Copper(II) complexes of cyclams with N-(2,2,2-trifluoroethyl)-aminoalkyl pendant arms as potential probes for 19F magnetic resonance imaging.

A series of Cu(II) complexes with cyclam-based ligands containing two N-(2,2,2-trifluoroethyl)-aminoalkyl pendant arms in 1,8-positions (L1: 1,2-ethylene spacer, L2: 1,3-propylene spacer; L3: 1,4-butylene spacer) was studied in respect to potential use as contrast agents for 19F magnetic resonance imaging (MRI). A number of structures of the complexes as well as of several organic precursors were determined by single-crystal X-ray diffraction analysis. Geometric parameters (especially distances between fluorine atoms and the central metal ion) were determined for each complex and the identity of isomeric complex species present in solution was established. The NMR longitudinal relaxation times (T1) of 19F nuclei in the ligands at clinically relevant fields and temperatures (1-2 s) were significantly shortened upon Cu(II) binding to 7-10 ms for [Cu(L1)]2+, 20-30 ms for [Cu(L2)]2+ and 20-50 ms for [Cu(L3)]2+. The trend of the relaxation time shortening is in accordance with the distance and number of chemical bonds between fluorine atoms and the Cu(II) ion. The signals show promising T2*/T1 ratios in the range 0.25-0.55, assuring their good applicability to 19F NMR/MRI. The results show that even the Cu(II) ion, with a small magnetic moment, causes significant relaxation enhancement with a long-range effect and can be considered as a highly suitable metal ion for efficient 19F MRI contrast agents.

Gadolinium- and manganite-based contrast agents with fluorescent probes for both magnetic resonance and fluorescence imaging of pancreatic islets: a comparative study.

Three magnetic resonance (MR)/fluorescence imaging probes were tested for visualization, cellular distribution, and survival of labeled pancreatic islets in vitro and following transplantation. As T(1) contrast agents (CAs), gadolinium(III) complexes linked to ß-cyclodextrin (Gd-F-ßCD) or bound to titanium dioxide (TiO2 @RhdGd) were tested. As a T(2) CA, perovskite manganite nanoparticles (LSMO@siF@si) were examined. Fluorescein or rhodamine was incorporated as a fluorescent marker in all probes. Islets labeled with gadolinium(III) CAs were visible as hyperintense spots on MR in vitro, but detection in vivo was inconclusive. Islets labeled with LSMO@siF@si CA were clearly visible as hypointense spots or areas on MR scans in vitro as well as in vivo. All CAs were detected inside the islet cells by fluorescence. Although the vitality and function of the labeled islets was not impaired by any of the tested CAs, results indicate that LSMO@siF@si CA is a superior marker for islet labeling, as it provides better contrast enhancement within a shorter scan time.

Gadolinium complexes of monophosphinic acid DOTA derivatives conjugated to cyclodextrin scaffolds: efficient MRI contrast agents for higher magnetic fields.

Middle-molecular-weight MRI contrast agents based on conjugates of a phosphinic acid DOTA analogue, 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl]phosphinic acid} (DO3AP(ABn)), with amino-substituted cyclodextrins were prepared and studied by a variety of physico-chemical methods. The conjugates were formed by reaction of the corresponding isothiocyanate with per-6-amino-α/ß-cyclodextrin and were complexed with the Ln(III) ion to get the final complexes, (LnL)(6)-α-CD and (LnL)(7)-ß-CD. Solution structure of the complexes was estimated by investigation of the Eu(III) complexes. The Gd(III) conjugate complexes are endowed with a short water residence time (τ(M) ∼ 10-15 ns at 298 K) and a high abundance of the twisted-square antiprismatic diastereoisomer. They show a high (1)H relaxivity at high fields due to a convenient combination of the fast water exchange rate and the slow rate of the molecular tumbling given by their macromolecular nature. The (1)H relaxation enhancements per molecule of a contrast agent (CA) are very high reaching for a larger (GdL)(7)-ß-CD conjugate ∼140 s(-1) mM(-1) and ∼100 s(-1) mM(-1) at 25 °C and magnetic fields 1.5 T and 3 T, respectively, which is the highest reported longitudinal relaxivity for kinetically stable contrast agents of an intermediate molecular mass (<10 kDa) with one water molecule in the first coordination sphere.

Cyclodextrin-based bimodal fluorescence/MRI contrast agents: an efficient approach to cellular imaging.

A novel bimodal fluorescence/MRI probe based on a cyclodextrin scaffold has been synthesized and characterized. The final agent employs the fluorescein (F) functionality as a fluorescence marker and the Gd(III) complex of a macrocyclic DOTA-based ligand (GdL) having one aminobenzyl-phosphinic acid pendant arm as an MRI probe, and has a statistical composition of (GdL)(6.9)-F(0.1)-beta-CD. Slow rotational dynamics (governed by a very rigid cyclodextrin scaffold) combined with fast water exchange (ensured by the chosen macrocyclic ligand) resulted in a high relaxivity of approximately 22 s(-1) mM(-1) per Gd(III) or approximately 150 s(-1) mM(-1) per molecule of the final conjugate (20 MHz, 25 degrees C). In vitro labelling of pancreatic islets (PIs) and rat mesenchymal stem cells has been successfully performed. The agent is not cytotoxic and is easily internalized into cells. The labelled cells can be visualized by MRI, as proved by the detection of individual labelled PIs. A fluorescence study performed on mesenchymal stem cells showed that the agent stays in the intracellular space for a long time.