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|Title:||Synthesis and Evaluation of [2 + 1] Re(I) and 99mTc(I) Complexes: New Synthons for the Preparation of Isostructural Optical and Nuclear Probes|
|Advisor:||Valliant, John F.|
|Abstract:||The synthesis, stability and photophysical properties of [2 + 1] Re(I) and Tc(I) complexes derived from bipyridine type ligands and a series of imidazole derivatives were investigated as a means of identifying complexes suitable for creating targeted isostructural optical/nuclear molecular imaging probes. The first generation complexes were prepared by combining [Re(CO)3(H2O)3]Br with 2,2'-bipyridine (bipy) to give [Re(CO)3(bipy)Br], which in turn was converted to the desired complexes by treatment with functionalized imidazoles. All products were fully characterized by conventional methods which included crystal structures of two new Re complexes. The corresponding 99mTc complexes [99mTc(CO)3(bipy)(L)]n (L = imidazole derivatives) were prepared by combining [99mTc(CO)3(bipy)(H2O)]Cl with the same series of monodentate ligands used with Re(I) and heating at 40 °C or 60 °C for 30 min. Quantitative transformation to the final products was confirmed in all cases by HPLC and the nature of the complexes verified by comparison to the authentic Re standards. Incubation in saline and plasma, and amino acid challenge experiments showed that N-substituted imidazole derivatives, bearing electron donating groups, exhibited superior stability to analogous metal complexes derived from less basic ligands. Imaging studies in mice revealed that with the appropriate choice of monodentate ligand, it is possible to prepare robust [2 + 1] Tc complexes that can be used as the basis for preparing targeted isostructural optical and nuclear probes. The synthesis, stability, photophysical properties and in vivo biodistribution of [M(CO)3(BPS)(L)]n (M = Re/99mTc, BPS = bathophenanthroline disulfonate, L = imidazole derivatives) were investigated as a second generation of isostructural multimodal optical and nuclear probes. [Re(CO)3(BPS)(MeIm)]- (MeIm = methylimidazole) was prepared in high yield as a model compound and showed enhanced optical properties to the corresponding bipy analogue. To prepare the radiolabeled compounds, BPS was added to [99mTc(CO)3(H2O)3]+ and the mixture heated to 40 °C for 15 min. The product, [99mTc(CO)3(BPS)(H2O)]- was immediately treated with N-methylimidazole (MeIm) and with heating at 40 °C for 15 min yielding [99mTc(CO)3(BPS)(MeIm)]- 3b in nearly quantitative radiochemical yield. A targeted analogue [99mTc(CO)3(BPS)(ImAln)]2- (ImAln = imidazolealendronate) capable of binding regions of calcium turn-over associated with bone metabolism was also created. Biodistribution studies showed that the targeted [99mTc(CO)3(BPS)(ImAln)]2- analogue cleared rapidly from non-target tissues and had significant accumulation in the shoulder (7.9 0.2% ID/g) and knees (15.1 0.9 % ID/g) by 6 h, with long residence in the skeleton, up to 24 h. The isostructural Re(I) analogue [Re(CO)3(BPS)(ImAln)]2- was incubated with MCF-7 cells and fluorescence microscopy used to detect the probe that was located predominantly in the cytoplasm. Having demonstrated in vivo targeting, [2 + 1] complexes of 99mTc(I) linked to a tetrazine were prepared and their utility for preparing radiopharmaceuticals using bioorthogonal chemistry was evaluated. Specifically, complexes of the type [99mTc(CO)3(N^N)(L)]n (N^N = BPS and bipy), where the monodentate ligand (L) was a tetrazine linked to the metal through an imidazole group, were prepared in nearly quantitative radiochemical yield by adding [99mTc(CO)3(N^N)(H2O)]n to the imidazole-tetrazine ligand and heating at 60 °C for 30 min. Measurement of the kinetics of the reaction between 10b and trans-cycloocteneol showed a second rate order constant of 8.6 × 103 M-1S-1 at 37 °C, which is suitable for pretargeting strategies that require rapid coupling to be effective in vivo. Stability studies showed that the products are resistant to ligand challenge and suitable for in vivo imaging. Biodistribution studies of the more water soluble BPS derivative in normal mice using pre-administered bisphosphonate conjugate of trans-cyclooctene (TCO-BP) showed high activity concentrations in the knee (9.27 0.32% ID/g) and shoulder (5.28 0.67% ID/g). SPECT/CT images showed that the [2 + 1] complex could also be used to visualize the damage associated with a bone tumor in a murine model further demonstrating the utility of this class of compounds for preparing new radiopharmaceuticals.|
|Appears in Collections:||Open Access Dissertations and Theses|
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