Formation of Ground State Triplet Diradicals from Annulated Rosarin Derivatives by Triprotonation

Annulated rosarins, β,β′-bridged hexaphyrin(1.0.1.0.1.0) derivatives <b>1</b>–<b>3</b>, are formally 24 π-electron antiaromatic species. At low temperature, rosarins <b>2</b> and <b>3</b> are readily triprotonated in the presence of trifluoroacetic acid in dichloromethane to produce ground state triplet diradicals, as inferred from electron paramagnetic resonance (EPR) spectral studies. From an analysis of the fine structure in the EPR spectrum of triprotonated rosarin <b>H</b>_<b>3</b><b>3</b>^<b>3+</b>, a distance of 3.6 Å between the two unpaired electrons was estimated. The temperature dependence of the singlet–triplet equilibrium was determined by means of an EPR titration. Support for these experimental findings came from calculations carried out at the (U)­B3LYP/6-31G* level, which served to predict a very low-lying triplet state for the triprotonated form of a simplified model system <b>1</b>

Amplifying the Sensitivity of Zinc(II) Responsive MRI Contrast Agents by Altering Water Exchange Rates

Given the known water exchange rate limitations of a previously reported Zn­(II)-sensitive MRI contrast agent, GdDOTA-diBPEN, new structural targets were rationally designed to increase the rate of water exchange to improve MRI detection sensitivity. These new sensors exhibit fine-tuned water exchange properties and, depending on the individual structure, demonstrate significantly improved longitudinal relaxivities (<i>r</i>₁). Two sensors in particular demonstrate optimized parameters and, therefore, show exceptionally high longitudinal relaxivities of about 50 mM^–1 s^–1 upon binding to Zn­(II) and human serum albumin (HSA). This value demonstrates a 3-fold increase in <i>r</i>₁ compared to that displayed by the original sensor, GdDOTA-diBPEN. In addition, this study provides important insights into the interplay between structural modifications, water exchange rate, and kinetic stability properties of the sensors. The new high relaxivity agents were used to successfully image Zn­(II) release from the mouse pancreas <i>in vivo</i> during glucose stimulated insulin secretion

Development and <i>in Vivo</i> Quantitative Magnetic Resonance Imaging of Polymer Micelles Targeted to the Melanocortin 1 Receptor

Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe­(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors <i>in vitro</i> and <i>in vivo</i> more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R