First report of 68Ga-PRGD2 PET/MRI molecular imaging of vaso-occlusion in a patient with sickle cell disease.

Increased vascular cell adhesion (hyperadhesion) to the endothelium is responsible for the hallmark acute pain episodes, or vaso-occlusive crises (VOC), of sickle cell disease. The integrin αvß3 plays an important role in VOC since it mediates sickle red blood cell adhesion to the endothelium, a process that leads to ischemia and painful bone infarction. In the pilot study presented herein, we hypothesized that real-time imaging of hyperadhesion could quantify VOC severity and identify the most vulnerable anatomical sites. We also hypothesized that harnessing hyperadhesion as a proximate event in VOC would provide sensitive, objective evidence of VOC before pain has developed. Specifically, we tested whether positron emission tomography (PET) imaging of integrin αvß3 using the PET tracer 68Ga-PRGD2 would successfully image hyperadhesion associated with VOC in a patient with sickle cell disease. We observed persistently higher tracer uptake in the femurs during VOC compared to baseline. In the vessel, after an initial and transient increase during VOC, blood pool activity was similar between baseline and VOC. These findings suggest that PET imaging of integrin αvß3 may be a valuable strategy for imaging of VOC.

Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications.

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]-. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.

A Macrocyclic Chelator That Selectively Binds Ln4+ over Ln3+ by a Factor of 1029.

A tetravalent cerium macrocyclic complex (CeLK4) was prepared with an octadentate terephthalamide ligand comprised of hard catecholate donors and characterized in the solution state by spectrophotometric titrations and electrochemistry and in the crystal by X-ray diffraction. The solution-state studies showed that L exhibits a remarkably high affinity toward Ce4+, with log ß110 = 61(2) and ΔG = -348 kJ/mol, compared with log ß110 = 32.02(2) for the analogous Pr3+ complex. In addition, L exhibits an unusual preference for forming CeL4- relative to formation of the analogous actinide complex, ThL4-, which has ß110 = 53.7(5). The extreme stabilization of tetravalent cerium relative to its trivalent state is also evidenced by the shift of 1.91 V in the redox potential of the Ce3+/Ce4+ couple of the complex (measured at -0.454 V vs SHE). The unprecedented behavior prompted an electronic structure analysis using L3- and M5,4-edge X-ray absorption near-edge structure (XANES) spectroscopies and configuration interaction calculations, which showed that 4f-orbital bonding in CeLK4 has partial covalent character due to ligand-to-metal charge transfer (LMCT) in the ground state. The experimental results are presented in the context of earlier measurements on tetravalent cerium compounds, indicating that the amount of LMCT for CeLK4 is similar to that observed for [Et4N]2[CeCl6] and CeO2 and significantly less than that for the organometallic sandwich compound cerocene, (C8H8)2Ce. A simple model to rationalize changes in 4f orbital bonding for tri- and tetravalent lanthanide and actinide compounds is also provided.

A macrocyclic chelator with unprecedented Th4⁺ affinity.

A novel macrocyclic octadentate ligand incorporating terephthalamide binding units has been synthesized and evaluated for the chelation of Th(4+). The thorium complex was structurally characterized by X-ray diffraction and in solution with kinetic studies and spectrophotometric titrations. Dye displacement kinetic studies show that the ligand is a much more rapid chelator of Th(4+) than prevailing ligands (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and diethylenetriaminepentaacetic acid). Furthermore, the resulting complex was found to have a remarkably high thermodynamic stability, with a formation constant of 10(54). These data support potential radiotherapeutic applications.