloučeniny * farmakokinetika   MeSH
• potkani Wistar MeSH
• radiofarmaka farmakokinetika   MeSH
• radioisotopová scintigrafie MeSH
• technecium 99mTc medronát * farmakokinetika   MeSH
• techniky in vitro MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• chelátory MeSH
• diethylenetriaminepenta(methylenephosphonic) acid MeSH Prohlížeč
• krevní proteiny MeSH
• organofosforové sloučeniny * MeSH
• organotechneciové sloučeniny * MeSH
• radiofarmaka MeSH
• technecium 99mTc medronát * MeSH

The pharmacokinetics and elimination of EDTMP chelates with different radionuclides (99mTc, 111In and 153Sm) has been investigated in rats. The biodistribution of the complexes under study was similar and two main processes, namely bone uptake and the elimination of glomerular filtration, take part in their rapid blood clearance. A substantially slower blood clearance of 111In-EDTMP in comparison with the other complexes suggests partial indium exchange between the chelate and transferrin. All the complexes exhibited high affinity for bone and the radionuclide uptake into the skeleton was in the order 153Sm > 111In > 99mTc. No specific extra-skeletal uptake was found.

• MeSH
• časové faktory MeSH
• chelátory farmakokinetika   MeSH
• izotopové značení metody   MeSH
• krysa rodu Rattus MeSH
• organofosforové sloučeniny farmakokinetika   MeSH
• potkani Wistar MeSH
• radioizotopy india farmakokinetika   MeSH
• radionuklidy farmakokinetika   MeSH
• samarium farmakokinetika   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
• srovnávací studie MeSH
• Názvy látek
• (ethylenedinitrilo)-tetramethylenephosphonic acid MeSH Prohlížeč
• chelátory MeSH
• organofosforové sloučeniny MeSH
• radioizotopy india MeSH
• radionuklidy MeSH
• samarium MeSH
• technecium MeSH