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A new synthetic strategy for the preparation of macromolecular MRI contrast agents (CAs) is reported. Four gadolinium(iii) complexes bearing either one or two polymerizable methacrylamide groups were synthesized, serving as monomers or crosslinkers for the preparation of water-soluble, polymeric CAs using Reversible Addition–Fragmentation Chain Transfer (RAFT) polymerization. Using this approach, macromolecular CAs were synthesized with different architectures, including linear, hyperbranched polymers and gels. The relaxivities of the polymeric CAs were determined by NMR relaxometry, revealing an up to 5-fold increase in relaxivity (60 MHz, 310 K) for the linear polymers compared with the clinically used CA, Gd-DOTA. Moreover, hyperbranched polymers obtained from Gd(iii) crosslinkers, displayed even higher relaxivities up to 22.8 mM−1 s−1, approximately 8 times higher than that of Gd-DOTA (60 MHz, 310 K). A detailed NMRD study revealed that the enhanced relaxivities of the hyperbranched polymers were obtained by limiting the local motion of the crosslinked Gd(iii) chelate. The versatility of RAFT polymerization of Gd(iii) monomers and crosslinkers opens the doors to more advanced polymeric CAs capable of multimodal, bioresponsive or targeting properties., A new synthetic strategy for the preparation of efficient macromolecular MRI contrast agents is reported.

Two pentadentate ligands built on the 2-aminomethylpiperidine structure and bearing two tertiary amino and three oxygen donors (three carboxylates in the case of AMPTA and two carboxylates and one phenolate for AMPDA-HB) were developed for Mn(II) complexation. Equilibrium studies on the ligands and the Mn(II) complexes were carried out using pH potentiometry, 1H-NMR spectroscopy and UV-vis spectrophotometry. The Mn complexes that were formed by the two ligands were more stable than the Mn complexes of other pentadentate ligands but with a lower pMn than Mn(EDTA) and Mn(CDTA) (pMn for Mn(AMPTA) = 7.89 and for Mn(AMPDA-HB) = 7.07). 1H and 17O-NMR relaxometric studies showed that the two Mn-complexes were q = 1 with a relaxivity value of 3.3 mM−1 s−1 for Mn(AMPTA) and 3.4 mM−1 s−1 for Mn(AMPDA-HB) at 20 MHz and 298 K. Finally, the geometries of the two complexes were optimized at the DFT level, finding an octahedral coordination environment around the Mn2+ ion, and MD simulations were performed to monitor the distance between the Mn2+ ion and the oxygen of the coordinated water molecule to estimate its residence time, which was in good agreement with that determined using the 17O NMR data.

Positron emission tomography (PET) is a non-invasive molecular imaging technology that is constantly expanding, with a high demand for specific antibody-derived imaging probes. The use of tracers based on temperature-sensitive molecules (i. e. Fab, svFab, nanobodies) is increasing and has led us to design a class of chelators based on the structure of 2-aminomethylpiperidine (AMP) with acetic and/or hydroxybenzyl pendant arms (2-AMPTA, NHB-2-AMPDA, and 2-AMPDA-HB), which were investigated as such for {Al18 F}2+ -core chelation efficiency. All the compounds were characterized by HPLC-MS analysis and NMR spectroscopy. The AlF-18 labeling reactions were performed under various conditions (pH/temperature), and the radiolabeled chelates were purified and characterized by radio-TLC and radio-HPLC. The stability of labeled chelates was investigated up to 240 min in human serum (HS), EDTA 5 mM, PBS and 0.9 % NaCl solutions. The in vivo stability of [Al18 F(2-AMPDA-HB)]- was assessed in healthy nude mice (n=6). Radiochemical yields between 55 % and 81 % were obtained at pH 5 and room temperature. High stability in HS was measured for [Al18 F(2-AMPDA-HB)]- , with 90 % of F-18 complexed after 120 min. High stability in vivo, rapid hepatobiliary and renal excretion, with low accumulation of free F-18 in bones were measured. Thus, this new Al18 F-chelator may have a great impact on immuno-PET radiopharmacy, by facilitating the development of new fluorine-18-labeled heat-sensitive biomolecules.

Polydentate chelators are an important part of an imaging probe, which consists of an agent that usually produces signals for imaging purposes connected to a targeting moiety. The goal of this study was to set up a generic protocol to prepare a library of polydentate ligands having a 6-amino-6-methyl-1,4-perhydrodiazepine (AMPED) core and able to chelate metal ions of interest for various diagnostic imaging techniques, including Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT). These ions, among which we can include Mn(ii), Cu(ii), Al(iii) or Ga(iii), require penta- or hexa-dentate chelators for this purpose, and the AMPED scaffold has considerable potential to support various pendant arms for coordination of such ions. AMPED already has three amino nitrogen donors; thus, only two or three additional arms should be introduced to obtain penta- or hexa-dentate systems. This condition implies that symmetrical or asymmetrical structures have to be developed, depending on the functionalization of cyclic and exocyclic amines. Starting from easily available materials, we have designed a convenient protocol for the preparation of multiple AMPED-based ligands endowed with different characteristics, several of which were synthesized as examples.

The first binuclear Gd‐complex of the 12‐membered pyridine‐based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C−C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA‐ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd‐complexes. Thus, the 1H relaxometric study on [Gd2PCTA2(H2O)4] and on [Gd2AAZTA2(H2O)4]2− highlighted the remarkable rigidity and compactness of the two binuclear complexes, which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca. 12–12.6 mM−1 s−1 with an increase of ca. 80 % at 1.5 T and 298 K (+70 % at 310 K) with respect to the corresponding mononuclear complexes., Two novel binuclear PCTA2 and AAZTA2 ligands were synthesized with a multistep process. Their GdIII‐complexes results in molecular relaxivities at 1.5 T and 298 K of ca. 24–25 mM−1 s−1 thanks to the rigidity and compactness of the ligands. These values are remarkably higher that those found for the corresponding mononuclear complexes.

High precision in vivo PET/CT imaging of solid tumors improves diagnostic credibility and clinical outcome of patients. An epitope of the oligomerization domain of Hsp70 is exclusively exposed on the membrane of a large variety of tumor types, but not on normal cells, and thus provides a universal tumor-specific target. Here we developed a novel PET tracer TPP-PEG24-DFO[89Zr] based on the tumor cell–penetrating peptide probe TPP, which specifically recognizes membrane Hsp70 (mHsp70) on tumor cells. The implemented PEG24 moiety supported tracer stability and improved biodistribution characteristics in vivo. The Kd of the tracer ranged in the low nanomolar range (18.9 ± 11.3 nmol/L). Fluorescein isothiocyanate (FITC)-labeled derivatives TPP-[FITC] and TPP-PEG24-[FITC] revealed comparable and specific binding to mHsp70-positive 4T1, 4T1+, a derivative of the 4T1 cell line sorted for high Hsp70 expression, and CT26 tumor cells, but not to mHsp70-negative normal fibroblasts. The rapid internalization kinetics of mHsp70 into the cytosol and the favorable biodistribution of the peptide-based tracer TPP-PEG24-DFO[89Zr] in vivo enabled a tumor-specific accumulation with a high tumor-to-background contrast and renal body clearance. The tumor-specific enrichment of the tracer in 4T1+ (6.2 ± 1.1%ID/g), 4T1 (4.3 ± 0.7%ID/g), and CT26 (2.6 ± 0.6%ID/g) mouse tumors with very high, high, and intermediate mHsp70 densities, respectively, reflected mHsp70 expression profiles of the different tumor types, whereas benign mHsp70-negative fibroblastic hyperplasia showed no tracer accumulation (0.2 ± 0.03%ID/g). The ability of our chemically optimized peptide-based tracer TPP-PEG24-DFO[89Zr] to detect mHsp70 in vivo suggests its broad applicability in targeting and imaging with high specificity for any tumor type that exhibits surface expression of Hsp70. Significance: A novel peptide-based PET tracer against the oligomerization domain of Hsp70 has potential for universal tumor-specific imaging in vivo across many tumor type. Cancer Res; 78(21); 6268–81. ©2018 AACR.

It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.

This study presents a series of light-harvesting materials, where multiple chromophores are organised into host-guest silica-micelle structures at specific locations by means of self-assembly strategies. Binary and ternary mesoscopic antennae were realized, using organometallic complexes and organic dyes as energy transfer units and varying their content and localization to manipulate transfer rate and efficiency inside the materials. Steady-state and time-resolved UV-visible spectroscopy revealed that the three-dye systems show excitation energy cascade from intramicellar dyes to a silica-grafted acceptor, with transfer efficiencies of 20-24% per step and overall light emission spanning the whole visible range. The two-dye system reaches analogous panchromatic response, featuring almost-white light emission and 47% efficient transfer, by exploiting the blue-green dual emission of a metallosurfactant as energy donor inside the micellar template and the red emission of a rhodamine acceptor on the silica framework. Both systems show that control over the donor-acceptor distances can be achieved to a certain extent in complex mesoscopic materials and that a vast potential is available for transfer and colour tuning, and specific use of the materials as solid-state sensitisers.

The synthesis of a novel constrained polydentate ligand CpAAZTA derived from the heptadentate polyaminocarboxylic ligand AAZTA (6-amino-6-methylperhydro-1,4-diazepine-N, N’,N’’,N’’-tetraacetic acid) in which the ethylene bridge of the 1,4-diazepine ring is replaced by a cyclopentyl bridge is reported. In order to compare the effect of the different size and rigidity induced on the chelate by a 5-membered ring vs. a previously-reported cyclohexane-derivative, the relaxivity of the corresponding bis-hydrated GdIII complex was also investigated as a function of the magnetic field, temperature and pH.

A nanosized drug delivery system based on mesoporous silica nanoparticles functionalized with highly stable GdDOTAGA complexes, rhodamine dyes and PEG3000 molecules was synthesized. The external side of the PEG was also functionalized with azadibenzocyclooctyne moieties in order to exploit the bioorthogonal Cu(I)-free click chemistry targeting approach after metabolic labeling of cell-surface glycans with azido-mannose molecules. The particles’ pores were then impregnated with the chemotherapeutic drug mitoxantrone to add a therapeutic function to the nanosystem. The bioorthogonal targeting of the nanotheranostic probe on mannose-treated breast cancer MCF7 and TS/A cells showed a minimal difference between cells metabolically labeled or not. However, MRI experiments on labeled MCF7 cells showed a significant 200% contrast enhancement with respect to untreated cells, thus confirming the high contrast efficiency even when the cells were incubated with nanoparticles for a few minutes. Moreover, administration of the nanoprobe to MCF7 cultures resulted in a higher cytotoxicity in comparison to the free drug at a similar concentration, confirming the successful delivery of the drug.

This study presents a new design of light-harvesting antenna materials using two dyes organised into mesoporous silica: an iridium(III) complex and a BODIPY-derived surfactant that undergo Forster resonance energy transfer (FRET), acting, respectively, as donor and acceptor. The chemical structure of each dye determines the position taken within the micellar templates used for the synthesis of the silica host, which maintains mesopore order as shown by TEM imaging. Steady-state and time-resolved UV-visible spectroscopy revealed that incorporation of the iridium complex into the silica shields it from oxygen-induced quenching and allows a degree of control over the donor-acceptor distance, yielding FRET efficiencies from 24 to 76 % and tuneable emission ranges. Such silica-based antennae show promising properties for the realisation of polychromatic sensitisers for photovoltaics and photocatalysis.

Neutron activation is widely applied for the preparation of radioactive isotopes to be used in imaging and/or therapy. The type of diagnostic/therapeutic agents varies from small chelates coordinating radioactive metal ions to complex nanoparticulate systems. Design of these agents often relies on conjugation of certain organic functionalities that determine their pharmacokinetics, biodistribution, targeting, and cell-penetrating abilities, or simply on tagging them with an optical label. The conjugation chemistry at the surface of nanoparticles and their final purification often require laborious procedures that become even more troublesome when radioactive materials are involved. This study represents a thorough investigation on the effects of neutron activation on the organic moieties of functionalized nanoparticles, with special focus on (166)Ho2O3 particles conjugated with PEG-fluorescein and PEG-polyarginine motives. Spectroscopic and thermogravimetric analyses demonstrate only a limited degradation of PEG-fluorescein upon irradiation of the particles up to 10 h using a thermal neutron flux of 5 × 10(16) m(-2) s(-1). Cell experiments show that the polyarginine-based mechanisms of membrane penetration remain unaltered after exposure of the functionalized particles to the mixed field of neutrons and gammas present during activation. This confirms that radiation damage on the PEG-polyarginines is minimal. Intrinsic radiations from (166)Ho do not seem to affect the integrity of conjugated organic material. These findings open up a new perspective to simplify the procedures for the preparation of functionalized metal-based nanosystems that need to be activated by neutron irradiation in order to be applied for diagnostic and/or therapeutic purposes.

N,N'-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-diazepines. The tandem retro-Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved.

International audience; Among the procedures to prepare lanthanide-containing nanoparticles a gap exists in the range between 5 and 40 nm. The miniemulsion technique presented here is intended to fill this discontinuity and offers a facile method that can be applied for the preparation of nanoparticles for various applications, e.g. medical imaging, optics and catalysis. We demonstrate that formation of nanodroplets under emulsion conditions is the key step in the size control of the nanoparticles. The type of surfactant and the nature of the dispersed and continuous phases strongly influence the interfacial activity and, consequently, the size of the final solid particles that result from the subsequent thermal decomposition. Moreover, the choice of the surfactant determines the final elemental composition of the particles, leading to either lanthanide oxides or oxysulfates when using Brij® 35 or sodium dodecyl sulfate, respectively. Nanoparticles of holmium and gadolinium were prepared and their applicability as magnetic resonance imaging contrast agents is shown.

We have synthesized a new macromolecular architecture, (PAMAM)-CD8 , which consists of eight β-cyclodextrin units (β-CD) attached to a generation 1 poly(amidoamine) (PAMAM) dendrimer through a disulfide bond, which can be cleaved under reducing conditions. This system shows a pronounced hosting capability towards Gd(III) chelates functionalized with hydrophobic groups, thus leading to well-defined supramolecular adducts. (1)H NMR relaxometric investigations were carried out to follow the formation of adducts with three Gd(III) chelates based on the ligand architectures of 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid (AAZTA) or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) suitably functionalized with benzyl or adamantyl (Ad) pendant groups. In particular, the ditopic complex composed of two AAZTA chelating units connected to a central aromatic ring that bears an adamantyl group showed a strong affinity (ca. 10(6) M(-1)) for the CD units of the dendrimer, which is two orders of magnitude higher than toward human serum albumin (HSA). Remarkable relaxivity enhancements (i.e., up to 71% at 1 T and 25 °C) were observed upon the formation of the macromolecular host-guest adducts due to a decrease in the molecular tumbling rate and fast water-exchange. Reduction experiments and competition studies between the paramagnetic dendrimer and HSA were carried out by relaxometric techniques. The results show that the metal complexes are not displaced by the protein, thus suggesting that this novel macromolecular probe is potentially suitable for applications in vivo.

N,N′-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-diazepines. The tandem retro-Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved.

Cyclic tetraamidic chiral selectors are efficient chiral solvating agents (CSAs) for NMR spectroscopy, which enantiodiscriminate several classes of chiral substrates, mainly endowed with a π-acidic aromatic ring. The great potential of DOSY techniques in the investigation of enantiodiscrimination phenomena, also in complex mixtures, was clearly demonstrated.

Perthiolated β-cyclodextrin-based nanocapsules incorporating diaquo Gd(III)-complexes represent a promising new type of bioresponsive MRI contrast agent, showing a pronounced relaxivity change upon degradation in a reducing environment.

Three different tetraazamacrocyclic ligands containing four amide substituents that feature groups (namely allyl, styryl and propargyl groups) suitable for polymerisation have been synthesised. Gadolinium(III) complexes of these three ligands have been prepared as potential monomers for the synthesis of polymeric MRI contrast agents. To assess the potential of these monomers as MRI contrast agents, their relaxation enhancement properties and cytotoxicity have been determined. A europium(III) complex of one of these ligands (with propargyl substituents) is also presented together with its PARACEST properties. In addition, to gain further insight into the coordination chemistry of the tetra-propargyl substituted ligand, the corresponding zinc(II) and cadmium(II) complexes have been prepared. The X-ray crystal structures of the tetra-propargyl ligand and its corresponding gadolinium(III), zinc(II) and cadmium(II) complexes are also presented.