Relevance of Oxocyclam from Palladium(II) Coordination to Radiopharmaceutical Development.

We provide a comprehensive study of the coordination of oxocyclam with palladium(II), including presentation of a novel bifunctional analogue, p-H2N-Bn-oxocyclam, bearing an aniline pendant. The complexation of palladium(II) with oxocyclam was examined by various techniques, including NMR analysis and potentiometric titrations which revealed that the Pd(II) complex can adopt different configurations such as trans-I and trans-III. In addition, oxocyclam forms a thermodynamically stable palladium(II) complex, the stabilization being attributed to the deprotonation of the amide function. The crystal structures of [Pd(H-1oxocyclam)]+ and [Pd(oxocyclam)]2+ were obtained, revealing the structural details previously anticipated, including, in the second case, the presence of the proton on the carbonyl oxygen atom. Additionally, the study explored the redox behavior of the Pd(II)-oxocyclam complex through reduction and oxidation voltammograms at different pH values. Successful 109Pd-labeling of oxocyclam and p-H2N-Bn-oxocyclam at pH 3.5 demonstrated high labeling efficiencies, whatever the species formed. The stability of the radiocomplexes was assessed and moderate transchelation toward EDTA was observed. Overall, oxocyclam displayed favorable properties for Pd(II) coordination and radiolabeling, suggesting its potential as a chelating agent for this metal in palladium-based applications.

Highly inert Cu(II) complexes of C-aryl bifunctional cyclam-picolinates with remarkable 64Cu-labelling and biodistribution.

Cyclam-picolinate chelators were functionalized via click chemistry with an additional carboxyl group for subsequent bioconjugation to antibodies or for the modification of the overall charge of the corresponding 64Cu-radiocomplexes. The C-aryl functionalization strategy developed here preserves the chemical properties of the radiocomplexes whilst deeply enhancing their applications within nuclear medicine.

Relevance of Palladium to Radiopharmaceutical Development Considering Enhanced Coordination Properties of TE1PA.

Invited for the cover of this issue are the group of Raphaël Tripier and Nathalie Le Bris at the University of Brest (UMR CNRS 6521 CEMCA; France), Cathryn H. S. Driver from the South African Nuclear Energy Corporation in Pretoria (South Africa), and their collaborators. The image depicts the beginning of a new area of research into palladium and complexation of its radioisotopes for applications in nuclear medicine. Read the full text of the article at 10.1002/chem.202200942.

Relevance of Palladium to Radiopharmaceutical Development Considering Enhanced Coordination Properties of TE1PA.

The limited use of palladium-103 and -109 radionuclides for molecular radiotherapy is surely due to the lack of appropriate ligands capable of fulfilling all criteria required for application in nuclear medicine. Furthermore, the thermodynamic properties of these complexes in solution remain difficult to establish. The challenge is compounded when considering that radiolabeling of compounds for translation to clinical trials requires fast complexation. Thus, the coordination of Pd(II) and 103/109 Pd-nuclides is a huge challenge in terms of molecular design and physicochemical characterization. Herein, we report a comprehensive study highlighting TE1PA, a monopicolinate cyclam - already established in nuclear imaging with 64 Cu-PET (positron emission tomography) imaging tracers - as a highly relevant chelator for natural Pd and subsequently 109 Pd-nuclide. The structural, thermodynamic, kinetic and radiolabeling studies of Pd(II) with TE1PA, as well as the comparison of this complex with three structurally related derivatives, support palladium-TE1PA radiopharmaceuticals as leading candidates for targeted nuclear medicine.

A molecular test based on RT-LAMP for rapid, sensitive and inexpensive colorimetric detection of SARS-CoV-2 in clinical samples.

Until there is an effective implementation of COVID-19 vaccination program, a robust testing strategy, along with prevention measures, will continue to be the most viable way to control disease spread. Such a strategy should rely on disparate diagnostic tests to prevent a slowdown in testing due to lack of materials and reagents imposed by supply chain problems, which happened at the beginning of the pandemic. In this study, we have established a single-tube test based on RT-LAMP that enables the visual detection of less than 100 viral genome copies of SARS-CoV-2 within 30 min. We benchmarked the assay against the gold standard test for COVID-19 diagnosis, RT-PCR, using 177 nasopharyngeal RNA samples. For viral loads above 100 copies, the RT-LAMP assay had a sensitivity of 100% and a specificity of 96.1%. Additionally, we set up a RNA extraction-free RT-LAMP test capable of detecting SARS-CoV-2 directly from saliva samples, albeit with lower sensitivity. The saliva was self-collected and the collection tube remained closed until inactivation, thereby ensuring the protection of the testing personnel. As expected, RNA extraction from saliva samples increased the sensitivity of the test. To lower the costs associated with RNA extraction, we performed this step using an alternative protocol that uses plasmid DNA extraction columns. We also produced the enzymes needed for the assay and established an in-house-made RT-LAMP test independent of specific distribution channels. Finally, we developed a new colorimetric method that allowed the detection of LAMP products by the visualization of an evident color shift, regardless of the reaction pH.

Coarse-Grained Parameterization of Nucleotide Cofactors and Metabolites: Protonation Constants, Partition Coefficients, and Model Topologies.

Nucleotides are structural units relevant not only in nucleic acids but also as substrates or cofactors in key biochemical reactions. The size- and timescales of such nucleotide-protein interactions fall well within the scope of coarse-grained molecular dynamics, which holds promise of important mechanistic insight. However, the lack of specific parameters has prevented accurate coarse-grained simulations of protein interactions with most nucleotide compounds. In this work, we comprehensively develop coarse-grained parameters for key metabolites/cofactors (FAD, FMN, riboflavin, NAD, NADP, ATP, ADP, AMP, and thiamine pyrophosphate) in different oxidation and protonation states as well as for smaller molecules derived from them (among others, nicotinamide, adenosine, adenine, ribose, thiamine, and lumiflavin), summing up a total of 79 different molecules. In line with the Martini parameterization methodology, parameters were tuned to reproduce octanol-water partition coefficients. Given the lack of existing data, we set out to experimentally determine these partition coefficients, developing two methodological approaches, based on 31P-NMR and fluorescence spectroscopy, specifically tailored to the strong hydrophilicity of most of the parameterized compounds. To distinguish the partition of each relevant protonation species, we further potentiometrically characterized the protonation constants of key molecules. This work successfully builds a comprehensive and relevant set of computational models that will boost the biochemical application of coarse-grained simulations. It does so based on the measurement of partition and acid-base physicochemical data that, in turn, covers important gaps in nucleotide characterization.

A colorimetric chemosensor for quantification of exchangeable Cu2+ in soil.

Chemosensors have already demonstrated potential for the detection and imaging of metal ions in solutions and biological systems, however, their applications to soil analysis are limited. This study explores the potential of utilizing a chemosensor for the detection of exchangeable Cu2+ in soils via qualitative (solution visual color change) and quantitative (UV-Vis spectrophotometry) approaches. Montmorillonite and kaolin clays were doped with Cu(NO3)2 solutions from 2.5 to 50 mM, and contaminated soil samples were collected from a historic copper mine. The exchangeable Cu2+ was extracted using a standard CaCl2 cation exchange approach, and the Cu2+ concentration in the resulting solutions determined by UV-Vis spectrophotometry, using a chemosensor, and compared to traditional ICP-MS analysis. Analytical results showed that the chemosensor provided a visual response in contaminated soils at concentrations of 25 µM and quantitative detection to concentrations of 1 µM using UV-Vis spectrophotometry. This work demonstrates the first reported chemosensor for exchangeable Cu2+ with application to soil systems.

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.

Ultrasensitive Colorimetric and Ratiometric Detection of Cu2+: Acid-Base Properties, Complexation, and Binding Studies.

Herein, we report the synthesis and characterization of a chemosensor, 5-(diethylamino)-2-(2,3-dihydro-1H-perimidin-2-yl)phenol (HL), synthesized from a condensation between 4-(diethylamino)salicylaldehyde and 1,8-diaminonaphthalene. Upon investigation of the sensing properties of HL, it was found that this sensor may be employed for simple yet efficient detection of Cu2+ in aqueous methanol solutions. The selective and ratiometric response to Cu2+ yielded an outstandingly low limit of detection of 3.7 nM by spectrophotometry and is also useful as a naked-eye sensor from 2.5 µM. The system was studied by spectrophotometric pH titrations to determine Cu2+ binding constants and complex speciation. Binding of Cu2+ to HL occurs in 1:1 stoichiometry, in good agreement with high-resolution electrospray ionization mass spectrometry (ESI-HRMS) results, Cu2+ titrations, and Job's plot experiments, while the coordination geometry was tentatively assigned as square pyramidal by spectroscopic studies.

Polyamide-Polyamine Cryptand as Dicarboxylate Receptor: Dianion Binding Studies in the Solid State, in Solution, and in the Gas Phase.

Polyamide-polyamine hybrid macrobicycle L is explored with respect to its ability to bind α,ω-dicarboxylate anions. Potentiometric studies of protonated L with the series of dianions from succinate (suc2-) through glutarate (glu2-), α-ketoglutarate (kglu2-), adipate (adi2-), pimelate (pim2-), suberate (sub2-), to azelate (aze2-) have shown adipate preference with association constant value of K = 4900 M-1 in a H2O/DMSO (50:50 v/v) binary solvent mixture. The binding constant increases from glu2- to adi2- and then continuously decreases with the length of the anion chain. Further, potentiometric studies suggest that hydrogen bonding between the guest anions and the amide/ammonium protons of the receptor also contributes to the stability of the associations along with electrostatic interactions. Negative-mode electrospray ionization of aqueous solutions of host-guest complexes shows clear evidence for the selective formation of 1:1 complexes. Single-crystal X-ray structures of complexes of the receptor with glutaric acid, α-ketoglutaric acid, adipic acid, pimelic acid, suberic acid, and azelaic acid assist to understand the observed binding preferences. The solid-state structures reveal a size/shape complementarity between the host and the dicarboxylate anions, which is nicely reflected in the solution state binding studies.

Copper(II) Complexes of Phenanthroline and Histidine Containing Ligands: Synthesis, Characterization and Evaluation of their DNA Cleavage and Cytotoxic Activity.

Copper(II) complexes have been intensely investigated in a variety of diseases and pathological conditions due to their therapeutic potential. The development of these complexes requires a good knowledge of metal coordination chemistry and ligand design to control species distribution in solution and tailor the copper(II) centers in the right environment for the desired biological activity. Herein we present the synthesis and characterization of two ligands HL1 and H2L2 containing a phenanthroline unit (phen) attached to the amino group of histidine (His). Their copper(II) coordination properties were studied using potentiometry, spectroscopy techniques (UV-vis and EPR), mass spectrometry (ESI-MS) and DFT calculations. The data showed the formation of single copper complexes, [CuL1]+ and [CuL2], with high stability within a large pH range (from 3.0 to 9.0 for [CuL1]+ and from 4.5 to 10.0 for [CuL2]). In both complexes the Cu2+ ion is bound to the phen unit, the imidazole ring and the deprotonated amide group, and displays a distorted square pyramidal geometry as confirmed by single crystal X-ray crystallography. Interestingly, despite having similar structures, these copper complexes show different redox potentials, DNA cleavage properties and cytotoxic activity against different cancer cell lines (human ovarian (A2780), its cisplatin-resistant variant (A2780cisR) and human breast (MCF7) cancer cell lines). The [CuL2] complex has lower reduction potential (Epc= -0.722 V vs -0.452 V for [CuL1]+) but higher biological activity. These results highlight the effect of different pendant functional groups (carboxylate vs amide), placed out of the coordination sphere, in the properties of these copper complexes.

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.

Investigating the Complexation of the Pb(2+)/Bi(3+) Pair with Dipicolinate Cyclen Ligands.

The complexation properties toward Pb(2+) and Bi(3+) of the macrocyclic ligands 6,6'-((1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2do2pa) and 6,6'-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid (H2Me-do2pa) have been investigated. A new three-step synthesis of H2do2pa following the bisaminal methodology has also been developed. The X-ray structures of [Pb(Me-do2pa)]·6H2O and [Bi(Me-do2pa)](NO3)·H2O show that the two metal ions are eight-coordinated by the ligand. The two complexes exist as the racemic Δ(δδδδ)/Λ(λλλλ) mixture both in the solid state and in solution, as indicated by NMR and DFT studies. The stability constants of the lead(II) and bismuth(III) complexes of the two ligands were determined in 0.5 M KCl using potentiometric and spectrophotometric techniques. The stability constants determined for the complexes of Pb(2+) are relatively high (log KML = 16.44 and 18.44 for H2do2pa and H2Me-do2pa, respectively) and exceptionally high for the complexes of Bi(3+) (log KML = 32.0 and 34.2 for H2do2pa and H2Me-do2pa, respectively). The [Pb(Me-do2pa)] complex presents rather fast formation and very good kinetic inertness toward transchelation. Additionally, the [Bi(Me-do2pa)](+) complex was found to present a remarkably fast complexation rate (full complexation in ∼2 min at pH 5.0, acetate buffer) and a very good kinetic inertness with respect to metal ion dissociation (half-life of 23.9 min in 1 M HCl), showing promise for potential applications in α-radioimmunotherapy.

Stable Mn(2+), Cu(2+) and Ln(3+) complexes with cyclen-based ligands functionalized with picolinate pendant arms.

In this study we present the results of the equilibrium, dissociation kinetics, DFT and X-ray crystallographic studies performed on the complexes of metal ions of biomedical importance (Mn(2+), Cu(2+) and Gd(3+)) formed with octadentate ligands based on a cyclen platform incorporating two picolinate pendant arms (dodpa(2-) and Medodpa(2-)). The stability constants of the complexes were accessed by multiple methods (pH-potentiometry, direct and competition UV-vis spectrophotometry and (1)H-relaxometry). The stability constants of the complexes formed with dodpa(2-) and Medodpa(2-) do not differ significantly (e.g. log K[Mn(dodpa)] = 17.40 vs. log K[Mn(Medodpa)] = 17.46, log K[Cu(dodpa)] = 24.34-25.17 vs. log K[Cu(Medodpa)] = 24.74 and log K[Gd(dodpa)](+) = 17.27 vs. log K[Gd(Medodpa)](+) = 17.59), which indicates that the steric hindrance brought by the methyl groups has no significant effect on the stability of the complexes. The stability constants of the Mn(2+) complexes formed with the cyclen dipicolinates were found to be ca. 3 log K units higher than those determined for the complex of the cyclen monopicolinate (dompa(-)), which indicates that the second picolinate moiety attached to the backbone of the macrocycle is very likely coordinated to the Mn(2+) ion. However, the stability of the [Cu(dodpa)] and [Cu(Medodpa)] complexes agrees well with the stability constant of [Cu(dompa)](+), in line with the hexadentate coordination around the metal ion observed in the X-ray structure of [Cu(Medodpa)]. The [Gd(dodpa)](+) and [Gd(Medodpa)](+) complexes display a fairly high kinetic inertness, as the rate constants of acid catalysed dissociation (k1 = 2.5(4) × 10(-3) and 8.3(4) × 10(-4) M(-1) s(-1) for [Gd(dodpa)](+) and [Gd(Medodpa)](+), respectively) are smaller than the value reported for [Gd(do3a)] (k1 = 2.5 × 10(-2) M(-1) s(-1)). The [Mn(dodpa)] complex was found to be more inert than [Mn(Medodpa)]. The results of the diffusion-ordered NMR spectroscopy (DOSY) and DFT calculations of diamagnetic [La(dodpa)](+) and [Lu(dodpa)](+) complexes indicate the formation of a trinuclear entity of the La complex in aqueous solution.

Reasons behind the relative abundances of heptacoordinate complexes along the late first-row transition metal series.

A series of transition metal complexes [ML(1)] (H2L(1) = 1,4,10-trioxa-7,13-diazacyclopentadecane-N,N'-diacetic acid, M = Co, Ni, Cu, or Zn) have been prepared and characterized. The X-ray structures of the [CoL(1)] and [CuL(1)] complexes reveal that the metal ions are seven-coordinated with a distorted pentagonal bipyramidal coordination. The five donor atoms of the macrocycle define the pentagonal plane of the bipyramid, while two oxygen atoms of the carboxylate groups coordinate apically. The [NiL(1)] complex presents a very distorted structure with long Ni-O distances involving two oxygen atoms of the crown moiety [2.544(3) Å]. This distortion is related to the Jahn-Teller effect that is expected to operate in d(8) pentagonal bipyramidal complexes. The spectroscopic characterization of the [ZnL(1)] and [CuL(1)] complexes using NMR and EPR and the theoretical calculation of the (13)C NMR shifts and g- and A-tensors using DFT confirm that these complexes retain the pentagonal bipyramidal coordination in aqueous solution. The stability trend of the [ML(1)] complexes (Co(2+) > Ni(2+) < Cu(2+) > Zn(2+)), which is in contradiction with the Irving-Williams order, has been analyzed using DFT calculations (TPSSh functional). The free energy values calculated in the gas phase for [CoL(1)](g) + [M(H2O)6](2+)(g) → [ML(1)](g) + [Co(H2O)6](2+)(g) (M = Ni, Cu, Zn) reproduce fairly well the stability trend observed experimentally, the agreement being improved significantly upon inclusion of solvent effects. Our results indicate that the pentagonal bipyramidal coordination is particularly unfavorable for Ni(2+), and thus preorganized ligands that favor this geometry such as L(1) are selective for Co(2+) over Ni(2+) cations.

H2Me-do2pa: an attractive chelator with fast, stable and inert (nat)Bi³âº and ²¹³Bi³âº complexation for potential α-radioimmunotherapy applications.

The complexation properties of H2Me-do2pa towards (nat)Bi(3+) reveal a rather fast formation of the [Bi(Me-do2pa)](+) complex, which is endowed with a very high thermodynamic stability (log K(BiL) = 34.2) and presents a single non-fluxional structure in solution. X-ray diffraction and solution NMR studies showed an octadentate binding of the ligand to the metal ion. The labelling of H2Me-do2pa with (213)Bi was performed and the resulting complex was stable in vitro, sustaining its use as an attractive alternative to taken here as a reference.

Monopicolinate cross-bridged cyclam combining very fast complexation with very high stability and inertness of its copper(II) complex.

The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb-cyclam) derivative bearing a picolinate arm (Hcb-te1pa) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid-base properties and coordination properties with Cu(2+) and Zn(2+) was investigated. The X-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temperature and that demonstrated high thermodynamic stability, which was measured by potentiometry (at 25 °C and 0.10 M in KNO3). The results also revealed that the complex exists as a monopositive copper(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu(2+) over Zn(2+). The copper(II) complex was synthesized and investigated in solution using different spectroscopic techniques and DFT calculations. The kinetic inertness of the copper(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissociation of the complex. The half-life of 96 days, in 5 M HClO4, and 465 min, in 5 M HCl at 25 °C, show the high kinetic stability of the copper(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Additionally, cyclic voltammetry experiments underlined the perfect electrochemical inertness of the complex as well as the quasi-reversible Cu(2+)/Cu(+) redox system. The coordination geometry of the copper center in the complex was established in aqueous solution from UV-vis and EPR spectroscopies.

Copper(II) and gallium(III) complexes of trans-bis(2-hydroxybenzyl) cyclen derivatives: absence of a cross-bridge proves surprisingly more favorable.

Two cyclen (1,4,7,10-tetraazacyclododecane) derivatives bearing trans-bis(2-hydroxybenzyl) arms, the 1,7-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane (H2do2ph) and its cross-bridged counterpart (H2cb-do2ph), have been synthesized, aiming toward the possible use of their copper(II) and gallium(III) complexes in nuclear medicine. The protonation of both compounds was studied in aqueous solution as well as their complexes with Cu(2+) and Ga(3+) cations. The complexes of both ligands with Ca(2+) and Zn(2+) metal ions were also studied due to the abundance of these cations in biological media. In mild conditions the complexes of Ca(2+) and Ga(3+) with H2cb-do2ph did not form. The behavior of the two ligands and their complexes was compared by the values of the equilibrium constants, the data of varied spectroscopic techniques, the values of redox potentials of their copper(II) complexes, and the resistance of the complexes to acid dissociation. It was expected that, as found for related pairs of cyclen and cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives, the cross-bridged macrocyclic derivative could be an excellent ligand for the complexation of copper(II). Additionally, the N-2-hydroxybenzyl groups were chosen due to their known ability to coordinate the gallium(III) cation. Due to the small size of the latter cation and its particular propensity to form hexacoordinate complexes, it was also expected that there would be a good ability of both ligands for the uptake of Ga(3+). Surprisingly, the results revealed that the cyclen derivative H2do2ph is the best ligand for the coordination of Cu(2+) and Ga(3+) cations, not only from their thermodynamic stability as expected but also from their kinetic inertness, when compared with its cross-bridged counterpart.