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Ca(II) ions are critical for the proper function of neurons by contributing to synaptic signaling and regulating neuronal plasticity. Dysregulation of Ca(II) is associated with a number of pathologies that cause neurodegeneration; therefore the ability to monitor Ca(II) intracellularly is an important target for molecular imaging. Contrast-enhanced MR imaging is a promising modality for imaging changes in Ca(II) concentrations. However, the majority of Ca(II) responsive MR agents are limited to the extracellular space or hindered by poor cellular uptake. Here, we describe a new class of multimodal, bioresponsive Ca(II) magnetic resonance agents that are coupled to the NIR probe IR-783. This new design is based on previous generations of our Ca(II) MR agents but overcomes two significant challenges: (1) the presence of the NIR probe dramatically increases cellular uptake of the agent and (2) provides histological validation of the MR signal using NIR fluorescence imaging. IR-783 targets organic anion transporter polypeptides, and we demonstrate that the agents are not toxic in HT-22 or U-87 MG cells up to 20 μM. The cellular uptake of complex

The impact on the morphology nanoceramic materials generated from group 4 metal alkoxides ([M(OR)4]) and the same precursors modified by 6,6'-(((2-hydroxyethyl)azanediyl)bis(methylene))bis(2,4-di- tert-butylphenol) (referred to as H3-AM-DBP2 (1)) was explored. The products isolated from the 1:1 stoichiometric reaction of a series of [M(OR)4] where M = Ti, Zr, or Hf; OR = OCH(CH3)2(OPr i); OC(CH3)3(OBu t); OCH2C(CH3)3(ONep) with H3-AM-DBP2 proved, by single crystal X-ray diffraction, to be [(ONep)Ti( k4( O,O',O'',N)-AM-DBP2)] (2), [(OR)M(μ( O)- k3( O',O'',N)-AM-DBP2)]2 [M = Zr: OR = OPr i, 3·tol; OBu t, 4·tol; ONep, 5·tol; M = Hf: OR = OBu t, 6·tol; ONep, 7·tol]. The product from each system led to a tetradentate AM-DBP2 ligand and retention of a parent alkoxide ligand. For the monomeric Ti derivative (2), the metal was solved in a trigonal bipyramidal geometry, whereas for the Zr (3-5) and Hf (6, 7) derivatives a symmetric dinuclear complex was formed where the ethoxide moiety of the AM-DBP2 ligand bridges to the other metal center, generating an octahedral geometry. High quality density functional theory level gas-phase electronic structure calculations on compounds 2-7 using Gaussian 09 were used for meaningful time dependent density functional theory calculations in the interpretation of the UV-vis absorbance spectral data on 2-7. Nanoparticles generated from the solvothermal treatment of the ONep/AM-DBP2 modified compounds (2, 5, 7) in comparison to their parent [M(ONep)4] were larger and had improved regularity and dispersion of the final ceramic nanomaterials.

New bifunctional hexa- and octadentate analogues of the hydroxamate-containing siderophore desferrichrome (DFC) have been synthesized and evaluated as 89Zr-chelating agents for immunoPET applications. The in vitro and in vivo inertness of these new ligands, Orn3-hx (hexadentate) and Orn-4hx derivatives (octadentate), was compared to the gold standard hexadentate, hydroxamate-containing chelator for 89Zr desferrioxamine (DFO). Density functional theory was employed to model the geometries of the resulting Zr(IV) complexes and to predict their relative stabilities as follows: Zr(Orn4-hx) > Zr(DFC) > Zr(Orn3-hx). Transchelation challenge experiments of the corresponding radiochemical complexes with excess ethylenediaminetetraacetate (EDTA) indicated complex stability in accordance with DFT calculations. Radiolabeling of these ligands with 89Zr was quantitative (0.25 μmol of ligand, pH 7.4, room temperature, 20 min). For antibody conjugation, the isothiocyanate (NCS) functional group was introduced to the N terminus of Orn3-hx and Orn-4hx. An additional trifunctional derivative that bears a silicon-rhodamine fluorophore on the C-terminus and NCS on the N terminus was also furnished. As proof of concept, all NCS derivatives were conjugated to the HER2-targeting antibody, trastuzumab. Radiolabeling of immunoconjugates with 89Zr was accomplished with radiochemical yields of 16 ± 2% to 95 ± 2%. These constructs were administered to naive mice (male, C57BL/6J, n = 4) to assess in vivo inertness, which is inversely correlated with uptake of 89Zr in bone, after 96 h circulation time. We found bone uptake to range from 7.0 ± 2.2 to 10.7 ± 1.3% ID/g, values that compare well to the corresponding DFO conjugate (7.1 ± 0.8% ID/g). In conclusion, we have rationally designed linear, bifunctional and trifunctional desferrichrome analogues suitable for the mild and inert radiolabeling of antibodies with the radionuclide 89Zr.