Raphaël Tripier

• Professor
• Professor (Full) at Université de Bretagne Occidentale

Synthesis, radiolabelling, conjugation and PET imaging

A versatile and efficient bisaminal template approach for the synthesis of cyclam and [13]aneN4 (homocyclen) bifunctional chelating agents (BCAs) bearing a hydroxyethyl function as a C-appended group is presented. The synthesis is rapid (two steps/one week) and does not require fastidious protection-deprotection steps or chromatographic purificatio...

The commercial availability of combined magnetic resonance imaging (MRI)/positron emission tomography (PET) scanners for clinical use has increased demand for easily prepared agents which offer signal or contrast in both modalities. Herein we describe a new class of silica coated iron-oxide nanorods (NRs) coated with polyethylene glycol (PEG) and/o...

The complexation properties of H2Me-do2pa towards natBi3+ reveal a rather fast formation of the [Bi(Me-do2pa)]+ complex, which is endowed with a very high thermodynamic stability (log KBiL = 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...

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+)...

Three macrocyclic tacn (1,4,7-triazacyclononane) derivatives containing one, two and three 2-methylpyridine pendant arms no1py , no2py and no3py , compared to the linear diamine tpen (N,N,N’,N’-Tetrakis(2-methylpyridinyl)-ethylenediamine) known for its capacity to induce...

An anisolyl-picolinate antenna grafted onto different macrocyclic ligands such as tacn, pyclen or cyclen renders the resulting terbium (III) complexes highly sensitive towards oxygen in aqueous solutions, enabling the design of ratiometric or lifetime-based molecular sensors. The underlying sensitization mechanism was investigated on analogous Gd(I...

Ligands combining two lateral bis‐pyridyl‐phosphonated‐pyclens were synthesized, using a flexible linear pegylated linker (L2) or a bulkier K22 crown‐ether (L3). A functionalized pyridyl‐phosphonated‐pyclen (L1) was also prepared as a mononuclear analogue. Coordination behavior of lanthanide cations was studied via NMR titration with Lu for L1, and...

Ligands combining 2 lateral bis‐pyridyl‐phosphonated‐pyclens were synthesized, using a linear pegylated linker L2 or a K22 crown‐ether L3. A functionalized pyridyl‐phosphonated‐pyclen L1 was also prepared as a mononuclear analogue. Coordination behavior of lanthanide cations was studied via NMR titration with Lu for L1, UV‐Vis and luminescence spec...

Macrocyclic chelators play a central role in medical imaging and nuclear medicine owing to their unparalleled metal cation coordination abilities. Their functionalization by fluorinated groups is an attractive design, to combine their properties with those of ¹⁸F for Positron Emission Tomography (PET) or natural ¹⁹F for Magnetic Resonance Imaging (...

This article presents the controlled synthesis of a rare example of C,C’-linked bis-cyclam architecture in mild conditions through to the “bis-aminal” route, previously used for the advantageous synthesis of cyclam,...

A novel family of sequence-defined gene vectors built on trehalose and trehalose-based macrocycles (cyclotrehalans) comprising linear or cyclic polyamine heads have been synthesized through procedures that exploit click chemistry reactions....

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, that could decrease the coordination properties, are addressed by introducing a robust C-functiona...

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 wer...

Citation: Métivier, C.; Le Saëc, P.; Gaschet, J.; Chauvet, C.; Marionneau-Lambot, S.; Hofgaard, P.O.; Bogen, B.; Pineau, J.; Le Bris, N.; Tripier, R.; et al. Preclinical Evaluation of a 64 Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma. Abstract: Although the concept of theranostics is neither new nor exclusive to nuclear medic...

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...

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...

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...

Copper (Cu) sensing in the nanomolar range is an important challenge for marine water monitoring, especially with eco-friendly materials and reagents. For this purpose, electrochemical Cu(II) sensors appear as fully suitable because of their relatively high sensitivity, selectivity and adaptability for in situ measurements. So far, one of the usual...

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 poss...

Résumé La treizième édition du workshop a porté sur les dernières avancées concernant les techniques d’imagerie en oncologie. L’objectif volontairement très large a consisté à réunir chimistes, biologistes, physiciens, pharmaciens et médecins autour du développement de l’imagerie en oncologie. Quatre grands thèmes ont été abordés, l’évolution de ce...

In this chapter, we analyze ligand structural features necessary for the design of stable and inert lanthanide complexes for use in biomedical applications. In the first sections of the chapter we provide a brief introduction to the coordination chemistry of the lanthanides and some general complex design principles. We then discuss the main synthe...

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 c...

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...

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...

Three new bifunctional copper chelators based on the 1,4,7-triazacyclononane (tacn) platform have been synthesized and conjugated to peptide. 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 methylpyr...

The coordination chemistry of palladium is poorly developed in nuclear medicine due to the lack of appropriate ligands capable of fulfilling all the criteria required for an in vivo application. By showing that the monopicolinate cyclam TE1PA is a highly relevant chelator for natural and radioactive Pd, we have opened avenues to enrich the area of...

We present here a novel strategy based on the covalent grafting of a C -functionalized Ni-cyclam complex onto glassy carbon to achieve heterogeneous electrocatalytic CO 2 reduction in neutral water at low...

We report a series of four cyclams and cross-bridged cyclams, N-functionalized by one hydroxyethyl arm, which may incorporate additional methyl(s) group(s). The Cu(II) and Zn(II) complexes of these ligands were synthesized and fully characterized. The investigation of the metal complexes in solid-state and in solution was carried via X-ray diffract...

Lung ventilation/perfusion (V/Q) positron emission tomography-computed tomography (PET/CT) is a promising imaging modality for regional lung function assessment. The same carrier molecules as a conventional V/Q scan (i.e., carbon nanoparticles for ventilation and macro aggregated albumin particles for perfusion) are used, but they are labeled with...

In view of the growing interest of palladium(II) for medical applications and the important role of polyamines in exploiting its properties, this review combines the published literature on the coordination of Pd(II) with small polyazacycloalkanes (three and four nitrogen atoms), such as 1,4,7-triazacyclononane, 1,5,9-triazacyclododecane, cyclen, c...

Pyclen-dipicolinate chelates proved to be very efficient chelators for the radiolabeling with β–-emitters such as 90Y. In this study, a pyclen-dipicolinate ligand functionalized with additional C12 alkyl chains was synthesized. The radiolabeling with 90Y proved that the addition of saturated carbon chains does not affect the efficiency of the radio...

Lung PET/CT is a promising imaging modality for regional lung function assessment. Our aim was to develop and validate a fast, simple, and fully automated GMP compliant [ ⁶⁸ Ga]Ga-MAA labeling procedure, using a commercially available [ 99m Tc]Tc-MAA kit, a direct gallium-68 eluate and including a purification of the [ ⁶⁸ Ga]Ga-MAA. Method: The syn...

MEGADORE (MEdical GAdolinium Recycling)

Herein, we report a comprehensive coordination study of the previously reported ligands cyclam , CB-cyclam TMC , DMC , 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...

New “all-in-one” theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene-picoli...

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 properti...

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 nitroge...

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...

An improved glucose‐chelator‐albumin bioconjugate (GluCAB) derivative, GluCAB‐2Mal, has been synthesized and studied for in vivo ⁶⁴Cu‐PET/CT imaging in breast cancer mice models together with its first‐generation analogue GluCAB‐1Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) eff...

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 properti...

For the first time, a highly encapsulating macrocycle derived from the cross-bridged cyclam platform has been used to build coordination polymers. The bibracchial dissymmetric lariat macrocycle H2cb-teapa works as an organic tecton yielding a Pb(II) 1D coordination polymer of formula {[Pb(Cl)(H2cb-teapa)](ClO4)}n (4), whose structure has been analy...

New "all-in-one" theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene-picoli...

New “all-in-one” theranostic systems, combining a magnetic resonance imaging (MRI) contrast agent with a biphotonic photodynamic therapy (2P-PDT) photosensitiser generating cytotoxic singlet oxygen, were envisaged and synthesised. They are based on azamacrocycles, regiospecifically functionalised by two-photon PDT π-conjugated dibromobenzene-picoli...

We report the synthesis of two pyclen-based regioisomer ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca1(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 regiospecific protection of one of the amine nitrogen ato...

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 either at 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...

Amyloid-β (Aβ) aggregation and metal ion dyshomeostasis are found to be pathological features upon the progress of Alzheimer's disease (AD). In addition, Aβ and metal ions are reported to interact with each other forming metal–Aβ complexes, which can affect the aggregation of Aβ and cause oxidative stress via the production of reactive oxygen speci...

The alternative analysis of A. Bianchi and M. Savastano is a valuable contribution to the understanding of the complex systems at stake in the complexation chemistry of Zr4+ by considering polynuclear species. Placed in the context of nuclear medicine where such aggregates are unlikely and considering recent literature data, this however points out...

Purpose: The use of 68Ga-labelled carbon nanoparticles has been proposed for lung ventilation PET/CT imaging. However, no study has assessed the physical properties of 68Ga-labelled carbon nanoparticles. The aim of this study therefore was to evaluate the shape and size of 68Ga-labelled carbon nanoparticles, and to determine the composition of the...

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 st...

In the aim to design small molecules capable of binding in vivo to albumin to form bioconjugates, a second generation GluCAB derivative(Glucose-Chelator-Albumin Bioconjugate) has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue. This series of radioligan...

Ligands L 1 and L 2 , 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 L 2 was not possible, a family of complexes has been prepared with L 1 , of the general formulae [LnL 1 H 2 ]Cl (Ln3+ = Lu,...

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 syn...

We report the synthesis of an original ligand scaffold based on a dimethyl-cyclen platform Medo2pa with two dithienylethene units attached to each picolinate arms and the corresponding yttrium(III), europium(III) and ytterbium(III) complexes. All three compounds show reversible photochromism with high photo-conversions. Photoluminescence experiment...

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 CytometryTM trials, based on ¹¹⁵In detecti...

In addition to the already described ligand L 4a , two pyclen-based lanthanide chelators, L 4b and L 4c , 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: [EuL 4a ],...

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 o...

A metal containing polymer (MCP) based on a polylysine functionalized by In(III) chelates was synthesized. The chelator is based on a constrained dipicolinate cyclam that forms a highly inert In(III) complex. The MCP was conjugated to anti CD20 antibody using the very strong neutravidin/biotin interaction. Two cell lines, one expressing CD20 the ot...

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 prepa...

A symmetrical squaraine-based ligand, sbdpa, bearing two dipicolylamine (dpa) units, was synthesized for the first time, using an environment friendly procedure, such as one-pot and solvent-free reaction. The sbdpa ligand was found to have a small blue-green emission, in aqueous solution, due to a photoinduced electron transfer (PET) mechanism. Met...

Two pyclen based lanthanide chelators, L^4b and L^4c, bearing two specific picolinate 2P antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized to form, with the already described ligand L^4a, a complete family of lanthanide luminescent bioprobes: [...

We report the synthesis of an original ligand scaffold based on a dimethyl-cyclen platform Medo2pa with two dithienylethene units attached to each picolinate arms and the corresponding yttrium(III), europium(III) and ytterbium(III) complexes. All three complexes show reversible photochromism with high photo-conversions. Photoluminescence experiment...

A new family of chiral C2 symmetric tetraazamacrocycles, coined ISAC for IminoSugar Aza-Crown, incorporating two iminosugars adopting a 4C1 conformation is disclosed. Multinuclear NMR experiments on the corresponding Cd2+ complex show that the ISAC is a strong chelator in water and its tetramine cavity adopts a conformation similar to that of the p...

Introduction L’étude de la ventilation pulmonaire est désormais transposable en TEP grâce à l’utilisation d’un aérosol de nanoparticules de carbone marquées au Ga-68, produit selon le même procédé que le Technegas® (Cyclopharm Ltd, Australie). Aucune étude à ce jour n’a évalué les propriétés physiques de ces particules qui conditionnent la biodisti...

p>Cationic lanthanide complexes are generally able to spontaneously internalize into living cells. Following our previous works based on diMe-cyclen framework, a second generation of cationic water-soluble lanthanide complexes based on a constrained cross-bridged cyclam macrocycle functionalized with donor-p-conjugated picolinate antennas has been...

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...

H2cb‐te2pa, a cross‐bridged cyclam functionalized by two picolinate arms, was used for the formation of an incredible inert InIII chelate. The inertness of the complex was evaluated by UV/Vis experiments in several competitive media and was highlighted by the comparison with [In(dota)]⁻ and [In(dtpa)]²⁻ (H4dota = 1,4,7,10‐tetraazacyclododecane‐1,4,...

Considering the current importance of unsymmetrical mono‐ and di‐N‐functionalized ethylene side‐bridged (sb) cyclams and the need to have their C‐appended derivatives bearing an additional function dedicated to a conjugation to an external moiety as a targeting biomolecule, we have developed a general procedure to obtain orthogonally N‐protected sb...

Towards improved lanthanide complexes for two‐photon mediated singlet oxygen production: The very large inter‐system crossing efficiency results from the combination and interplay of bromine atom substituents, placed along the π‐conjugated antenna, and a heavy rare‐earth element coordinated to a central TACN ligand. Two‐photon activated singlet oxy...

Two trispicolinate 1,4,7‐triazacyclonane (TACN)‐based ligands bearing three picolinate biphotonic antennae were synthetized and their Yb³⁺ and Gd³⁺ complexes isolated. One series differs from the other by the absence (L¹)/presence (L²) of bromine atoms on the antenna backbone, offering respectively improved optical and singlet‐oxygen generation pro...

In the search for receptors suitable for the recognition of phosphate or polyphosphate anions a new unsymmetrical squaramide-based ligand bearing dipicolylamine (dpa) and ethylpiperazine units (L) was designed and prepared. The acid-base reactions of L, its copper(II) complexation behaviour as well as the binding of phosphate and polyphosphate anio...

Although positron emission tomography (PET) imaging with 18-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker for the identification of myeloma cells and could be used in phenotype tumor imaging. In this study, we...

Three tacn (1,4,7-triazacyclononane)-based ligands substituted by methylthiazolylcarboxylate (tha) and/or methylthiazolyl (th) arms have been examined for copper complexation in the aim to study the impact of the carboxylate groups on the complexation of Cu(II), which can present an endo- or exocyclic coordination. Two new ligands have been synthes...

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 ( ⁶⁴ Cu) positron emission tomography imaging. The first one bears an isothio...

The invention relates to new macrocyclic ligands of formula (I) and complexes thereof, particularly radioactive complexes, and to the uses thereof and a method for preparing same. The ligands have a reinforced pyclene core.

Pyclen-based ligand bearing picolinate ILCT antenna forms highly luminescent one- and two-photon Eu( iii ) and Sm( iii ) complexes.

The triethylbenzene-bis-cyclen (cyclen = 1,4,7,10-tetraazacyclododecane) compound (tbmce) was designed with an imposed structural rigidity at the m-xylyl spacer to be compared to a less restrained and known parent compound (bmce). The framework of both compounds differs only in the substituents of the m-xylyl spacer. The study was centered in the d...

According to the excellent copper(II) and 64-copper(II) complexation of TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while keeping intact its chelating properties. Overcoming the already known drawback of a grafting by its carboxyl group, essential to the overall ligand asse...

Targeting copper ions to either remove or redistribute them is currently viewed as a possible therapeutic strategy in the context of Alzheimer's disease (AD). Thermodynamic parameters, as for instance the copper(II) affinity of the drug candidate or the copper(II) over zinc(II) selectivity, are considered in the design of the drug candidate. In con...