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The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3APPrA and DO3APABn) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with 45Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc–DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc–DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with 44Sc was performed using the radioisotope from two sources, a 44Ti/44Sc generator and 44mSc/44Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of 44Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the 44Sc–DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine. [ABSTRACT FROM AUTHOR]

Bártíková, H., Křížová, V., Lamka, J., Kubíček, V., Skálová, L., Szotáková, B. Flubendazole metabolism and biotransformation enzymes activities in healthy sheep and sheep with haemonchosis. J. vet. Pharmacol. Therap. 33, 56–62. The aim of this project was to study the influence of haemonchosis, a common parasitic infection of small ruminants caused by Haemonchus contortus, on the activity of biotransformation enzymes and on in vitro flubendazole (FLU) biotransformation in liver and small intestine of lambs ( Ovis aries). Twelve lambs were divided into three groups: non-infected animals, animals orally infected with larvae of H. contortus ISE strain for 7 weeks and for 11 weeks. At the end of the experiment, hepatic and intestinal subcellular fractions were prepared and used for assays of biotransformation enzymes activities and FLU metabolism testing. The activities of hepatic cytochromes P450, flavine monooxygenases and carbonyl-reducing enzymes were decreased in infected animals. UDP-glucuronosyl transferase activity was significantly lower (by 35%) in 11 weeks infected animals than that in control animals. When in vitro metabolism of FLU was compared in control and infected animals, significantly lower velocity of FLU reduction was found in infected animals. Slower FLU reduction may be beneficial for the haemonchosis treatment using FLU, because FLU will remain longer in the organism and could cause longer contact of parasites with FLU. [ABSTRACT FROM AUTHOR]

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) -CH 2 -PO 2 H-CH 2 -PO 2 H(R) (R = H, OH, substituted alkyl) pendant arms were synthesized. Bifunctionalization on the distant phosphorus atom was carried out by employing P -nitrobenzyl (R = CH 2 -Ph-4-NO 2 ) 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 64 Cu. 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.

The cellular adhesion receptor αvβ6-integrin is highly expressed in many cancers, e.g., pancreatic, lung, head-and-neck, cervical, bladder, and esophageal carcinoma. Multimerization of αvβ6-integrin-specific RGD peptides increases the target affinity and retention but affects biodistribution and pharmacokinetics. Amide formation of the terminal carboxylic acid moieties of the square-symmetrical bifunctional chelator DOTPI with 3-azidopropylamine yields derivatives with 4, 3, and 2 terminal azides and zero, 1, and 2 remaining carboxylic acids, respectively, whereby formation of the 2-cis-isomer is preferred according to NMR investigation of the Eu(III)-complexes. Cu(II)-catalyzed alkyne-azide cycloaddition (CuAAC) of the alkyne-functionalized αvβ6-integrin binding peptide cyclo[YRGDLAYp( N Me)K(pent-4-ynoic amide)] (Tyr2) yields the respective di-, tri-, and tetrameric conjugates for Lu-177-labeling. In mice bearing αvβ6-integrin-expressing xenografts of H2009 (human lung adenocarcinoma) cells, the Lu-177-labeled trimer's tumor-to-blood ratio of 112 exceeds that of the tetramer (10.4) and the dimer (54). Co-infusion of gelofusine (succinylated gelatin) reduces the renal uptake of the trimer by 89%, resulting in a 10-fold better tumor-to-kidney ratio, while no improvement of that ratio is observed with arginine/lysine, para -aminohippuric acid (PAH), and hydroxyethyl starch (HES) coinfusions. Since the Lu-177-labeled Tyr2-trimer outperforms the dimer and the tetramer, such trimers are considered the best lead structures for the ongoing development of αvβ6-integrin targeted anticancer theranostics.

An easy and cheap method for measurement of Ga III complexation kinetics was developed. The method is based on UV-Vis quantification of non-complexed chelators after the addition of Cu II ions at individual time points. The method was evaluated using established ligands, H 3 nota and H 6 notP Pr , and was utilized to study the kinetics of Ga III complexation with four new symmetric derivatives of 1,4,7-triazacyclononane bearing methylphosphonate/phosphinate pendant arms - TRAP ligands. Chelators bearing ethoxy groups (H 3 L1) or 2,2,2-trifluoroethyl groups (H 3 L2) on the phosphorus atoms showed fast formation ( t 99% = 21 and 10 min, respectively, at pH 2.0) and efficient radiolabelling which were comparable to the previously reported chelators bearing the 2-carboxyethyl group (H 6 notP Pr ). Chelators bearing ( N , N -dibenzyl-amino)methyl (H 3 L3) and aminomethyl (H 3 L4) substituents showed a significantly slower complexation ( t 99% = 4.4 and 3.6 h, respectively, at pH 2.0) and inefficient radiolabelling, mainly at room temperature or low pH. This was caused by protonation of the amino groups of the pendant arms leading to coulombic repulsion between the Ga III ion and the positively charged protonated amines. The trends in complexation rates determined by the UV-Vis method correlated well with the results of the 68 Ga radiolabelling study.

A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound 9a was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial in silico study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure-activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens., Competing Interests: The authors declare no competing financial interest nor any other conflict of interest., (This journal is © The Royal Society of Chemistry.)

A new hexadentate 1,4,7-triazacyclononane-based ligand bearing three coordinating methylene-(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent (Mg 2+ , Ca 2+ , Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+ ) and trivalent (Cr 3+ , Fe 3+ , Co 3+ ) transition metal ions was studied. The ligand forms stable complexes with late divalent transition metal ions (from Co 2+ to Zn 2+ ) and the complexes of these metal ions are formed above pH ∼3. A number of complexes with divalent metal ions were structurally characterized by means of single-crystal X-ray diffraction. The complex of the larger Mn 2+ ion adopts a twisted trigonally antiprismatic geometry with a larger coordination cavity and smaller torsion of the pendant arms, whereas the smaller ions Ni 2+ , Cu 2+ and Zn 2+ form octahedral species with a smaller cavity and larger pendant arm torsion. In the case of the Co 2+ complexes, both coordination arrangements were observed. The complexes with paramagnetic metal ions were studied from the point of view of potential utilization in 19 F magnetic resonance imaging. A significant shortening of the 19 F NMR longitudinal relaxation times was observed: a sub-millisecond range for complexes of Cr 3+ , Mn 2+ and Fe 3+ with symmetric electronic states ( t 2g 3 and HS- d 5 ), the millisecond range for the Ni 2+ and Cu 2+ complexes and tens of milliseconds for the Co 2+ complex. Such short relaxation times are consistent with a short distance between the paramagnetic metal ion and the fluorine atoms (∼5.5-6.5 Å). Among the redox-active complexes (Mn 3+ /Mn 2+ , Fe 3+ /Fe 2+ , Co 3+ /Co 2+ , Cu 2+ /Cu + ), the cobalt complexes show sufficient stability and a paramagnetic-diamagnetic changeover with the redox potential lying in a physiologically relevant range. Thus, the Co 3+ /Co 2+ complex pair can be potentially used as a smart redox-responsive contrast agent for 19 F MRI.

We report here the improved synthesis of the tripodal picolinate chelator Tpaa , with an overall yield of 41% over five steps, in comparison to the previously reported 6% yield. Tpaa was investigated for its coordination chemistry with Ga(III) and radiolabeling properties with gallium-68 ( 68 Ga). The obtained crystal structure for [Ga( Tpaa )] shows that the three picolinate arms coordinate to the Ga(III) ion, fully occupying the octahedral coordination geometry. This is supported by 1 H NMR which shows that the three arms are symmetrical when coordinated to Ga(III). Assessment of the thermodynamic stability through potentiometry gives log K Ga- Tpaa = 21.32, with a single species being produced across the range of pH 3.5-7.5. Tpaa achieved >99% radiochemical conversion with 68 Ga under mild conditions ([ Tpaa ] = 6.6 μM, pH 7.4, 37 °C) with a molar activity of 3.1 GBq μmol -1 . The resulting complex, [ 68 Ga][Ga( Tpaa )], showed improved stability over the previously reported [ 68 Ga][Ga( Dpaa )(H 2 O)] in a serum challenge, with 32% of [ 68 Ga][Ga( Tpaa )] remaining intact after 30 min of incubation with fetal bovine serum.

A new cyclam-based ligand bearing two methylene(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent transition metal ions [Co(II), Ni(II), Cu(II), Zn(II)] was studied. The ligand was found to be very selective for the Cu(II) ion according to the common Williams-Irving trend. Complexes with all the studied metal ions were structurally characterized. The Cu(II) ion forms two isomeric complexes; the pentacoordinated isomer pc -[Cu(L)] is the kinetic product and the octahedral trans-O , O '-[Cu(L)] isomer is the final (thermodynamic) product of the complexation reaction. Other studied metal ions form octahedral cis-O , O '-[M(L)] complexes. The complexes with paramagnetic metal ions showed a significant shortening of 19 F NMR longitudinal relaxation times ( T 1 ) to the millisecond range [Ni(II) and Cu(II) complexes] or tens of milliseconds [Co(II) complex] at the temperature and magnetic field relevant for 19 F magnetic resonance imaging (MRI). Such a short T 1 results from a short distance between the paramagnetic metal ion and the fluorine atoms (∼6.1-6.4 Å). The complexes show high kinetic inertness towards acid-assisted dissociation; in particular, the trans-O , O '-[Cu(L)] complex was found to be extremely inert with a dissociation half-time of 2.8 h in 1 M HCl at 90 °C. Together with the short relaxation time, it potentially enables in vitro / in vivo utilization of the complexes as efficient contrast agents for 19 F MRI.

Tuberculosis remains a serious killer among infectious diseases due to its incidence, mortality, and occurrence of resistant mycobacterial strains. The challenge to discover new antimycobacterial agents forced us to prepare a series of N -(1-hydroxy-1,3-dihydrobenzo[ c ][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides 1-19 via the acylation of 6-aminobenzo[ c ][1,2]oxaborol-1(3 H )-ol with various activated (hetero)arylcarboxylic acids. These novel compounds have been tested in vitro against a panel of clinically important fungi and bacteria, including mycobacteria. Some of the compounds inhibited the growth of mycobacteria in the range of micromolar concentrations and retained this activity also against multidrug-resistant clinical isolates. Half the maximal inhibitory concentrations against the HepG2 cell line indicated an acceptable toxicological profile. No growth inhibition of other bacteria and fungi demonstrated selectivity of the compounds against mycobacteria. The structure-activity relationships have been derived and supported with a molecular docking study, which confirmed a selectivity toward the potential target leucyl-tRNA synthetase without an impact on the human enzyme. The presented compounds can become important materials in antimycobacterial research.

The chelator Bn 2 DT3A was used to produce a novel 68 Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. Bn 2 DT3A complexes Ga 3+ in a hexadentate manner, forming a mer-mer complex with log K ([Ga( Bn 2 DT3A )]) = 18.25. Above pH 5, the hydroxide ion coordinates the Ga 3+ ion following dissociation of a coordinated amine. Bn 2 DT3A radiolabeling displayed a pH-dependent speciation, with [ 68 Ga][Ga( Bn 2 DT3A )(OH)] - being formed above pH 5 and efficiently radiolabeled at pH 7.4. Surprisingly, [ 68 Ga][Ga( Bn 2 DT3A )(OH)] - was found to show an increased stability in vitro (for over 2 h in fetal bovine serum) compared to [ 68 Ga][Ga( Bn 2 DT3A )]. The biodistribution of [ 68 Ga][Ga( Bn 2 DT3A )(OH)] - in healthy rats showed rapid clearance and excretion via the kidneys, with no uptake seen in the lungs or bones.

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 (H 5 te1P BP ). The ligand showed a high selectivity to Cu II over Zn II and Ni II ions, and the bis(phosphonate) group was not coordinated in the Cu II complex, strongly interacting with other metal ions in solution. The Cu II 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 Cu II -te1P BP complex also showed a high resistance to acid-assisted hydrolysis ( t 1/2 2.7 h; 1 M HClO 4 , 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H 5 te1P BP radiolabeling with [ 64 Cu]CuCl 2 was fast and efficient, with specific activities of approximately 30 GBq 64 Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [ 64 Cu]Cu II -te1P BP 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 [ 18 F]fluoride. Moreover, [ 64 Cu]Cu II -te1P BP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [ 64 Cu]Cu II -te1P BP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [ 18 F]fluoride, albeit with a longer half-life (12.7 h) than 18 F (1.8 h), thereby enabling extended observation times.

The vicarious nucleophilic substitution of hydrogen (VNS) reaction in electron-deficient nitroquinolines was studied. Properties of all new products have been characterized by several techniques: MS, HRMS, FTIR, GC-MS, electronic absorption spectroscopy, and multinuclear NMR. The structures of 4-chloro-8-nitroquinoline, 8-( tert -butyl)-2-methyl-5-nitroquinoline, 9-(8-nitroquinolin-7-yl)-9 H -carbazole and ( Z )-7-(9 H -carbazol-9-yl)-8-(hydroxyimino)quinolin-5(8 H )-one were determined by single-crystal X-ray diffraction measurements. The 9-(8-nitroquinolin-7-yl)-9 H -carbazole and ( Z )-7-(9 H -carbazol-9-yl)-8-(hydroxyimino)quinolin-5(8 H )-one illustrate the nitro/nitroso conversion within VNS reaction. Additionally, 9-(8-isopropyl-2-((8-isopropyl-2-methyl-5-nitroquinolin-6-yl)methyl)-5-nitrosoquinolin-6-yl)-9 H -carbazole is presented as a double VNS product. It is postulated that the potassium counterion interacts with the oxygen on the nitro group, which could influence nucleophile attack in that way.

Al(iii) complexes are extensively studied as [18F]fluoride carriers in positron emission tomography. However, our limited knowledge on their thermodynamic and kinetic properties has hindered efforts to easily prepare radiochemically pure compounds while simultaneously reducing the overall labeling time. Thus, to improve our understanding of fluoride binding to coordinatively unsaturated Al(iii) complexes, we investigated the ternary system Al(iii)-H3NTA-F- (H3NTA = nitrilo-triacetic acid) by NMR, potentiometry and X-ray diffraction. Our results show that the [Al(NTA)] complex binds two water molecules, which are replaced by fluorides. Individual species and isomers show separate 19F NMR signals and different stability constants. The two available positions on the [Al(NTA)] complex feature significantly different properties in terms of basicity of the coordinated water molecules and preferential binding of fluoride anions. Fluorides are effectively bound in weakly acidic or neutral solutions, whereas hydroxido species are preferentially formed in alkaline solutions. Our experimental observations were rationalized by theoretical calculations: predictions of the energy ordering of complexes and isomers, interpretation of 19F NMR chemical shifts, and natural bonding orbital analysis. Radiolabeling of [Al(NTA)] with [18F]fluoride gave low yields that confirmed a high affinity of the complex for hydroxide anions.

Cross-bridged cyclam derivatives bearing two phosphonate (H 4 L 1 ), bis(phosphinate) (H 4 L 2 ), or phosphinate (H 2 L 3 ) pendant arms were synthesized and studied with respect to their application as copper radioisotope carriers in nuclear medicine. The ligands show high macrocycle basicity (p K 1 > 14) and high Cu(II) complex stability (log K = 20-24). The complexation and dissociation kinetics of the Cu(II) complexes were studied by ultraviolet-visible spectroscopy. Phosphonate Cu(II)-H 4 L 1 and bis(phosphinate) Cu(II)-H 4 L 2 complexes form very quickly, reaching quantitative formation within 1 s at pH ∼6 and millimolar concentrations. Conversely, the formation of the phosphinate complex Cu(II)-H 2 L 3 is much slower (9 min at pH ∼6) due to the low stability of the out-of-cage reaction intermediate. All studied complexes are highly kinetically inert, showing half-lives of 120, 11, and 111 h for Cu(II)-H 4 L 1 , Cu(II)-H 4 L 2 , and Cu(II)-H 2 L 3 complexes, respectively, in 1 M HClO 4 at 90 °C. The high thermodynamic stability, fast formation, and extreme kinetic inertness of Cu(II) complexes indicate that phosphonate and bis(phosphinate) derivatives are promising ligands for nuclear medicine.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra , M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa , and fungal strains, including Candida albicans and Aspergillus flavus . Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 µM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing ʟ-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-ᴅ/ʟ-Pgl-Me, MIC < 1.95 µg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the ᴅ- and ʟ-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

We prepared a series of substituted N -(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity when compared to our previous compounds of amide or retro-amide linker type. Only two compounds, 4-amino- N -(pyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 25 μM) and 4-amino- N -(6-chloropyrazin-2-yl)benzenesulfonamide (MIC = 6.25 μg/mL, 22 μM) exerted good antitubercular activity against M. tuberculosis H37Rv. However, they were excluded from the comparison as they-unlike the other compounds-possessed the pharmacophore for the inhibition of folate pathway, which was proven by docking studies. We performed target fishing, where we identified matrix metalloproteinase-8 as a promising target for our title compounds that is worth future exploration.

Flubendazole (FLU), an anthelmintic drug of benzimidazole type, is now considered a promising anti-cancer agent due to its tubulin binding ability and low system toxicity. The present study was aimed at determining more information about FLU reduction in human liver, because this information has been insufficient until now. Subcellular fractions from the liver of 12 human patients (6 male and 6 female patients) were used to study the stereospecificity, cellular localization, coenzyme preference, enzyme kinetics, and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Our study showed that FLU is predominantly reduced in cytosol, and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven, and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein were found in male patients than in female patients, but overall inter-individual variability was relatively low. Hepatic intrinsic clearance of FLU is very low, and FLU had no effect on doxorubicin carbonyl reduction in the liver and in cancer cells. All these results fill the gaps in the knowledge of FLU metabolism in human.

We report the design, synthesis, and in vitro antimicrobial activity of a series of N -substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino- N -(2,4-dimethoxyphenyl)pyrazine-2-carboxamide ( 17 , MIC = 12.5 µg/mL, 46 µM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans . The four most active compounds (compounds 10 , 16 , 17 , 20 ) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.

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 K a ∼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.

H 4 dota and its analogues are routinely used for complexation of lanthanide radioisotopes in nuclear medicine. Many of the radioisotopes have short half-lives and, thus, the complexation rate plays an important role. Notwithstanding that, the relationship between ligand structures and complexation rates is not well understood. Here we report a complexation study of H 4 dota and its analogues bearing one phosphonate or phosphinate pendant arm. The substituents on the phosphinate group were non-coordinating (-H) or contained another coordinating group (-CH 2 N(CH 2 COOH) 2 , -CH 2 PO 2 H 2 or -CH 2 NH 2 ). The basicity of ligands, stability of reaction intermediates, formation rates of Ce III complexes, and 177 Lu III radiolabelling were studied. The complexation rates and labelling yields do not show any correlation with ligand basicity. In contrast, the additional chelating group attached to the pendant arm plays an important role. A decreased complexation rate and lower labelling yield were found for compounds bearing an additional amino group, whereas improved properties were found for the compound bearing a geminal bis(phosphinate) pendant arm. It indicates that the introduction of chelating pendant arms with acidic coordinating groups might be a promising strategy to improve radiolabelling of macrocyclic carriers with metal radioisotopes.

H 3 nota derivatives are among the most studied macrocyclic ligands and are widely used for metal ion binding in biology and medicine. Despite more than 40 years of chemical research on H 3 nota, the comprehensive study of its solution chemistry has been overlooked. Thus, the coordination behavior of H 3 nota with several divalent metal ions was studied in detail with respect to its application as a chelator for copper radioisotopes in medical imaging and therapy. In the solid-state structure of the free ligand in zwitterionic form, one proton is bound in the macrocyclic cavity through a strong intramolecular hydrogen-bond system supporting the high basicity of the ring amine groups (log K a = 13.17). The high stability of the [Cu(nota)] - complex (log K ML = 23.33) results in quantitative complex formation, even at pH <1.5. The ligand is moderately selective for Cu(II) over other metal ions (e.g., log K ML (Zn) = 22.32 and log K ML (Ni) = 19.24). This ligand forms a more stable complex with Mg(II) than with Ca(II) and forms surprisingly stable complexes with alkali-metal ions (stability order Li(I) > Na(I) > K(I)). Thus, H 3 nota shows high selectivity for small metal ions. The [Cu(nota)] - complex is hexacoordinated at neutral pH, and the equatorial N 2 O 2 interaction is strengthened by complex protonation. Detailed kinetic studies showed that the Cu(II) complex is formed quickly (millisecond time scale at c Cu ≈ 0.1 mM) through an out-of-cage intermediate. Conversely, conductivity measurements revealed that the Zn(II) complex is formed much more slowly than the Cu(II) complex. The Cu(II) complex has medium kinetic inertness (τ 1/2 46 s; pH 0, 25 °C) and is less resistant to acid-assisted decomplexation than Cu(II) complexes with H 4 dota and H 4 teta. Surprisingly, [Cu(nota)] - decomplexation is decelerated in the presence of Zn(II) ions due to the formation of a stable dinuclear complex. In conclusion, H 3 nota is a good carrier of copper radionuclides because the [Cu(nota)] - complex is predominantly formed over complexes with common impurities in radiochemical formulations, Zn(II) and Ni(II), for thermodynamic and, primarily, for kinetic reasons. Furthermore, the in vivo stability of the [Cu(nota)] - complex may be increased due to the formation of dinuclear complexes when it interacts with biometals.

Sesquiterpenes, the main components of plant essential oils, are often taken in the form of folk medicines and dietary supplements. Several sesquiterpenes possess interesting biological activities but they could interact with concurrently administered drugs via inhibition of drug-metabolizing enzymes. Therefore, the present study was designed to test the potential inhibitory effect of tree structurally relative sesquiterpenes β-caryophyllene (CAR), β-caryophyllene oxide (CAO) and α-humulene (HUM) on the activities of the main drug-metabolizing enzymes. For this purpose, rat and human hepatic subcellular fractions were incubated with CAR, CAO or HUM together with specific substrates for oxidation, reduction and conjugation enzymes and their coenzymes. HPLC, spectrophotometric and spectrofluorimetric analyses of product formations were used. All tested sesquiterpenes significantly inhibited cytochromes P4503A (CYP3A) activities in rats as well as in human hepatic microsomes, with CAO being the strongest inhibitor. A non-competitive type of inhibition was found. On the other hand, none of the tested sesquiterpenes significantly affected the activities of carbonyl-reducing enzymes (CBR1, AKRs, NQO1) or conjugation enzymes (UGTs, GSTs, SULTs, COMT). As CYP3A enzymes metabolize many drugs, their inhibition by CAO, CAR and HUM might affect the pharmacokinetics of concurrently administered drugs. Similar results obtained in rat and human hepatic microsomes indicate that rats could be used for further testing of possible drug-sesquiterpenes interactions in vivo., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Gallium-68 ( 68 Ga) has been the subject of increasing interest for its potential in the production of radiotracers for diagnosis of diseases. In this work we report the complexation of 68 Ga by the amino acid based tripodal chelate H 3 Dpaa, and two bifunctional derivatives, H 3 Dpaa.dab and H 4 Dpaa.ga, under a range of conditions with particular emphasis on the rapid complexation of 68 Ga at pH 7.4. 100 μM H 3 Dpaa achieved a radiochemical yield of 95% at pH 7.4 in 5 minutes at 37 °C. The bifunctional derivatives H 4 Dpaa.ga and H 3 Dpaa.dab achieved 94% and 84% radiochemical yields, respectively, under the same conditions. The resulting Ga(iii) complexes show thermodynamic stabilities of log K GaDpaa = 18.53, log K GaDpaa.dab = 22.08, log K GaDpaa.ga = 18.36. Unfortunately, the resulting radiolabelled species do not present sufficient serum stability for in vivo application. Herein we show a flexible synthesis for bifunctional chelators based on amino acids that rapidly complex 68 Ga under physiological conditions.

The new ligand H 6 do3aP ida combines the macrocyclic DOTA-like cavity and the open-chain iminodiacetate group connected through a coordinating phosphinate spacer. Its acid-base and coordination properties in solution were studied by potentiometry. Thermodynamic coordination characteristics of both chelating units are similar to those reported for H 4 dota and iminodiacetic acid themselves, respectively, so, macrocyclic and iminodiacetate units behave independently. The formation kinetics of the Ce(iii)-H 6 do3aP ida complex was studied by UV-Vis spectrophotometry. Various out-of-cage intermediates were identified with 1 : 1, 1 : 2 and 2 : 1 ligand-to-metal ratios. The presence of the strongly coordinating iminodiacetate group significantly slows down the metal ion transfer into the macrocyclic cavity and, so, the formation of the in-cage complex is two orders of magnitude slower than that reported for the Ce(iii)-H 4 dota system. The kinetic inertness of the [Ce(do3aP ida )] 3- complex towards acid-assisted dissociation is comparable to that of the [Ce(dota)] - complex. The coordination modes of the ligand are demonstrated in the solid-state structure of [Cu 4 (do3aP ida )(OH)(H 2 O) 4 ]Cl·7.5H 2 O.

Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans -nerolidol, cis -nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug-sesquiterpene interactions should be verified in in vivo experiments.

A series of substituted N -benzyl-3-chloropyrazine-2-carboxamides were prepared as positional isomers of 5-chloro and 6-chloro derivatives, prepared previously. During the aminolysis of the acyl chloride, the simultaneous substitution of chlorine with benzylamino moiety gave rise to N -benzyl-3-(benzylamino)pyrazine-2-carboxamides as side products, in some cases. Although not initially planned, the reaction conditions were modified to populate this double substituted series. The final compounds were tested against four mycobacterial strains. N -(2-methylbenzyl)-3-((2-methylbenzyl)amino)pyrazine-2-carboxamide ( 1a ) and N -(3,4-dichlorobenzyl)-3-((3,4-dichlorobenzyl)amino)pyrazine-2-carboxamide ( 9a ) proved to be the most effective against Mycobacterium tuberculosis H37Rv, with MIC = 12.5 μg·mL -1 . Compounds were screened for antibacterial activity. The most active compound was 3-chloro- N -(2-chlorobenzyl)pyrazine-2-carboxamide ( 5 ) against Staphylococcus aureus with MIC = 7.81 μM, and Staphylococcus epidermidis with MIC = 15.62 μM. HepG2 in vitro cytotoxicity was evaluated for the most active compounds; however, no significant toxicity was detected. Compound 9a was docked to several conformations of the enoyl-ACP-reductase of Mycobacterium tuberculosis . In some cases, it was capable of H -bond interactions, typical for most of the known inhibitors.

Background: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [(89)Sr]SrCl2 and [(153)Sm]Sm-EDTMP. No-carrier-added (n.c.a.) (177)Lu is remarkably suitable for an application in this scope., Methods: Five 1,4,7,10-tetraazacyclododecane N,N',N'',N''-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. (177)Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [(177)Lu]citrate., Results: Radiolabelling yields for [(177)Lu]Lu-DOTA and [(177)Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All (177)Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. (177)Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [(177)Lu]Lu-DO2A(P(BP))2; SUVfemur = 5.41 ± 0.46 for [(177)Lu]Lu-DOTA(M(BP))2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [(177)Lu]Lu-DO2A(P(BP))2; SUVblood = 1.43 ± 0.32 for [(177)Lu]Lu-DOTA(M(BP))2)., Conclusions: Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.

Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)M BP (L1). The ligands were labeled with 68 Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [ 68 Ga]L1. [ 68 Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [ 68 Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [ 68 Ga]L1 than for [ 68 Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in 177 Lu therapeutic agent with the same ligand (a theranostic pair)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine.

Cyclam derivatives bearing one geminal bis(phosphinic acid), -CH2PO2HCH2PO2H2 (H2L(1)), or phosphinic-phosphonic acid, -CH2PO2HCH2PO3H2 (H3L(2)), pendant arm were synthesized and studied as potential copper(II) chelators for nuclear medical applications. The ligands showed good selectivity for copper(II) over zinc(II) and nickel(II) ions (log KCuL = 25.8 and 27.7 for H2L(1) and H3L(2), respectively). Kinetic study revealed an unusual three-step complex formation mechanism. The initial equilibrium step leads to out-of-cage complexes with Cu(2+) bound by the phosphorus-containing pendant arm. These species quickly rearrange to an in-cage complex with cyclam conformation II, which isomerizes to another in-cage complex with cyclam conformation I. The first in-cage complex is quantitatively formed in seconds (pH ≈5, 25 °C, Cu:L = 1:1, cM ≈ 1 mM). At pH >12, I isomers undergo nitrogen atom inversion, leading to III isomers; the structure of the III-[Cu(HL(2))] complex in the solid state was confirmed by X-ray diffraction analysis. In an alkaline solution, interconversion of the I and III isomers is mutual, leading to the same equilibrium isomeric mixture; such behavior has been observed here for the first time for copper(II) complexes of cyclam derivatives. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H3L(2) compared with analogous data for isomeric complexes of cyclam derivatives with one or two methylphosphonic acid pendant arm(s). Acid-assisted dissociation proved the kinetic inertness of the complexes. Preliminary radiolabeling of H2L(1) and H3L(2) with (64)Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of (64)Cu per 1 μmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand). These specific activities were much higher than those of H3nota and H4dota complexes prepared under identical conditions. The rare combination of simple ligand synthesis, very fast copper(II) complex formation, high thermodynamic stability, kinetic inertness, efficient radiolabeling, and expected low bone tissue affinity makes such ligands suitably predisposed to serve as chelators of copper radioisotopes in nuclear medicine.

The sheep tapeworm Moniezia expansa is very common parasite, which affects ruminants such as sheep, goats as well as other species. The benzimidazole anthelmintics albendazole (ABZ), flubendazole (FLU) and mebendazole (MBZ) are often used to treat the infection. The drug-metabolizing enzymes of helminths may alter the potency of anthelmintic treatment. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (ABZ, MBZ and FLU) in M. expansa. Activities of biotransformation enzymes were determined in subcellular fractions. Metabolites of the anthelmintics were detected and identified using high performance liquid chromatography/ultra-violet/VIS/fluorescence or ultra-high performance liquid chromatography/mass spectrometry. Reduction of MBZ, FLU and oxidation of ABZ were proved as well as activities of various metabolizing enzymes. Despite the fact that the conjugation enzymes glutathione S-transferase, UDP-glucuronosyl transferase and UDP-glucosyl transferase were active in vitro, no conjugated metabolites of anthelmintics were identified either ex vivo or in vitro. The obtained results indicate that sheep tapeworm is able to deactivate the administered anthelmintics, and thus protects itself against their action.

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., (Copyright © 2014 John Wiley & Sons, Ltd.)

Monepantel (MOP), a new amino-acetonitrile anthelmintic for the treatment and control of gastrointestinal nematode infections and associated diseases in sheep, is approved and marketed as oral solution under the trade name Zolvix® (Novartis Animal Health Inc., Switzerland). The effect of MOP on hepatic cytochromes P450 (CYP) has been investigated in sheep. In an in vivo experiment, castrated rams (9-months old) were treated with the recommended therapeutic dose of MOP. Non-treated animals represented the controls. After 24 h, the animals were stunned and exsanguinated. Microsomal fractions and total RNA were prepared from liver homogenates. The activities towards alkyloxyresorufins, 7-methoxy-4-trifluoromethylcoumarin and midazolam were assayed and mRNAs of individual CYP isoforms were quantified. In an in vitro procedure, primary cultures of ovine hepatocytes were incubated with or without MOP (10 μM) for 24 h and then expression levels of individual CYP isoforms were analyzed. Results showed that MOP significantly increased all CYP-related activities and CYP3A24 mRNA in sheep. The induction effect of MOP on CYP3A was similar or even higher than those of dexamethasone and rifampicin, well-known CYP3A inducers. As CYP3A enzymes belongs to the most important biotransformation enzymes, their induction may have serious pharmacological and/or toxicological consequences. These facts should be taken into account when other drugs together with or after MOP (Zolvix®) are administered to sheep., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) scandium(III) complexes were investigated in the solution and solid state. Three (45)Sc NMR spectroscopic references suitable for aqueous solutions were suggested: 0.1 M Sc(ClO4)3 in 1 M aq. HClO4 (δSc =0.0 ppm), 0.1 M ScCl3 in 1 M aq. HCl (δSc =1.75 ppm) and 0.01 M [Sc(ox)4](5-) (ox(2-) = oxalato) in 1 M aq. K2C2O4 (δSc =8.31 ppm). In solution, [Sc(dtpa)](2-) complex (δSc = 83 ppm, Δν = 770 Hz) has a rather symmetric ligand field unlike highly unsymmetrical donor atom arrangement in [Sc(dota)](-) anion (δSc = 100 ppm, Δν = 4300 Hz). The solid-state structure of K8[Sc2(ox)7]⋅13 H2O contains two [Sc(ox)3](3-) units bridged by twice "side-on" coordinated oxalate anion with Sc(3+) ion in a dodecahedral O8 arrangement. Structures of [Sc(dtpa)](2-) and [Sc(dota)](-) in [(Hguanidine)]2[Sc(dtpa)]⋅3 H2O and K[Sc(dota)][H6 dota]Cl2⋅4 H2O, respectively, are analogous to those of trivalent lanthanide complexes with the same ligands. The [Sc(dota)](-) unit exhibits twisted square-antiprismatic arrangement without an axial ligand (TSA' isomer) and [Sc(dota)](-) and (H6 dota)(2+) units are bridged by a K(+) cation. A surprisingly high value of the last DOTA dissociation constant (pKa =12.9) was determined by potentiometry and confirmed by using NMR spectroscopy. Stability constants of scandium(III) complexes (log KScL 27.43 and 30.79 for DTPA and DOTA, respectively) were determined from potentiometric and (45)Sc NMR spectroscopic data. Both complexes are fully formed even below pH 2. Complexation of DOTA with the Sc(3+) ion is much faster than with trivalent lanthanides. Proton-assisted decomplexation of the [Sc(dota)](-) complex (τ1/2 =45 h; 1 M aq. HCl, 25 °C) is much slower than that for [Ln(dota)](-) complexes. Therefore, DOTA and its derivatives seem to be very suitable ligands for scandium radioisotopes., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)