H3nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga3+ Coordination and 67Ga3+ Radiolabeling.

We synthesized, thanks to the regiospecific N-functionalization using an orthoamide intermediate, two 1,4,7-triazacyclononane derivatives containing an acetate arm and either a methylpyridine or a picolinic acid group, respectively, Hnoapy and H2noapa, as new Ga3+ chelators for potential use in nuclear medicine. The corresponding Ga3+ complexes were synthesized and structurally characterized in solution by 1H and 13C NMR. The [Ga(noapy)]2+ complex appears to exist in solution as two diasteroisomeric pairs of enantiomers, as confirmed by density functional theory (DFT) calculations, while for [Ga(noapa)]+, a single species is present in solution. Solid-state investigations were possible for the [Ga(noapa)]+ complex, which crystallized from water as a pair of enantiomers. The average length of the N-Ga bonds of 2.090 Å is identical with that found for the [Ga(nota)] complex, showing that the presence of the picolinate arm does not hinder the coordination of the ligand to the metal ion. Protonation constants of noapy- and noapa2- were determined by potentiometric titrations, providing an overall basicity ∑log KiH (i = 1-4) that increases in the order noapy- < noapa2- < nota3- with increases in the negative charge of the ligand. Stability constants determined by pH-potentiometric titrations supplemented with 71Ga NMR data show that the stabilities of [Ga(noapy)]2+ and [Ga(noapa)]+ are lower compared to that of [Ga(nota)] but higher than those of other standards such as [Ga(aazta)]-. 67Ga radiolabeling studies were performed in order to demonstrate the potential of these chelators for 67/68Ga-based radiopharmaceuticals. The labelings of Hnoapy and H2noapa were nearly identical, outperforming H3nota. Stability studies were conducted in phosphate-buffered saline and in the presence of human serum transferrin, revealing no significant decomplexation of [67Ga][Ga(noapy)]2+ and [67Ga][Ga(noapa)]+ compared to [67Ga][Ga(nota)]. Finally, all complexes were found to be highly hydrophilic, with calculated log D7.4 values of -3.42 ± 0.05, -3.34 ± 0.04, and -3.00 ± 0.23 for Hnoapy, H2noapa, and H3nota, respectively, correlating with the charge of each complex and the electrostatic potentials obtained with DFT.

On the dissociation pathways of copper complexes relevant as PET imaging agents.

Several bifunctional chelators have been synthesized in the last years for the development of new 64Cu-based PET agents for in vivo imaging. When designing a metal-based PET probe, it is important to achieve high stability and kinetic inertness once the radioisotope is coordinated. Different competitive assays are commonly used to evaluate the possible dissociation mechanisms that may induce Cu(II) release in the body. Among them, acid-assisted dissociation tests or transchelation challenges employing EDTA or SOD are frequently used to evaluate both solution thermodynamics and the kinetic behavior of potential metal-based systems. Despite of this, the Cu(II)/Cu(I) bioreduction pathway that could be promoted by the presence of bioreductants still remains little explored. To fill this gap we present here a detailed spectroscopic study of the kinetic behavior of different macrocyclic Cu(II) complexes. The complexes investigated include the cross-bridge cyclam derivative [Cu(CB-TE1A)]+, whose structure was determined using single-crystal X-ray diffraction. The acid-assisted dissociation mechanism was investigated using HClO4 and HCl to analyse the effect of the counterion on the rate constants. The complexes were selected so that the effects of complex charge and coordination polyhedron could be assessed. Cyclic voltammetry experiments were conducted to investigate whether the reduction to Cu(I) falls within the window of common bioreducing agents. The most striking behavior concerns the [Cu(NO2Th)]2+ complex, a 1,4,7-triazacyclononane derivative containing two methylthiazolyl pendant arms. This complex is extremely inert with respect to dissociation following the acid-catalyzed mechanism, but dissociates rather quickly in the presence of a bioreductant like ascorbic acid.

Bioconjugated chelates based on (methylpyridinyl)tacn: synthesis, 64Cu labeling and in vitro evaluation for prostate cancer targeting.

Three new bifunctional copper chelators based on the 1,4,7-triazacyclononane (tacn) platform have been synthesized and conjugated to peptides. The first one is constituted of the tacn with two methylpyridinyl and one methylthiazolyl carboxylic acid pendant arms, while, in the second and third ones, the macrocycle is functionalized by three methylpyridinyl groups, with an additional hexynoic acid chain on a carbon of one or two pyridine rings. These three bifunctional chelators have been conjugated to the antagonist DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide for targeting the gastrin-releasing peptide receptor, which is overexpressed in prostate cancer. The resulting monomeric bioconjugates have shown their efficiency to be radiolabeled with ß+ emitter 64Cu, and the hydrophilicity and PC-3 cell internalization properties of these radiolabeled conjugates have been studied. PC-3 cell binding affinity of mono- and dimeric metal-free and natCu metallated conjugates have been evaluated by IC50 measurements. The results demonstrate the potential of these methylpyridinyl tacn derivatives for radiopharmaceutical applications.

New Triazacycloalkane Derivatives as Cytotoxic Agents for CLL Treatment: From Proof of Concept to the Targeting Biomolecule.

The 1,4,7-tris-(2-pyridinylmethyl)-1,4,7-triazacyclononane ligand (no3py) and its bifunctional analogue no3pyCOOK were synthesized to investigate their action toward zinc(II) depletion related to the apoptosis phenomenon in chronic lymphocytic leukemia (CLL) cells. no3py was used as the "free" ligand, while its "graftable" derivative was conjugated on a newly synthesized bifunctional sialoglycan, 6'-SL-NH2, selected to specifically bind CD22 biomarker expressed on the B-CLL cell surface. Both compounds were produced with good yields thanks to a Sonogashira coupling reaction and an orthoester function, respectively, for the chelator and the targeting moiety. The newly reported bioconjugate 6'-SL-no3py was then obtained through a peptidic coupling reaction. Biological in vitro studies of no3py and 6'-SL-no3py consisting of real-time detection of cell health (cytotoxicity and proliferation) and caspases 3/7 activation (crucial enzymes whose activation triggers cell death signaling pathways) have been investigated. First, Ramos, Daudi, and Raji B-cell lines, which present different sensitivity to zinc(II) content variation, were incubated with no3py and 6'-SL-no3py. Then, a videomicroscope allowed the real-time monitoring of the morphological changes leading to cell death from the detection of the cytotoxicity, the antiproliferative effect, and the caspasic activity. In terms of mechanism, the Zn2+ chelator cytotoxic effect of no3py has been evidenced by a culture medium ion supplementation study and by the decrease of intracellular fluorescence of Zn-specific fluorophore zinquin in the presence of no3py and 6'-SL-no3py chelators. Finally, flow cytometry analysis with classical Annexin V staining was conducted to detect no3py- and 6'-SL-no3py-induced apoptotic cell death in B-CLL cells. Time-course analysis, using the Incucyte Live-Cell Analysis System, demonstrated that no3py induced cell death in a time- and dose-dependent manner with variability across cell lines. 6'-SL-no3py exhibited the same dose-dependent trend as no3py, showing the efficiency of the targeting moiety. In both cases, the chelators depicted proliferation curves that were inversely correlated with kinetic death. Morphological changes specific to apoptosis and caspase 3/7 activation were observed for the three cell lines treated with no3py and 6'-SL-no3py, highlighting their role as apoptotic agents. A higher concentration of 6'-SL-no3py is needed to reach 50% of the B-CLL mortality, confirming a targeting of the chelator to the cell membrane. Overall, our results proved that the biological properties of the triazamacrocyclic chelator still remain even after addition of the targeting moiety. The free chelator as well as the bioconjugate constitute promising cytotoxic agents for CLL therapy through apoptosis induction.

Unexpected Trends in the Stability and Dissociation Kinetics of Lanthanide(III) Complexes with Cyclen-Based Ligands across the Lanthanide Series.

We report a detailed study of the thermodynamic stability and dissociation kinetics of lanthanide complexes with two ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms linked to two nitrogen atoms of the macrocycle in either cis (1,4-H3DO2APA) or trans (1,7-H3DO2APA) positions. The stability constants of the Gd3+ complexes with these two ligands are very similar, with log KGdL values of 16.98 and 16.33 for the complexes of 1,4-H3DO2APA and 1,7-H3DO2APA, respectively. The stability constants of complexes with 1,4-H3DO2APA follow the usual trend, increasing from log KLaL = 15.96 to log KLuL = 19.21. However, the stability of [Ln(1,7-DO2APA)] complexes decreases from log K = 16.33 for Gd3+ to 14.24 for Lu3+. The acid-catalyzed dissociation rates of the Gd3+ complexes differ by a factor of ∼15, with rate constants (k1) of 1.42 and 23.5 M-1 s-1 for [Gd(1,4-DO2APA)] and [Gd(1,7-DO2APA)], respectively. This difference is magnified across the lanthanide series to reach a 5 orders of magnitude higher k1 for [Yb(1,7-DO2APA)] (1475 M-1 s-1) than for [Yb(1,4-DO2APA)] (5.79 × 10-3 M-1 s-1). The acid-catalyzed mechanism involves the protonation of a carboxylate group, followed by a cascade of proton-transfer events that result in the protonation of a nitrogen atom of the cyclen unit. Density functional theory calculations suggest a correlation between the strength of the Ln-Ocarboxylate bonds and the kinetic inertness of the complex, with stronger bonds providing more inert complexes. The 1H NMR resonance of the coordinated water molecule in the [Yb(1,7-DO2APA)] complex at 176 ppm provides a sizable chemical exchange saturation transfer effect thanks to a slow water exchange rate of (15.9 ± 1.6) × 103 s-1.

Cationic Biphotonic Lanthanide Luminescent Bioprobes Based on Functionalized Cross-Bridged Cyclam Macrocycles.

Cationic lanthanide complexes are generally able to spontaneously internalize into living cells. Following our previous works based on a diMe-cyclen framework, a second generation of cationic water-soluble lanthanide complexes based on a constrained cross-bridged cyclam macrocycle functionalized with donor-π-conjugated picolinate antennas was prepared with europium(III) and ytterbium(III). Their spectroscopic properties were thoroughly investigated in various solvents and rationalized with the help of DFT calculations. A significant improvement was observed in the case of the Eu3+ complex, while the Yb3+ analogue conserved photophysical properties in aqueous solvent. Two-photon (2P) microscopy imaging experiments on living T24 human cancer cells confirmed the spontaneous internalization of the probes and images with good signal-to-noise ratio were obtained in the classic NIR-to-visible configuration with the Eu3+ luminescent bioprobe and in the NIR-to-NIR with the Yb3+ one.

Picolinate-appended tacn complexes for bimodal imaging: Radiolabeling, relaxivity, photophysical and electrochemical studies.

Based on our previous works involving two 1,4,7-triazacyclononane (tacn)-based ligands Hno2py1pa (1-Picolinic acid-4,7-bis(pyridin-2-ylmethyl)-1,4,7-triazacyclononane) and Hno1pa (1-Picolinic acid-1,4,7-triazacyclononane), we report here the synthesis of analogues bearing picolinate-based π-conjugated ILCT (Intra-Ligand Charge Transfer) transition antenna (HL1, HL2), using regiospecific N-functionalization of the tacn skeleton and their related transition metal complexes (e.g. Cu2+, Zn2+ and Mn2+). Coordination properties as well as their photophysical and electrochemical properties were investigated in order to quantify the impact of such antenna on the luminescent or relaxometric properties of the complexes. The spectroscopic properties of the targeted ligands and metal complexes have been studied using UV-Vis absorption and fluorescence spectrocopies. While the zinc complex formed with HL1 possesses a moderate quantum yield of 5%, complexation of Cu2+ led to an extinction of the luminescence putatively attributed to a photo-induced electron transfer, as supported by spectroscopic and electrochemical evidences. The [Mn(L2)]+ complex is characterized by a fluorescence quantum yield close to 8% in CH2Cl2. The potential interest of such systems as bimodal probes has been assessed from radiolabeling experiments conducted on HL1 and 64Cu2+ as well as confocal microscopy analyses and from relaxometric studies carried out on the cationic [Mn(L2)]+ complex. These results showed that HL1 can be used for radiolabeling, with a radiochemical conversion of 40% in 15 min at 100 °C. Finally, the relaxivity values obtained for [Mn(L2)]+, r1p = 4.80 mM-1·s-1 and r2p = 8.72 mM-1·s-1, make the Mn(II) complex an ideal candidate as a probe for Magnetic Resonance Imaging.

endo- versus exo-Cyclic coordination in copper complexes with methylthiazolylcarboxylate tacn derivatives.

Three tacn (1,4,7-triazacyclononane)-based ligands substituted by methylthiazolylcarboxylate (tha) and/or methylthiazolyl (th) arms have been examined for copper complexation with the aim to study the impact of carboxylate groups on the complexation of Cu(ii), which can present an endo- or exo-cyclic coordination. Two new ligands have been synthesised: H3no3tha, tacn bearing three methylthiazolylcarboxylate arms, and H2no1th2tha, tacn with one methylthiazolyl and two methylthiazolylcarboxylate arms, while Hno2th1tha had already been described. Their complexation behaviour with 1 or 1.5 equivalents of metal was studied on the basis of preliminary results showing the tendency of tha arms to form exocyclic polynuclear species. The solid state studies of the Cu(ii) and Zn(ii) complexes were investigated and some of their structures were characterised by X-ray diffraction. The physicochemical properties of the complexes in solution were also investigated by means of potentiometric measurements, UV-vis spectroscopy, EPR and computational studies, NMR characterisation of the corresponding Zn(ii) complexes and redox behaviour by electrochemistry. Mono- and tri-nuclear complexes ML and M3L2 were formed and isolated, highlighting the tendency of methylthiazolylcarboxylate arms, when carried by a tacn platform, to form exo-cyclic and polynuclear complexes. However, this exhaustive study evidences that the "out of cage" and "in cage" present different behaviour in terms of stability.

Methylthiazolyl Tacn Ligands for Copper Complexation and Their Bifunctional Chelating Agent Derivatives for Bioconjugation and Copper-64 Radiolabeling: An Example with Bombesin.

We present here the synthesis of two new bifunctionalized azachelators, no2th-EtBzNCS and Hno2th1tha, as bioconjugable analogues of two previously described di- and trimethylthiazolyl 1,4,7-triazacyclononane (tacn) ligands, no2th and no3th, for potential uses in copper-64 (64Cu) positron emission tomography imaging. The first one bears an isothiocyanate group on the remaining free nitrogen atom of the tacn framework, while the second one presents an additional carboxylic function on one of the three heterocyclic pendants. Their syntheses required regiospecific N-functionalization of the macrocycles. In order to investigate their suitability for in vivo applications, a complete study of their copper(II) chelation was performed. The acid-base properties of the ligands and their thermodynamic stability constants with copper(II) and zinc(II) cations were determined using potentiometric techniques. Structural studies were conducted in both solution and the solid state, consolidated by theoretical calculations. The kinetic inertness in an acidic medium of both copper(II) complexes was determined by spectrophotometry, while cyclic voltammetry experiments were performed to evaluate the stability at the copper(I) redox state. UV-vis, NMR (of the zinc complexes), electron paramagnetic resonance spectroscopy, and density functional theory studies showed excellent agreement between the solution structures of the complexes and their crystallographic data. These investigations unambiguously prove that these bifunctional derivatives display similar coordination properties as their no2th and no3th counterparts, opening the door to targeted bioapplications. The no2th-EtBzNCS and Hno2th1tha ligands were then conjugated to a bombesin antagonist peptide for targeting the gastrin-releasing peptide receptor (GRPr). To highlight the potential of the two chelators for radiopharmaceutical development, the 64Cu-radiolabeling properties, in vitro stability, and binding affinity to GRPr of the corresponding bioconjugates were determined. Altogether, the results of this work warrant the further development of 64Cu-based radiopharmaceuticals comprising our novel bifunctional chelators.

Definition of the Labile Capping Bond Effect in Lanthanide Complexes.

Two macrocyclic ligands containing a cyclen unit, a methyl group, a picolinate arm, and two acetate pendant arms attached to two nitrogen atoms of the macrocycle either in trans (1,7-H3 Medo2 ampa = 2,2'-(7-((6-carboxypyridin-2-yl)methyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetic acid) or in cis (1,4-H3 Medo2 ampa) positions are reported. These ligands provide eight-coordination to the Ln3+ ions, leaving a coordination position available for a water molecule that occupies a capping position in the twisted square antiprismatic polyhedron (1,4-H3 Medo2 ampa) or one of the positions of the square antiprism (1,7-H3 Medo2 ampa). The charge neutral [Gd(1,7-Medo2 ampa)] complex presents an unprecedentedly low water-exchange rate (kex298 =8.8×103  s-1 ), whereas water exchange in [Gd(1,4-Medo2 ampa)] is three orders of magnitude faster (kex298 =6.6×106  s-1 ). These results showcase the labile capping bond phenomenon: A ligand occupying a capping position is hindered by the environment and thus is intrinsically labile.

Dinuclear Spin-Crossover Complexes Based on Tetradentate and Bridging Cyanocarbanion Ligands.

Spin-crossover (SCO) Fe(II) dinuclear complexes of formula [Fe2(tmpa)2(µ2-tcpd)2]·0.8(CH3OH) (1·MeOH) and [Fe2(andmpa)2(µ2-tcpd)2]·2CH3OH (2·MeOH) (tmpa = tris(2-pyridylmethyl)amine, andmpa = bis(2-pyridylmethyl)aminomethyl)aniline, (tcpd)(2-) = 2-dicyanomethylene-1,1,3,3-tetracyanopropanediide) have been synthesized and characterized by infrared spectroscopy, X-ray diffraction, and magnetic measurements. The crystal structure determinations of the two complexes (1·MeOH and 2·MeOH) and the desolvated complex 1 (from 1·MeOH) revealed a neutral centrosymmetrical dinuclear structure in which the (tcpd)(2-) cyanocarbanion acts as a double µ2-bridging ligand between two [FeL](2+) (L = tmpa (1), andmpa (2)) units involving two free coordination sites in the cis configuration. Examination of the shortest intermolecular contacts in 1·MeOH and 1 reveals no significant hydrogen bonding between the dinuclear units, while in 2·MeOH these units are held together by significant hydrogen bonds between one of the uncoordinated nitrile groups and the anilate function, giving rise to 1D supramolecular structure. The three dinuclear complexes 1, 2·MeOH, and 2 exhibit SCO behaviors which have been evidenced by the thermal evolutions of the χmT product and by the average values of the six Fe-N distances for 1 and 2·MeOH, that reveal a gradual conversion with transition temperatures (T1/2) at ca. 352 K (1), 196 K (2), and 180 K (2·MeOH). For the solvated 1·MeOH, the sharp SCO transition observed around 365 K was induced by the desolvatation process above 330 K during the magnetic measurements.

Elastic Frustration Triggering Photoinduced Hidden Hysteresis and Multistability in a Two-Dimensional Photoswitchable Hofmann-Like Spin-Crossover Metal-Organic Framework.

We report a two-dimensional Hofmann-like spin-crossover (SCO) material, [Fe(trz-py)2{Pt(CN)4}]·3H2O, built from [FePt(CN)4] layers separated by interdigitated 4-(2-pyridyl)-1,2,4,4H-triazole (trz-py) ligands with two symmetrically inequivalent FeII sites. This compound exhibits an incomplete first-order spin transition at 153 K between fully high-spin (HS-HS) and intermediate high-spin low-spin (HS-LS) ordered states. At low temperature, it undergoes a bidirectional photoswitching to HS-HS and fully low-spin (LS-LS) states with green and near-IR light irradiation, respectively, with associated T(LIESST = Light-Induced Excited Spin-State Trapping) and T(reverse-LIESST) values of 52 and 85 K, respectively. Photomagnetic investigations show that the reverse-LIESST process, performed from either HS-HS or HS-LS states, enables access to a hidden stable LS-LS state, revealing the existence of a hidden thermal hysteresis. Crystallographic investigations allowed to identify that the strong metastability of the HS-LS state originates from the existence of a strong elastic frustration causing antiferroelastic interactions within the [FePt(CN)4] layers, through the rigid NC-Pt-CN bridges connecting the inequivalent FeII sites. The existence of the stable LS-LS state paves the way for a multidirectional photoswitching and allows potential applications for electronic devices based on ternary digits.

Improving the stability and inertness of Cu(ii) and Cu(i) complexes with methylthiazolyl ligands by tuning the macrocyclic structure.

A tacn based ligand bearing two methylthiazolyl arms (no2th) was synthesized with the aim to find ligands forming very stable and inert complexes with Cu(ii) and Cu(i) in aqueous medium for radiopharmaceutical applications. The no2th ligand was efficiently prepared following the orthoamide intermediate synthesis. The complexes with Cu(2+) and Zn(2+) were obtained and analyzed by X-ray diffraction. The [Cu(no2th)](2+) complex presents a pentacoordinated distorted square pyramidal coordination geometry, while the metal ion in [Zn(no2th)](2+) adopts a hexacoordinated distorted trigonal prismatic geometry involving the coordination of a perchlorate counter ion. The acid-base properties of no2th have been studied using potentiometric titrations, and the stability constants of Cu(2+) and Zn(2+) complexes were determined by potentiometric and UV-vis titrations using H4edta as a competitor ligand. The stability constant determined for the Cu(2+) complex is rather high (log KCuL = 20.77 and pCu = 17.15), and moreover no2th exhibits a high selectivity for copper(ii) in relation to zinc(ii). The kinetics of the copper(ii) complexation process is very fast even in acidic medium. In addition, the [Cu(no2th)](2+) complex was found to be inert under rather harsh conditions (up to 2 M HCl and 60 °C), displaying a very high half-life time of about 15 days in 2 M HCl at 90 °C. The electrochemical reduction of the copper(ii) complex in water leads to the reversible formation of a stable copper(i) species. Spectroscopic studies performed by NMR, UV-vis and EPR, assisted by theoretical calculations, show that the [Cu(no2th)](2+) complex presents a structure in solution similar to that observed in the solid state. When compared to its cyclam di-N-methylthiazolyl counterpart, the results reported in this paper unambiguously show that replacing the cyclam unit by a tacn moiety improves the stability and inertness of its Cu(ii) and Cu(i) complexes.

Cyclams with Ambidentate Methylthiazolyl Pendants for Stable, Inert, and Selective Cu(II) Coordination.

Aiming to develop new copper chelates for application in nuclear medicine we report two new chelators, te1th and te2th, based on a cyclam backbone mono-N- or di-N1,N8-functionalized by methylthiazolyl arms. The acid-base properties of both ligands were investigated as well as their coordination chemistry, especially with Cu(2+), when possible in aqueous solution and in the solid state. Single-crystal X-ray diffraction structures of complexes were determined. Stability constants of the copper(II) and zinc(II) complexes showed that the complexes of both ligands with Cu(2+) are thermodynamically very stable, and they exhibit an important selectivity for Cu(2+) over Zn(2+). The kinetic inertness in acidic medium of both copper(II) complexes was evaluated revealing a quite good resistance to dissociation (the half-life times of complexes with te1th and te2th are 50.8 and 5.8 min, respectively, in 5 M HCl and 30 °C). The coordination geometry of the metal center in the complexes was established in aqueous solution based on UV-visible, electron paramagnetic resonance (EPR) spectroscopy, DFT studies, and NMR by using the zinc(II) complex analogues. The [Cu(te1th)](2+) and [Cu(te2th)](2+) complexes adopt trans-I and trans-III configurations both in the solid state and in solution, while the [Zn(te2th)](2+) complex crystallizes as the cis-V isomer but exists in solution as a mixture of trans-III and cis-V forms. Cyclic voltammetry experiments in acetonitrile point to a relatively easy reduction of [Cu(te2th)](2+) in acetonitrile solution (Epc = -0.41 V vs NHE), but the reduced complex does not undergo dissociation in the time scale of our electrochemical experiments. The results obtained in these studies revealed that despite the limited solubility of its copper(II) chelate, te2th is an attractive chelator for Cu(2+) that provides a fast complexation process while forming a complex with a rather high thermodynamic stability and kinetic inertness with respect to dissociation even upon electrochemical reduction.

Gd(3+)-Based Magnetic Resonance Imaging Contrast Agent Responsive to Zn(2+).

We report the heteroditopic ligand H5L, which contains a DO3A unit for Gd(3+) complexation connected to an NO2A moiety through a N-propylacetamide linker. The synthesis of the ligand followed a convergent route that involved the preparation of 1,4-bis(tert-butoxycarbonylmethyl)-1,4,7-triazacyclononane following the orthoamide strategy. The luminescence lifetimes of the Tb((5)D4) excited state measured for the TbL complex point to the absence of coordinated water molecules. Density functional theory calculations and (1)H NMR studies indicate that the EuL complex presents a square antiprismatic coordination in aqueous solution, where eight coordination is provided by the seven donor atoms of the DO3A unit and the amide oxygen atom of the N-propylacetamide linker. Addition of Zn(2+) to aqueous solutions of the TbL complex provokes a decrease of the emission intensity as the emission lifetime becomes shorter, which is a consequence of the coordination of a water molecule to the Tb(3+) ion upon Zn(2+) binding to the NO2A moiety. The relaxivity of the GdL complex recorded at 7 T (25 °C) increases by almost 150% in the presence of 1 equiv of Zn(2+), while Ca(2+) and Mg(2+) induced very small relaxivity changes. In vitro magnetic resonance imaging experiments confirmed the ability of GdL to provide response to the presence of Zn(2+).

Picolinate-containing macrocyclic Mn2+ complexes as potential MRI contrast agents.

We report the synthesis of the ligand Hnompa (6-((1,4,7-triazacyclononan-1-yl)methyl)picolinic acid) and a detailed characterization of the Mn(2+) complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10-tetraazacyclododecan-1-yl)methyl)picolinic acid) and Htempa (6-((1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of logKMnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn(2+) complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn2(nompa)2(H2O)2](ClO4)2 shows that the Mn(2+) ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa(-) ligand acting as a bridging bidentate carboxylate group (µ-η(1)-carboxylate). Nuclear magnetic relaxation dispersion ((1)H NMRD) profiles and (17)O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn(nompa)](+) indicate that the Mn(2+) ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the (1)H NMRD and (17)O NMR data provides a very high water exchange rate of the inner-sphere water molecule (kex(298) = 2.8 × 10(9) s(-1)) and an unusually high value of the (17)O hyperfine coupling constant of the coordinated water molecule (AO/ℏ = 73.3 ± 0.6 rad s(-1)). DFT calculations performed on the [Mn(nompa)(H2O)](+)·2H2O system (TPSSh model) provide a AO/ℏ value in excellent agreement with the one obtained experimentally.

Hyperfine coupling constants on inner-sphere water molecules of a triazacyclononane-based Mn(II) complex and related systems relevant as MRI contrast agents.

We report the synthesis of the ligand H2MeNO2A (1,4-bis(carboxymethyl)-7-methyl-1,4,7-triazacyclononane) and a detailed experimental and computational study of the hyperfine coupling constants (HFCCs) on the inner-sphere water molecules of [Mn(MeNO2A)] and related Mn(2+) complexes relevant as potential contrast agents in magnetic resonance imaging (MRI). Nuclear magnetic relaxation dispersion (NMRD) profiles, (17)O NMR chemical shifts, and transverse relaxation rates of aqueous solutions of [Mn(MeNO2A)] were recorded to determine the parameters governing the relaxivity in this complex and the (17)O and (1)H HFCCs. DFT calculations (TPSSh model) performed in aqueous solution (PCM model) on the [Mn(MeNO2A)(H2O)]·xH2O and [Mn(EDTA)(H2O)](2-)·xH2O (x = 0-4) systems were used to determine theoretically the (17)O and (1)H HFCCs responsible for the (17)O NMR chemical shifts and the scalar contributions to (17)O and (1)H NMR relaxation rates. The use of a mixed cluster/continuum approach with the explicit inclusion of a few second-sphere water molecules is critical for an accurate calculation of HFCCs of coordinated water molecules. The impact of complex dynamics on the calculated HFCCs was evaluated with the use of molecular dynamics simulations within the atom-centered density matrix propagation (ADMP) approach. The (17)O and (1)H HFCCs calculated for these complexes and related systems show an excellent agreement with the experimental data. Both the (1)H and (17)O HFCCs (A(iso) values) are dominated by the spin delocalization mechanism. The A(iso) values are significantly affected by the distance between the oxygen atom of the coordinated water molecule and the Mn(2+) ion, as well as by the orientation of the water molecule plane with respect to the Mn-O vector.

Monopicolinate-dipicolyl derivative of triazacyclononane for stable complexation of Cu2+ and 64Cu2+.

The synthesis and characterization of Hno1pa2py, a new tacn-based ligand, is reported. The complexation process with Cu(2+) was proved to be very fast even in acidic medium. Potentiometric titrations allowed us to establish that Hno1pa2py exhibits an overall low basicity as well as a high selectivity for Cu(2+) over Zn(2+) cations. The copper(II) complex was synthesized and characterized using UV-vis and EPR spectroscopies and density functional theory (DFT) calculations. The studies clearly showed that the [Cu(no1pa2py)](+) complex is present in solution as a mixture of two isomers in which the ligand is coordinated to the metal center using a N5O donor set with the metal center in a distorted octahedral geometry. The very high kinetic inertness of the [Cu(no1pa2py)](+) complex was demonstrated by using acid-assisted dissociation assays as well as cyclic voltammetry. Preliminary investigations of (64)Cu complexation were performed to validate the potential use of such chelating agent for further application in nuclear medicine. The X-ray crystal structures of copper(II) complexes of L1, the ester derivative of Hno1pa2py, have been determined.

Macrocycle-based spin-crossover materials.

New iron(II) complexes of formula [Fe(L1)](BF(4))(2) (1) and [Fe(L2)](BF(4))(2) x H(2)O (2) (L1 = 1,7-bis(2'-pyridylmethyl)-1,4,7,10-tetraazacyclododecane; L2 = 1,8-bis(2'-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane) have been synthesized and characterized by infrared spectroscopy, variable-temperature single-crystal X-ray diffraction, and variable-temperature magnetic susceptibility measurements. The crystal structure determinations of 1 and 2 reveal in both cases discrete iron(II) monomeric structures in which the two functionalized tetraazamacrocycles (L1 and L2) act as hexadentate ligands; the iron(II) ions are coordinated with six nitrogen atoms: four from the macrocycle and two from two pyridine groups occupying two cis positions around the metal ion. In 1, the N-Fe-N bond angles indicate that the Fe(II) ion adopts an unusual distorted trigonal prismatic geometry. In agreement with the observed paramagnetic behavior, the average of the six Fe-N distances at 293 K (2.218(6) A) and at 90 K (2.209(2) A) correspond well with distances observed for high-spin (HS) Fe(II) complexes with a coordination index of 6. For 2, the Fe(II) ion adopts a distorted octahedral geometry for which the six Fe-N distances (average 2.197(4) A) at room temperature are in the range expected for HS Fe(II) complexes. The crystal structure solved at 90 K showed a strong modification of the iron coordination sphere, suggesting the presence of a spin-crossover transition from HS to low spin (LS). Surprisingly, the averaged Fe-N value (2.077(4) A) at this temperature is not in agreement with the magnetic measurements since the chi(m)T product versus T showed a full LS state at 90 K. This may be explained by the presence of important distortions arising from the macrocycle constraints. To understand how the crystal and the lattice parameters were affected by the magnetic transition, the temperature dependence of the lattice parameters of 2 was determined in the range 293-90 K: the a and b parameters show essentially linear and gradual decreases, while the c and beta parameters show dramatic decreases nearly similar to that observed in the magnetic behavior.

Complexation of the triphosphate anion: tuning the structure of cyclen based macrotricycles with 1,3-dimethylbenzene and 2,6-dimethylpyridine linkers. A potentiometric and NMR study.

The host-guest interaction between orthophosphate, pyrophosphate and triphosphate anions and three cyclen-based macrotricyclic ligands was investigated by potentiometric measurements and NMR spectroscopy. The ligands differ from one another by the nature of their spacers, which are 1,3-dimethylbenzene (TMC), 2,6-dimethylpyridine (TPyC) or a combination of the two (TMPyC). In aqueous solution, each ligand gave protonated species that further formed ternary complexes after binding with anions; these complexes were analyzed as a result of hydrogen bond formation and coulombic attraction between the organic host and the inorganic guest. The equilibrium constants found for all the detected species are reported and the selectivity, illustrated with species distribution diagrams, is discussed. The results unambiguously showed that the ligand possessing a single supplementary anchoring site (the pyridinyl spacer) exhibited the greatest affinity for the phosphate species in a large p[H] range.