A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is La, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Fe, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T) of the fluorine nuclei. The shorter T allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T/T ratio. In water, the optimal metal complexes for imaging applications are those containing Ho and Fe, and to a lesser extent Tm and Yb. Whereas T of the lanthanide complexes are little affected by blood, the T are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, Ho-DOTAm-F12, could not be detected in blood. Tm yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of Fe-DOTAm-F12 are similar in water and in blood. That complex has the highest T/T ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T/T of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

Fluorine magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) of chemical and physiological processes is becoming more widespread. The strength of this technique comes from the negligible background signal in in vivo 19F MRI and the large chemical shift window of 19F that enables it to image concomitantly more than one marker. These same advantages have also been successfully exploited in the design of responsive 19F probes. Part of the recent growth of this technique can be attributed to novel designs of 19F probes with improved imaging parameters due to the incorporation of paramagnetic metal ions. In this review, we provide a description of the theories and strategies that have been employed successfully to improve the sensitivity of 19F probes with paramagnetic metal ions. The Bloch-Wangsness-Redfield theory accurately predicts how molecular parameters such as internuclear distance, geometry, rotational correlation times, as well as the nature, oxidation state, and spin state of the metal ion affect the sensitivity of the fluorine-based probes. The principles governing the design of responsive 19F probes are subsequently described in a “how to” guide format. Examples of such probes and their advantages and disadvantages are highlighted through a synopsis of the literature.

Accurate mapping of small changes in pH is essential to the diagnosis of diseases such as cancer. The difficulty in mapping pH accurately in vivo resides in the need for the probe to have a ratiometric response so as to be able to independently determine the concentration of the probe in the body independently from its response to pH. The complex Fe-DOTAm-F12 behaves as an MRI contrast agent with dual F and CEST modality. The magnitude of its CEST response is dependent both on the concentration of the complex and on the pH, with a significant increase in saturation transfer between pH 6.9 and 7.4, a pH range that is relevant to cancer diagnosis. The signal-to-noise ratio of theF signal of the probe, on the other hand, depends only on the concentration of the contrast agent and is independent of pH. As a result, the complex can ratiometrically map pH and accurately distinguish between pH 6.9 and 7.4. Moreover, the iron(II) complex is stable in air at room temperature and adopts a rare 8-coordinate geometry.

The isolation of pure [2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) tribromide ( 6) has been achieved by modifying the reported procedure, which involved transmetalation of [2-(phenylazo)phenyl-C, N 0 ]mercury(II) chloride (7) with TeBr 4 . The mixed-valent derivative bis[2-(phenylazo)phenyl-C, N 0 ]ditellurium dichloride (19), incorporating both a divalent and a tetravalent tellurium, was obtained serendipitously during the reduction of [2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) trichloride (16) with hydrazine hydrate. Bis[2-(phenylazo)phenyl-C,N 0 ]telluride (10) has been synthesized by the ortholithiation route. Telluride 10, on treatment with SO 2 Cl 2 and Br 2 , underwent oxidative addition to give the expected Te(IV) halogenated products bis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) dichloride (13) and bis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) dibromide (11), respectively. However, a similar reaction of 10 with I 2 resulted in the formation of an unexpected telluronium cation, iodobis[2-(phenylazo)phenyl-C,N 0 ]telluronium triiodide (14), and [2-(phenylazo)phenyl-C,N 0 ]tellurenenyl(II) iodide (12). Alkaline hydrolysis of 16 under reflux conditions resulted in the formation of monomeric [2-(phenylazo)phenyl-C,N 0 ]tellurinic acid (20) and its sodium salt (21) as a cocrystal. Bis[[2-(phenylazo)phenyl-C,N 0 ]tellurium]oxide (22) was obtained from the hydrolysis of [2-(phenylazo)phenyl-C,N 0 ]tellurium(II) chloride (17). The reaction of 13 with an alkaline solution resulted in the formation of the corresponding bis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) oxide (23) and dichlorobis[2-(phenylazo)phenyl-C,N 0 ]tellurium(IV) oxide ( 24). The identity of all the derivatives was confirmed by multinuclear NMR ( 1 H, 13 C, 125 Te) and FT-IR spectroscopy, elemental analysis, and ESI-MS. The structures for tellurium derivatives 6, 10-14, 17, 19, 20-23, and 23A were also confirmed by X-ray crystallography. Density functional theory (DFT) was utilized for optimizing the geometries of 11, 13, and 14 to examine the possibility of a four-membered intramolecular Te 3 3 3 N interaction.