Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.

• Klíčová slova
• 68Ga radiopharmaceuticals, NOTA derivatives, PET imaging, bis(phosphonate), bone targeting, in vivo imaging, macrocyclic complexes, nuclear medicine, phosphinate complexes, radiotracer biodistribution,
• MeSH
• bisfosfonáty * chemie   farmakokinetika   farmakologie   MeSH
• femur diagnostické zobrazování   metabolismus   MeSH
• galium * chemie   farmakokinetika   farmakologie   MeSH
• kontrastní látky * chemie   farmakokinetika   farmakologie   MeSH
• krysa rodu Rattus MeSH
• pozitronová emisní tomografie metody   MeSH
• radioaktivní indikátory * MeSH
• radiografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bisfosfonáty * MeSH
• galium * MeSH
• kontrastní látky * MeSH
• radioaktivní indikátory * MeSH

Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (H5te1PBP). The ligand showed a high selectivity to CuII over ZnII and NiII ions, and the bis(phosphonate) group was not coordinated in the CuII complex, strongly interacting with other metal ions in solution. The CuII complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The CuII-te1PBP complex also showed a high resistance to acid-assisted hydrolysis (t1/2 2.7 h; 1 M HClO4, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H5te1PBP radiolabeling with [64Cu]CuCl2 was fast and efficient, with specific activities of approximately 30 GBq 64Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [64Cu]CuII-te1PBP for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [18F]fluoride. Moreover, [64Cu]CuII-te1PBP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [64Cu]CuII-te1PBP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [18F]fluoride, albeit with a longer half-life (12.7 h) than 18F (1.8 h), thereby enabling extended observation times.

• MeSH
• cyklamy * MeSH
• fluoridy MeSH
• heterocyklické sloučeniny MeSH
• krysa rodu Rattus MeSH
• ligandy MeSH
• měď MeSH
• myši MeSH
• organofosfonáty * MeSH
• PET/CT MeSH
• radioizotopy mědi MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyclam MeSH Prohlížeč
• cyklamy * MeSH
• fluoridy MeSH
• heterocyklické sloučeniny MeSH
• ligandy MeSH
• měď MeSH
• organofosfonáty * MeSH
• radioizotopy mědi MeSH

Three 1,4,7,10-tetraazacyclododecane-based ligands disubstituted in 1,4-positions with phosphonic acid, phosphonate monoethyl-ester, and H-phosphinic acid pendant arms, 1,4-H4do2p, 1,4-H2do2pOEt, and 1,4-H2Bn2do2pH, were synthesized and their coordination to selected metal ions, Mg(II), Ca(II), Mn(II), Zn(II), Cu(II), Eu(III), Gd(III), and Tb(III), was investigated. The solid-state structure of the phosphonate ligand, 1,4-H4do2p, was determined by single-crystal X-ray diffraction. Protonation constants of the ligands and stability constants of their complexes were obtained by potentiometry, and their values are comparable to those of previously studied analogous 1,7-disubstitued cyclen derivatives. The Gd(III) complex of 1,4-H4do2p is ~1 order of magnitude more stable than the Gd(III) complex of the 1,7-analogue, probably due to the disubstituted ethylenediamine-like structural motif in 1,4-H4do2p enabling more efficient wrapping of the metal ion. Stability of Gd(III)-1,4-H2do2pOEt and Gd(III)-H2Bn2do2pH complexes is low and the constants cannot be determined due to precipitation of the metal hydroxide. Protonations of the Cu(II), Zn(II), and Gd(III) complexes probably takes place on the coordinated phosphonate groups. Complexes of Mn(II) and alkali-earth metal ions are significantly less stable and are not formed in acidic solutions. Potential presence of water molecule(s) in the coordination spheres of the Mn(II) and Ln(III) complexes was studied by variable-temperature NMR experiments. The Mn(II) complexes of the ligands are not hydrated. The Gd(III)-1,4-H4do2p complex undergoes hydration equilibrium between mono- and bis-hydrated species. Presence of two-species equilibrium was confirmed by UV-Vis spectroscopy of the Eu(III)-1,4-H4do2p complex and hydration states were also determined by luminescence measurements of the Eu(III)/Tb(III)-1,4-H4do2p complexes.

• Klíčová slova
• MRI contrast agents, copper, cyclen derivatives, gadolinium, macrocyclic ligands, manganese, metal complexes, phosphinate ligands, phosphonate ligands, protonation constants, stability constants,
• MeSH
• cyklamy MeSH
• europium chemie   MeSH
• gadolinium chemie   MeSH
• heterocyklické sloučeniny chemie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   MeSH
• kontrastní látky MeSH
• krystalografie rentgenová MeSH
• kyseliny fosfinové chemie   MeSH
• ligandy MeSH
• magnetická rezonanční spektroskopie MeSH
• mangan chemie   MeSH
• organofosfonáty chemie   MeSH
• potenciometrie MeSH
• spektrofotometrie ultrafialová MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cyclen MeSH Prohlížeč
• cyklamy MeSH
• ethyl phosphonate MeSH Prohlížeč
• europium MeSH
• gadolinium MeSH
• heterocyklické sloučeniny MeSH
• komplexní sloučeniny MeSH
• kontrastní látky MeSH
• kyseliny fosfinové MeSH
• ligandy MeSH
• mangan MeSH
• organofosfonáty MeSH

A novel alpha- and beta-configured pyrrolidine nucleoside phosphonates in adenine series were synthesized from trans-4-hydroxy-L-proline as starting material. d(ApA) analogues were also prepared and studied with respect to their hybridization properties with polyU.

• MeSH
• adenosin chemie   MeSH
• dinukleosidfosfáty chemie   MeSH
• hydroxyprolin MeSH
• indikátory a reagencie MeSH
• nukleotidy chemická syntéza   chemie   MeSH
• oligonukleotidy chemická syntéza   MeSH
• organofosfonáty chemie   MeSH
• poly U chemie   MeSH
• pyrrolidiny chemie   MeSH
• stereoizomerie MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenosin MeSH
• dinukleosidfosfáty MeSH
• hydroxyprolin MeSH
• indikátory a reagencie MeSH
• nukleotidy MeSH
• oligonukleotidy MeSH
• organofosfonáty MeSH
• poly U MeSH
• pyrrolidiny MeSH

A new phosphinic-acid DOTA-like ligand, DO3AP(BP), containing a geminal bis(phosphonic acid) moiety as a highly effective bone-seeking group, was synthesized in high yield. Its crystal structure was determined by X-ray analysis. Complexation with lanthanide(iii) ions occurs under mild conditions (pH = 8-9, 25 degrees C, 2-3 h). (1)H, (31)P, and (17)O NMR spectroscopy show that DO3AP(BP) forms nine-coordinated lanthanide(iii) complexes with one water molecule in the first coordination sphere except for Ln = Er-Lu, which have in addition a species without lanthanide(iii)-bound water. Selective formation of only two diastereomers (out of four possible) suggests that the coordinated phosphinate phosphorus atom occurs exclusively in one of the enantiomeric forms. The ratio of the twisted square antiprism (TSA) and square antiprism (SA) diastereomers changes along the lanthanide series; the gadolinium(iii) complex has about 35% of the TSA species. The bis(phosphonate) moiety remains free for anchoring to osseous tissue. The (1)H longitudinal relaxivity of the Gd-DO3AP(BP) complex (r(1) = 7.4 s(-1) mM(-1), 20 MHz, 25 degrees C, pH = 7.5) is unexpectedly high compared to that of other monohydrated chelates of similar size thanks to a significant contribution from the second hydration sphere. The water residence time tau(M)(298) is 198 ns. Further increase in the relaxivity was observed in the presence of Zn(ii), Mg(ii) or Ca(ii) ions, due to formation of coordination polymers. Slowing down of the tumbling rate of the Gd-DO3AP(BP) complex upon adsorption on hydroxyapatite also leads to an increase of the relaxivity (r(1) = 17 s(-1) mM(-1), 20 MHz, 25 degrees C, pH = 7.5).

• MeSH
• chelátory chemie   MeSH
• diagnostické zobrazování metody   MeSH
• gadolinium chemie   MeSH
• heterocyklické sloučeniny monocyklické chemie   MeSH
• hydroxyapatit chemie   MeSH
• kalcinóza * diagnostické zobrazování   patologie   radioterapie   MeSH
• kontrastní látky chemie   MeSH
• kosti a kostní tkáň cytologie   metabolismus   MeSH
• krystalografie rentgenová MeSH
• lanthanoidy chemie   MeSH
• molekulární struktura MeSH
• organofosfonáty chemie   MeSH
• radiografie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid MeSH Prohlížeč
• chelátory MeSH
• gadolinium MeSH
• heterocyklické sloučeniny monocyklické MeSH
• hydroxyapatit MeSH
• kontrastní látky MeSH
• lanthanoidy MeSH
• organofosfonáty MeSH

A novel and efficient method for the one-pot synthesis of diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates, starting from free phosphonic acids or phosphonate diesters is reported. The approach from phosphonate diesters via their bis(trimethylsilyl) esters is highly convenient, eliminates isolation and tedious purification of the phosphonic acids, and affords the corresponding bis-amidates in excellent yields (83-98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar concentrations with minimal cytotoxicity.

• MeSH
• adjuvancia imunologická chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• diamid chemická syntéza   chemie   farmakologie   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• látky proti HIV chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nukleosidy chemie   MeSH
• organofosfonáty chemie   MeSH
• preklinické hodnocení léčiv MeSH
• prekurzory léčiv chemická syntéza   chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• diamid MeSH
• látky proti HIV MeSH
• nukleosidy MeSH
• organofosfonáty MeSH
• prekurzory léčiv MeSH

The isopolar nonisosteric phosphonate analogs of ApA differing in the position of extra methylene group introduced into the sugar-phosphate backbone, featuring both possible 2',5'- and 3',5'- pairs as well as their conformationally restricted congeners, were investigated for their ability to form complexes with polyU. The results may lead to the specification of candidates for synthesis of novel oligonucleotides.

• MeSH
• adenin * MeSH
• dinukleosidfosfáty chemie   MeSH
• kinetika MeSH
• konformace nukleové kyseliny * MeSH
• molekulární struktura MeSH
• oligonukleotidy chemie   MeSH
• organofosfonáty * MeSH
• poly U chemie   MeSH
• spektrofotometrie ultrafialová MeSH
• termodynamika MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin * MeSH
• dinukleosidfosfáty MeSH
• oligonukleotidy MeSH
• organofosfonáty * MeSH
• poly U MeSH

New triphenylphosphines substituted with the gem-bis(phosphonate) moiety in the form of ethyl esters, tetraethyl [4-(diphenylphosphanyl)benzyl]methylene-bis(phosphonate) (2a) and octaethyl bis[4-(diphenylphosphanyl)benzyl]methylene-bis(phosphonate) (2b), and the corresponding free acids 3a and 3b were prepared by a multi-step synthesis and characterized by multinuclear NMR spectroscopy and mass spectrometry. The ester ligands 2a and 2b were conveniently purified through their borane adducts. The X-ray structure of 2b x 2BH3 x H2O was determined. Coordination properties of new ligands towards Rh(I), Pd(II) and Pt(II) ions were studied. 1H, 31P and 195Pt NMR spectroscopy showed that ligands 2a and 3a form the expected [RhCl(eta2:eta2-cod)(L)] (cod = cycloocta-1,5-diene) and [MCl2(L)2] (M = Pd, Pt) complexes. The compounds 2b and 3b behave as bridging bidentate ligands forming dinuclear complexes of the {[RhCl(eta2:eta2-cod)]2(mu-L-kappa2P,P')} and [M2Cl4(mu-L-kappa2P,P')2] (M = Pd, Pt) type. These findings are consistent with mass spectrometry and far-IR and Raman spectroscopy results. X-Ray structures of trans-[PdCl2(2a-kappaP)2] and cis,trans-[Pt2Cl4(mu-2b-kappa2P,P)2] were determined; the dinuclear complex exhibits a different arrangement on the Pt(II) centres which was observed for the first time in the solid state. Salts of complexes of the free acid 3a are highly soluble in water.

• Publikační typ
• časopisecké články MeSH

Dinucleotides (3'-5')-ApU and UpA and their 3'-O-phosphonylmethyl and 5'-O-phosphonylmethyl analogues were studied as substrates in the primed abortive synthesis catalysed by Escherichia coli DNA-dependent RNA polymerase on poly[d(A-T)] template. All phosphonate analogues of dinucleotides containing the anomalous sugar-phosphate backbone are substrates for the holoenzyme as verified by RNase A and RNase T2 digestion of the trinucleotide analogues obtained. The finding that phosphonate dinucleotides act as primers for transcription indicates that steric requirements at the initiation site are not as specific as previously supposed. Analysis of kinetic constants of ordered bibi reaction Kia, KmA, KmB and Vmax suggests that the instability of short RNA-DNA hybrids contributes to the abortive release of trinucleotides formed.

• MeSH
• dinukleosidfosfáty metabolismus   MeSH
• DNA řízené RNA-polymerasy metabolismus   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• Escherichia coli enzymologie   MeSH
• genetická transkripce MeSH
• kinetika MeSH
• organofosfonáty MeSH
• poly dA-dT metabolismus   MeSH
• substrátová specifita MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dinukleosidfosfáty MeSH
• DNA řízené RNA-polymerasy MeSH
• organofosfonáty MeSH
• poly dA-dT MeSH

Copper radioisotopes can be used for imaging as well as for therapy and, thus, can form ideal theranostic pairs. The Cu(II) complexes of cross-bridged cyclam (cb-cyclam) derivatives are considered to be highly stable in vivo. However, the complexes are mostly formed under harsh conditions not compatible with sensitive biomolecules. Here, a new class of cb-cyclam derivatives, cross-bridged bis(phosphinate)cyclams ("cb-BPC"), were investigated. Ligands with one or two methylene-bis(phosphinate) -CH2-PO2H-CH2-PO2H(R) (R = H, OH, substituted alkyl) pendant arms were synthesized. Bifunctionalization on the distant phosphorus atom was carried out by employing P-nitrobenzyl (R = CH2-Ph-4-NO2) precursors and/or, for cb-BPC with two bis(phosphinate) pendant arms, by reactions of silyl-phosphites obtained by silylation of their P(O)-H fragments. The reactive bifunctional groups include amine, carboxylate, azide, isothiocyanate, maleimide and/or tetrazine, and also their orthogonally reactive combination in a single molecule of chelator. The cb-BPCs with one bis(phosphinate) arm were not efficiently radiolabelled with 64Cu. The cb-BPCs with two pendant arms were radiolabelled even at room temperature and with only a small excess of chelator, leading to a high specific activity. Radiolabelling was fully comparable with that of analogous bis(phosphinate) derivatives of cyclam and identical radiolabelling of cyclam and cb-cyclam derivatives was observed for the first time. The cb-BPCs with two bis(phosphinate) pendant arms represent a new class of rigid chelators for copper radioisotopes that are easily synthetically modifiable, highly hydrophilic and radiolabelled under mild conditions.

• Publikační typ
• časopisecké články MeSH