Extending the Scope of the C-Functionalization of Cyclam via Copper(I)-Catalyzed Alkyne-Azide Cycloaddition to Bifunctional Chelators of Interest.

Cyclam, known for its potent chelation properties, is explored for diverse applications through selective N-functionalization, offering versatile ligands for catalysis, medical research, and materials science. The challenges arising from N-alkylation, which could decrease the coordination properties, are addressed by introducing a robust C-functionalization method. The facile two-step synthesis proposed here involves the click chemistry-based C-functionalization of a hydroxyethyl cyclam derivative using Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Boc-protecting groups prevent undesired copper coordination, resulting in compounds with a wide range of functionalities. The optimized synthesis conditions enable C-functional cyclams to be obtained easily and advantageously, with high application potential in the previously cited fields. The methodology has been extended to trehalose-based Siamese twin amphiphiles, enabling efficient gene delivery applications.

Exploring the Limits of Ligand Rigidification in Transition Metal Complexes with Mono-N-Functionalized Pyclen Derivatives.

We report the synthesis of a new family of side-bridged pyclen ligands. The incorporation of an ethylene bridge between two adjacent nitrogen atoms was reached from the pyclen-oxalate precursor described previously. Three new side-bridged pyclen macrocycles, Hsb-3-pc1a, sb-3-pc1py, and Hsb-3-pc1pa, were obtained with the aim to assess their coordination properties toward Cu2+ and Zn2+ ions. We also prepared their nonreinforced analogues H3-pc1a, 3-pc1py, and H3-pc1pa as comparative benchmarks. The two series of ligands were characterized and their coordination properties were investigated in detail. The Zn2+ and Cu2+ complexes with the nonside-bridged series H3-pc1a, 3-pc1py, and H3-pc1pa were successfully isolated and their structures were assessed by X-ray diffraction studies. In the case of the side-bridged family, the synthesis of the complexes was far more difficult and, in some cases, unsuccessful. The results of our studies demonstrate that this difficulty is related to the extreme stiffening and basicity of such side-bridged pyclens.

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.

Selective synthesis of an elusive C-functional bis-cyclam and study of its inhibition of the CXCR4 chemokine receptor.

This article presents the controlled synthesis of a rare example of C,C'-linked bis-cyclam architecture in mild conditions through the "bis-aminal" route previously used for the advantageous synthesis of cyclam, N- and C-functional cyclams and N,N'-bis-cyclams. Two synthetic pathways were explored with the smart design of α,ß-unsaturated ketones or alkyl halides bis-cyclizing agents. The first led to the isolation of a key intermediate for the future design of N-functionalized bis-cyclams, whereas the second allowed the preparation of the targeted C,C'-xylylene-bis-cyclam under mild conditions with decent yield. This compound was then studied as a CXCR4 receptor inhibitor, one of the main applications known for bis-macrocyclic compounds, in particular in the context of HIV (human immunodeficiency virus) infection. Although results demonstrated that its potency is lower (i.e. 137-fold higher IC50) than the gold standard AMD3100 against HIV infection, clear evidence of CXCR4 inhibition is presented, confirming the potential of this novel architecture and related compounds in this research field.

Multistep synthesis of a novel copper complex with potential for Alzheimer's disease diagnosis.

Positron emission tomography (PET) imaging of Aß plaques, is recognized as a tool for the diagnosis of Alzheimer's disease. As a contribution to the development of new strategies for early diagnosis of the disease, using PET medical imaging technique, a new copper complex, the [Cu(TE1PA-ONO)]+ was synthesized in ten steps. The key step of our strategy is the coupling of a monopicolinate-N-alkylated cyclam-based ligand with a moiety capable of recognizing Aß plaques via a successful and challenging Buchwald-Hartwig coupling reaction. To our knowledge, it is the first time that such a strategy is used to functionalize polyazamacrocyclic derivatives. The thermodynamic stability constants determined in MeOH/H2O solvent indicate that the attachment of this moiety does not weaken the chelating properties of TE1PA-ONO ligand in relation to parent HTE1PA. The novel complex described here is able to recognize amyloid plaques in brain sections from Alzheimer's disease patients and shows low toxicity to human neuronal cells.

Design of Bifunctional Pyclen-Based Lanthanide Luminescent Bioprobes for Targeted Two-Photon Imaging.

In the past, Lanthanide Luminescent Bioprobes (LLBs) based on pyclen-bearing π-extended picolinate antennas were synthesized and demonstrated well-adapted optical properties for biphotonic microscopy. The objective of this work is to develop a strategy to design bifunctional analogues of the previously studied LLBs presenting an additional reactive chemical group to allow their coupling to biological vectors to reach deep in vivo targeted two-photon bioimaging. Herein, we elaborated a synthetic scheme allowing the introduction of a primary amine on the para position of the macrocyclic pyridine unit. The photophysical and bioimaging studies demonstrate that the introduction of the reactive function does not alter the luminescent properties of the LLBs paving the way for further applications.

A Phosphine Oxide-Functionalized Cyclam as a Specific Copper(II) Chelator.

Although cyclam-based ligands are among the strongest copper(II) chelators available, they also usually present good affinity for other divalent cations [Zn(II), Ni(II), and Co(II)], with no copper(II)-specific cyclam ligands having been described so far. As such a property is highly desirable in a wide range of applications, we present herein two novel phosphine oxide-appended cyclam ligands that could be efficiently synthesized through Kabachnik-Fields type reactions on protected cyclam precursors. Their copper(II) coordination properties were closely studied by different physicochemical techniques [electron paramagnetic resonance (EPR) and ultraviolet-visible (UV-vis) spectroscopies, X-ray diffraction, and potentiometry]. The mono(diphenylphosphine oxide)-functionalized ligand demonstrated a copper(II)-specific behavior, unprecedented within the cyclam family of ligands. This was evidenced by UV-vis complexation and competition studies with the parent divalent cations. Density functional theory calculations also confirmed that the particular ligand geometry in the complexes strongly favors copper(II) coordination over that of competing divalent cations, rationalizing the specificity observed experimentally.

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.

Synthesis and Photophysical Properties of Lanthanide Pyridinylphosphonic Tacn and Pyclen Derivatives: From Mononuclear Complexes to Supramolecular Heteronuclear Assemblies.

Synthetic methodologies were developed to achieve the preparation of ligands L1 and L2 consisting of tacn- and pyclen-based chelators decorated with pyridinylphosphonic pendant arms combined with ethylpicolinamide or acetate coordinating functions, respectively. Phosphonate functions have been selected for their high affinity toward Ln3+ ions compared to their carboxylated counterparts and for their steric hindrance that favors the formation of less-hydrated complexes. Thanks to regiospecific N-functionalization of the macrocyclic backbones, the two ligands were isolated with good yields and implicated in a comprehensive photophysical study for the complexation of Eu3+, Tb3+, and Yb3+. The coordination behavior of L1 and L2 with these cations has been first investigated by means of a combination of UV-vis absorption spectroscopy, steady-state and time-resolved luminescence spectroscopy, and 1H and 31P NMR titration experiments. Structural characterization in solution was assessed by NMR spectroscopy, corroborated by theoretical calculations. Spectroscopic characterization of the Ln3+ complexes of L1 and L2 was done in water and D2O and showed the effective sensitization of the lanthanide metal-centered emission spectra, each exhibiting typical lanthanide emission bands. The results obtained for the phosphonated ligands were compared with those reported previously for the corresponding carboxylated analogues.

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.

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.

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.

Pyclen-Based Ligands Bearing Pendant Picolinate Arms for Gadolinium Complexation.

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with picolinic acid pendant arms either at positions 3,9-pc2pa (L5) or 3,6-pc2pa (L6) of the macrocyclic fragment. The ligands were prepared by the regiospecific protection of one of the amine nitrogen atoms of the macrocycle using Boc and Alloc protecting groups, respectively. The X-ray structure of the Gd(III) complex of L5 contains trinuclear [(GdL5)3(H2O)3]3+ entities in which the monomeric units are joined by µ2-η1:η1-carboxylate groups. However, the 1H and 89Y NMR spectra of its Y(III) analogue support the formation of monomeric complexes in solution. The Tb(III) complexes are highly luminescent, with emission quantum yields of up to 28% for [TbL5]+. The luminescence lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion, as also evidenced by the 1H relaxivities measured for the Gd(III) analogues. The Gd(III) complexes present very different exchange rates of the coordinated water molecule (kex298 = 87.1 × 106 and 1.06 × 106 s-1 for [GdL5]+ and [GdL6]+, respectively). The very high water exchange rate of [GdL5]+ is associated with the steric hindrance originating from the coordination of the ligand around the water binding site, which favors a dissociatively activated water exchange process. The Gd(III) complexes present rather high thermodynamic stabilities (log KGdL = 20.47 and 19.77 for [GdL5]+ and [GdL6]+, respectively). Furthermore, these complexes are remarkably inert with respect to their acid-assisted dissociation, in particular the complex of L5.

Complexation of C-Functionalized Cyclams with Copper(II) and Zinc(II): Similarities and Changes When Compared to Parent Cyclam Analogues.

Herein, we report a comprehensive coordination study of the previously reported ligands cyclam, CB-cyclam, TMC, DMC, and CB-DMC and of their C-functional analogues, cyclam-E, CB-cyclam-E, TMC-E, DMC-E, and CB-DMC-E. This group of ligands includes cyclam, cross-bridged cyclams, their di- or tetramethylated derivatives, and the analogues bearing an additional hydroxyethyl group on one ß-N position of the ring. The Cu(II) and Zn(II) complexes of these macrocycles have been highlighted previously for the biological interest, but the details of their structures in the solid state and in solution remained largely unexplored. In particular, we analyzed the impact that adding noncoordinating N-methyl and C-hydroxyethyl functionalities has in the structures of the complexes. All the Cu(II) and Zn(II) complexes were synthesized and investigated using single crystal X-ray diffraction and NMR, electronic absorption, and EPR spectroscopies, along with DFT studies. Dissociation kinetics experiments in acidic conditions and electrochemical studies were also performed. Special attention was paid to analyze the different configurations present in solution and in the solid state, as well as the impact of the C-appended hydroxyethyl group on the coordination behavior. Various ratios of the trans-I, trans-III, and cis-V configurations have been observed depending on the degree of N-methylation and the presence of the ethylene cross-bridge.

Cyclam-Based Chelators Bearing Phosphonated Pyridine Pendants for 64Cu-PET Imaging: Synthesis, Physicochemical Studies, Radiolabeling, and Bioimaging.

Herein we present the preparation of two novel cyclam-based macrocycles (te1pyp and cb-te1pyp), bearing phosphonate-appended pyridine side arms for the coordination of copper(II) ions in the context of 64Cu PET imaging. The two ligands have been prepared through conventional protection-alkylation sequences on cyclam, and their coordination properties have been thoroughly investigated. The corresponding copper complexes have been fully characterized in the solid state (X-ray diffraction analysis) and in solution (EPR and UV-vis spectroscopies). Potentiometric studies combined with spectrometry have also allowed us to determine their thermodynamic stability constants, confirming their high affinity for copper(II) cations. The kinetic inertness of the complexes has been verified by acid-assisted dissociation experiments, enabling their use in 64Cu-PET imaging in mice for the first time. Indeed, the two ligands could be quantitatively radiolabeled under mild conditions, and the resulting 64Cu complexes have demonstrated excellent stability in serum. PET imaging demonstrated a set of features emerging from the combination of picolinates and phosphonate units: high stability in vivo, fast clearance from the body via renal elimination, and most interestingly, very low fixation in the liver. This is in contrast with what was observed for monopicolinate cyclam (te1pa), which had a non-negligible accumulation in the liver, owing probably to its different charge and lipophilicity. These results thus pave the way for the use of such phosphonated pyridine chelators for in vivo 64Cu-PET imaging.

Complexation of Mn(II) by Rigid Pyclen Diacetates: Equilibrium, Kinetic, Relaxometric, Density Functional Theory, and Superoxide Dismutase Activity Studies.

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms at either positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability [log KMnL = 17.09(2)] than the 3,6-PC2A analogue [log KMnL = 15.53(1); 0.15 M NaCl]. Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM-1 s-1 for the complexes with 3,6-PC2A and 3,9-PC2A, respectively, at 25 °C and 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex298) are 140 × 106 and 126 × 106 s-1 for [Mn(3,6-PC2A)(H2O)] and [Mn(3,9-PC2A)(H2O)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with half-lives of 63 and 21 h, respectively, at pH = 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)(H2O)]2- (H4EDTA = ethylenediaminetetraacetic acid) and [Mn(PhDTA)(H2O)]2- (H4PhDTA = phenylenediamine-N,N,N',N'-tetraacetic acid), indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/p-nitro blue tetrazolium chloride assay at pH = 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable of assisting decomposition of the superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by 1 order of magnitude than that of 3,6-PC2A.

Pyclen-Based Ln(III) Complexes as Highly Luminescent Bioprobes for In Vitro and In Vivo One- and Two-Photon Bioimaging Applications.

In addition to the already described ligand L4a, two pyclen-based lanthanide chelators, L4b and L4c, bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: [EuL4a], [SmL4a], [YbL4b], [TbL4c], and [DyL4c]. Additionally, the symmetrically arranged regioisomer L4a' was also synthesized as well as its [EuL4a'] complex to highlight the astonishing positive impact of the dissymmetrical N-distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition, in vivo two-photon microscopy was performed for the first time on a living zebrafish model with [EuL4a]. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.

Enabling Indium Channels for Mass Cytometry by Using Reinforced Cyclam-Based Chelating Polylysine.

The synthesis of a polylysine polymer functionalized with the previously reported astonishingly inert [In(cb-te2pa)]+ chelate was performed. A biotin end group allowed the conjugation to biotinylated beads by the intermediary of a fluorescein isothiocyanate/neutravidin receptor. High quality imaging mass cytometry trials, based on 115In detection were performed to highlight the behavior of the material. Anti-CD20 antibody was labeled by the so-obtained In(III)-modified polylysine using the biotin/neutravidin interaction. Ramos (CD20[+]) and HL-60 (CD20[-]) cell lines were costained with the In(III)-modified bioconjugate by finding the best staining conditions. Both immunofluorescence microscopy (IF-M) and mass cytometry analyses confirmed the specific binding of anti-CD20 onto Ramos cells. CyTOF histograms constructed on the 115In detection allowed us to define and to separate, with a good signal-to-noise ratio, two populations (Ramos and HL-60). The inertness of In(III)-MCP-NAv over a three-month storage period was proved by performing new functionality tests involving Jurkat cells (CD20[-]) and multiparametric trials involving the 115In channel. The results ensure a promising future use of the previously announced [In(cb-te2pa)]+ complex-based polymers for mass cytometry.

Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Potential Theranostic Applications.

A family of three picolinate pyclen-based ligands, previously investigated for the complexation of Y3+ and some lanthanide ions (Gd3+, Eu3+), was studied with 161Tb and 177Lu in view of potential radiotherapeutic applications. The set of six Tb3+ and Lu3+ complexes was synthesized and fully characterized. The coordination properties in the solid state and in solution were thoroughly studied. Potentiometric titrations, supported by density functional theory (DFT) calculations, showed the very high stability constants of the Tb3+ and Lu3+ complexes, associated with remarkable kinetic inertness for up to 30 days in 1 M HCl. A complete radiolabeling study performed with both 161Tb and 177Lu radionuclides, including experiments with regard to the stability with and without scavengers and kinetic inertness using challenging agents, proved that the ligands could reasonably compete with the DOTA analogue. To conclude, the potential of using the same ligand for both radiotherapy and optical imaging was highlighted for the first time.

Formation of Heteropolynuclear Lanthanide Complexes Using Macrocyclic Phosphonated Cyclam-Based Ligands.

Ligands L1 and L2, respectively based on a cyclam and a cross-bridged cyclam scaffold functionalized at N1 and N8 by 6-phosphonic-2-methylene pyridyl groups, are described. While complexation of lanthanide (Ln) cations with L2 was not possible, a family of complexes has been prepared with L1, of the general formulae [LnL1H2]Cl (Ln3+ = Lu, Tb, Yb) or [LnL1H] (Ln3+ = Eu). The solution, structural, potentiometric, and photophysical data for these novel ligands and their complexes have been investigated, including a solid-state study by X-ray diffraction (L1, L2, and [EuL1H]), 1H NMR complexation investigations (Lu3+), as well as UV-vis absorption and luminescence spectroscopy in water and D2O (pH ≈ 7). L1 forms 1:1 metal-ligand stoichiometric octadentate complexes in solution. Importantly, the pyridyl phosphonate functions are capable of simultaneous chelation to the metal center and of interaction with a second metal center. 1H NMR (Lu3+) and spectrophotometric titrations of the isolated [TbL1]- complex by EuCl3 salts demonstrated the formation of high-order (hetero)polymetallic species in aqueous solution (H2O, pH = 7). Global analysis of the luminescence titration experiment points to the formation of 4:1, 3:1, and 3:2 [TbL1]/Eu heteropolynuclear assemblies, exhibiting a strong preference to forming [TbL1]3Eu2 at increased europium concentrations, with energy transfer occurring between the kinetically inert terbium complex and added europium cations.