Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T₁ relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)^? as expected for mono‐amide derivatives. The water proton T₁ relaxivity (r₁), bound water residence lifetime (τ_M) and rotational correlation time (τ_R) of both complexes was determined by relaxivity measurements, variable temperature ¹⁷O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r₁=6.38 mM ^?1 s^?1 at 20 MHz , τ_M=0.71 μs, τ_R=141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N₂ as evidenced by an approximately twofold decrease in T₁ measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.     

Diblock‐Copolymer‐Mediated Self‐Assembly of Protein‐Stabilized Iron Oxide Nanoparticle Clusters for Magnetic Resonance Imaging

Superparamagnetic iron oxide nanoparticles (SPIONs) can be used as efficient transverse relaxivity (T₂) contrast agents in magnetic resonance imaging (MRI). Organizing small (D<10 nm) SPIONs into large assemblies can considerably enhance their relaxivity. However, this assembly process is difficult to control and can easily result in unwanted aggregation and precipitation, which might further lead to lower contrast agent performance. Herein, we present highly stable protein–polymer double‐stabilized SPIONs for improving contrast in MRI. We used a cationic–neutral double hydrophilic poly(N‐methyl‐2‐vinyl pyridinium iodide‐block‐poly(ethylene oxide) diblock copolymer (P2QVP‐b‐PEO) to mediate the self‐assembly of protein‐cage‐encapsulated iron oxide (γ‐Fe₂O₃) nanoparticles (magnetoferritin) into stable PEO‐coated clusters. This approach relies on electrostatic interactions between the cationic N‐methyl‐2‐vinylpyridinium iodide block and magnetoferritin protein cage surface (pI≈4.5) to form a dense core, whereas the neutral ethylene oxide block provides a stabilizing biocompatible shell. Formation of the complexes was studied in aqueous solvent medium with dynamic light scattering (DLS) and cryogenic transmission electron microcopy (cryo‐TEM). DLS results indicated that the hydrodynamic diameter (D_h) of the clusters is approximately 200 nm, and cryo‐TEM showed that the clusters have an anisotropic stringlike morphology. MRI studies showed that in the clusters the longitudinal relaxivity (r₁) is decreased and the transverse relaxivity (r₂) is increased relative to free magnetoferritin (MF), thus indicating that clusters can provide considerable contrast enhancement.     

Ultrasmall Superparamagnetic Iron Oxide Nanoparticles with Europium(III) DO3A as a Bimodal Imaging Probe

A new prototype consisting of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles decorated with europium(III) ions encapsulated in a DO3A organic scaffold was designed as a platform for further development of bimodal contrast agents for MRI and optical imaging. The USPIO nanoparticles act as negative MRI contrast agents, whereas the europium(III) ion is a luminophore that is suitable for use in optical imaging detection. The functionalized USPIO nanoparticles were characterized by TEM, DLS, XRD, FTIR, and TXRF analysis, and a full investigation of the relaxometric and optical properties was conducted. The typical luminescence emission of europium(III) was observed and the main red emission wavelength was found at 614 nm. The relaxometric study of these ultrasmall nanoparticles showed r₂ values of 114.8 mm ^?1_Fes^?1 at 60 MHz, which is nearly double the r₂ relaxivity of Sinerem^®.     

Relaxivity and Transmetallation Stability of New Benzyl‐Substituted Derivatives of Gadolinium?DTPA Complexes

In our efforts of finding new specific contrast agents of higher relaxivity and selectivity, we have prepared the two new benzyl‐functionalized DTPA (‘diethylenetriamine pentaacetate’) gadolinium complexes (S)‐ 3 and (R,S)‐ 4 , and compared their properties with those of the known regioisomers (S)‐ 2 and (S)‐ 1 . The theoretical fitting of the reduced transverse relaxation rates of the ¹⁷O‐nucleus of H₂O gave values for the water‐residence time (τ_M) of 86–143 ns at 310 K, values that are not limiting the proton relaxivity at body temperature. ¹H‐NMRD (nuclear magnetic‐relaxation dispersion) Profiles showed that the relaxivity of 1 – 4 (r₁=4.3–5.1 s^?1 mM ^?1 at 20 MHz and 310 K) is higher than for the Gd? DTPA parent compound 5 . Transmetallation assessment demonstrated that all substituted compounds, except for (S)‐ 2 , are more stable than 5 . The highest stability towards Zn²⁺‐induced transmetallation was achieved with complexes 3, 1 , and 4 (in decreasing order). Apparently, the steric hindrance of the benzyl substituents in positions 5, 4, and 2, respectively, favorably reduces the accessibility of Zn ions. From a synthetic point of view, 4‐substituted DTPA complexes of type 1 are more readily accessible than 5‐substituted compounds of type 3 . Therefore, the former seem to be superior for linking substituted DTPA complexes to macromolecules or specific vectors.     

Biotin-Conjugated Poly(Acrylic Acid)-Grafted Ultrasmall Gadolinium Oxide Nanoparticles for Enhanced Tumor Imaging

Herein, biotin (Bio)-conjugated poly(acrylic acid) (PAA)-grafted ultrasmall gadolinium oxide nanoparticles (Bio-PAA-Gd₂O₃ NPs) were synthesized for enhanced tumor imaging using Bio as a tumor-targeting ligand. The average particle diameter of Gd₂O₃ NPs was 2.1 nm. The Bio-PAA-Gd₂O₃ NPs exhibited excellent colloidal stability (i. e., no precipitation) and a high longitudinal water proton spin relaxivity (r₁) of 23.8 s⁻¹ mM⁻¹ (r₂/r₁=1.6 and r₂=transverse water proton spin relaxivity), which was ∼6 times higher than those of commercial Gd-chelated magnetic resonance imaging (MRI) contrast agents. Cytotoxicity tests using two cell lines showed that the Bio-PAA-Gd₂O₃ NPs were almost non-toxic up to the measured concentration of 500 μM Gd. The enhanced tumor imaging of the Bio-PAA-Gd₂O₃ NPs was demonstrated through their higher positive contrasts and longer contrast retention at the tumor after intravenous injection in T₁ MR images, compared with those of the control PAA-Gd₂O₃ NPs.     

Serum Albumin Targeted,pH‐Dependent Magnetic Resonance Relaxation Agents

The objective of this work was the synthesis of serum albumin targeted, Gd^III‐based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH‐dependent relaxivity. Two new complexes ( Gd‐glu and Gd‐bbu ) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents α to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH‐dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r₁). In the absence of human serum albumin (HSA), r₁ increases from 2.0 to 6.0 mM ^?1 s^?1 for Gd‐glu and from 2.4 to 9.0 mM ^?1 s^?1 for Gd‐bbu from pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM ) are bound (>98.9 %) to HSA (0.69 mM ) over the pH range 5–8.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r₁ increased 120 % (pH 5) and 550 % (pH 8.5) for Gd‐glu and 42 % (pH 5) and 260 % (pH 8.5) for Gd‐bbu . The increases in r₁ at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd‐bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K_d1=0.65, K_d2=18, K_d3=1360 μM . The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the Eu^III analogue revealed that the inner‐sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r₁ at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r₁ of the albumin‐bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (1–2 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin‐bound pH‐dependent relaxivity.     

Selected‐Control Fabrication of Multifunctional Fluorescent–Magnetic Core–Shell and Yolk–Shell Hybrid Nanostructures

The selected‐control preparation of uniform core–shell and yolk–shell architectures, which combine the multiple functions of a superparamagnetic iron oxide (SPIO) core and europium‐doped yttrium oxide (Y₂O₃:Eu) shell in a single material with tunable fluorescence and magnetic properties, has been successfully achieved by controlling the heat‐treatment conditions. Furthermore, the shell thickness and interior cavity of SPIO@Y₂O₃:Eu core–shell and yolk–shell nanostructures can be precisely tuned. Importantly, as‐prepared SPIO@Y₂O₃:Eu yolk–shell nanocapsules (NCs) modified with amino groups as cancer‐cell fluorescence imaging agents are also demonstrated. To the best of our knowledge, this is the first report on the selected‐control fabrication of uniform SPIO@Y₂O₃:Eu core–shell nanoparticles and yolk–shell NCs. The combined magnetic manipulation and optical monitoring of magnetic–fluorescent SPIO@Y₂O₃:Eu yolk–shell NCs will open up many exciting opportunities in dual imaging for targeted delivery and thermal therapy.     

Synthesis and Physicochemical Characterization of New C‐Functionalized Derivatives of the Gadolinium(III) Complex with 3,6,10‐Tris(carboxymethyl)‐3,6,10‐triazadodecanedioic Acid (H5ttda) Exhibiting Fast Water Exchange – Potential Paramagnetic Reporters for Molecular Imaging

To confirm the observation that [Gd(ttda)] derivatives have a significantly shorter residence time τ_M of the coordinated H₂O molecule than [Gd(dtpa)], four new C‐functionalized [Gd(ttda)] complexes, [Gd(4‐Me‐ttda)] ( 1 ), [Gd(4‐Ph‐ttda)] ( 2 ), [Gd(9‐Me‐ttda)] ( 3 ), and [Gd(9‐Ph‐ttda)] ( 4 ), were prepared and characterized (H₅ttda=3,6,10‐tris(carboxymethyl)‐3,6,10‐triazadodecanedioic acid; H₅dtpa=3,6,9‐tris(carboxymethyl)‐3,6,9‐triazaundecanedioic acid). The temperature dependence of the proton relaxivity for these complexes at 0.47 T and of the ¹⁷O transverse relaxation rate of H₂¹⁷O at 7.05 T confirm that the proton relaxivity is not limited by the H₂O‐exchange rate. The residence time of the H₂O molecules in the first coordination sphere of the gadolinium complexes at 310 K, as calculated from ¹⁷O‐NMR data, is 13, 43, 2.9, and 56 ns for 1, 2, 3 , and 4 , respectively. At 310 K, the longitudinal relaxivity of 2 is higher than for the parent compound [Gd(ttda)] and the other complexes of the series. The stability of the new compounds was studied by transmetallation with Zn²⁺ ions. All the new complexes are more stable than the parent compound [Gd(ttda)].     

Amphiphilic Ditopic Bis‐Aqua Gd‐AAZTA‐like Complexes Enhance Relaxivity of Lipidic MRI Nanoprobes

Two amphiphilic mono‐ and dimeric GdAAZTA‐like chelates composed of stable bis‐aquo Gd^III complexes (q=2) linked to one (for the monomer) or two dodecyl aliphatic chains (for the dimer) were synthesized. Both chelates showed high relaxivity when incorporated into the lipid bilayer of liposomes or after interaction with human serum albumin (HSA). The ditopic complex shows a significantly decreased internal motion relative to the monomeric complex, associated with an enhanced relaxivity (r₁≈60 mm ^?1 s^?1, at 30 MHz and 310 K). The presence of two metal‐bound water molecules in fast exchange and the restricted rotational freedom make the relaxivity of this system the highest measured for paramagnetic liposomes.     

A Chemical Strategy for the Relaxivity Enhancement of GdIII Chelates Anchored on Mesoporous Silica Nanoparticles

Functionalised MCM‐41 mesoporous silica nanoparticles were used as carriers of Gd^III complexes for the development of nanosized magnetic resonance imaging contrast agents. Three Gd^III complexes based on the 1,4,7,10‐tetraazacyclododecane scaffold (DOTA; monoamide‐, DOTA‐ and DO3A‐like complexes) with distinct structural and magnetic properties were anchored on the silica nanoparticles functionalised with NH₂ groups. The interaction between Gd^III chelates and surface functional groups markedly influenced the relaxometric properties of the hybrid materials, and were deeply modified passing from ionic ? NH₃⁺ to neutral amides. A complete study of the structural, textural and surface properties together with a full ¹H relaxometric characterisation of these hybrid materials before and after surface modification was carried out. Particularly for the anionic complex 2 attached to MCM‐41, an impressive increase in relaxivity (r_1p) was observed (from 20.3 to 37.8 mM ^?1 s^?1, 86.2 % enhancement at 20 MHz and 310 K), mainly due to a threefold faster water exchange rate after acetylation of the surface ? NH₃⁺ ions. This high r_1p value, coupled with the large molar amount of grafted 2 onto the silica nanoparticles gives rise to a value of relaxivity per particle of 29 500 mM ^?1 s^?1, which possibly allows it to be used in molecular imaging procedures. Smaller changes were observed for the hybrid materials based on neutral 1 and 3 complexes. In fact, whereas 1 shows a weak interaction with the surface and acetylation induced only some decrease of the local rotation, complex 3 appears to be involved in a strong interaction with surface silanols. This results in the displacement of a coordinated water molecule and in a decrease of the accessibility of the solvent to the metal centre, which is unaffected by the modification of ammonium ions to neutral amides.     

Metal‐Ion Sensing Europium(III) Complexes with Bidentate Phosphine Oxide Ligands Containing a 2,2′‐Bipyridine Framework

Novel Eu^III complexes with bidentate phosphine oxide ligands containing a bipyridine framework, i.e., [3,3′‐bis(diphenylphosphoryl)‐2,2′‐bipyridine]tris(hexafluoroacetylacetonato)europium(III) ([Eu(hfa)₃(BIPYPO)]) and [3,3′‐bis(diphenylphosphoryl)‐6,6′‐dimethyl‐2,2′‐bipyridine]tris(hexafluoroacetylacetonato)europium(III) ([Eu(hfa)₃(Me‐BIPYPO)]), were synthesized for lanthanide‐based sensor materials having high emission quantum yields and effective chemosensing properties. The emission quantum yields of [Eu(hfa)₃(BIPYPO)] and [Eu(hfa)₃(Me‐BIPYPO)] were 71 and 73%, respectively. Metal‐ion sensing properties of the Eu^III complexes were also studied by measuring the emission spectra of Eu^III complexes in the presence of Zn^II or Cu^II ions. The metal‐ion sensing and the photophysical properties of luminescent Eu^III complexes with a bidentate phosphine oxide containing 2,2′‐bipyridine framework are demonstrated for the first time.     

Novel radical‐responsive MRI contrast agent based on paramagnetic liposomes

A novel, radical responsive MRI contrast agent based on a gadolinium chelate conjugated to a liposome through a disulfide linker was synthesized, with the aim of pursuing the in vivo mapping of radicals. The liposome was prepared by incorporating a thiol‐activated phospholipid, which was subsequently reacted with a gadolinium chelate containing a free thiol group. The long reorientational motion of the supramolecular adduct endows the paramagnetic agent with a relaxivity significantly higher than that of the free complex. The disulfide bond represents a radical‐sensitive moiety and a large decrease in contrast efficacy (T₁ relaxivity) is shown upon its cleavage. A preliminary assessment of the system was made by means of in vitro gamma‐irradiation and thiol–disulfide bond exchange with dithiothreitol. Both methods showed a clear dose‐dependent decrease in T₁‐relaxivity. Copyright © 2003 John Wiley & Sons, Ltd.     

Organic electroluminescent devices using europium complex‐doped poly(N‐vinylcarbazole)

Electroluminescence (EL) properties of europium (Eu) complex‐doped poly(N‐vinylcarbazole) (PVK) were investigated. A device structure of glass substrate/indium‐tin oxide/hole‐injection layer/Eu complex‐doped PVK/hole‐blocking layer/electron transport layer/electron‐injection layer/Al was employed. Red emission originating from Eu complex was observed. Relatively high luminance of 50 cd/m² and an efficiency of 0.2% were obtained. Copyright © 2004 John Wiley & Sons, Ltd.     

Tetraphenylporphyrin‐based dual‐functional medical agent for magnetic resonance and fluorescence imaging

A bimodal magnetic resonance imaging contrast agent, TPP‐M‐Gd, was developed by modifying tetraphenylporphyrin (TPP) with a small dendritic molecule as a ligand (M) to chelate gadolinium (Gd) ions. The ligand featured four carboxylate groups, which contributed to good water solubility and a strong combination with metal ions. The longitudinal relaxivity (R₁) of the resulting agent was calculated to be 12.45 mM^?1 s^?1, which is much higher than that of DTPA‐Gd (4.49 mM^?1 s^?1). The magnetic resonance imaging experiments showed that the newly synthesized contrast agent could enhance T₁‐weighted magnetic resonance imaging quality both in vitro and in vivo. In addition, TPP‐M‐Gd exhibited good fluorescent property as shown in cell imaging experiments. The cytotoxicity of TPP‐M‐Gd was even better than that of clinically approved DTPA‐Gd, which makes it a promising dual‐functional medical imaging agent to provide more detailed information about biological and disease‐related events.     

Syntheses,Molecular Structure and Thermodynamic Properties of 3‐Nitro‐1,2,4‐triazol‐5‐one Europium Complex [Eu(NTO)3(H2O)5]·5H2O

3‐Nitro‐1,2,4‐triazol‐5‐one (NTO) europium complex of [Eu(NTO)₃(H₂O)₅]·5H₂O was synthesized by mixing the aqueous solution of lithium 3‐nitro‐1,2,4‐triazol‐5‐onate and the dilute nitric acid solution of europium oxide. The title complex was characterized by elemental analysis and IR spectra. The single crystal structure was determined by a four‐circle x‐ray diffractometer. The title complex is monoclinic with space group P2₁/n and unit cell parameters of a = 1.8720(2) nm, b = 0.6548(3) nm, c = 1.9323(3) nm and β = 95.33(1)°. The coordination geometry around the europium ion is a distorted dodecahedron and there are five crystalline water molecules to form the stable structure of the crystal. From measurements of the enthalpy of solution in water at 298.15 K, the standard enthalpy of formation, lattice enthalpy and lattice energy have been determined as ‐(3798.6 ± 3.7), ?4488.4 and ?4452.4 kJ·mol^?;1, respectively.     

Functional Graphene by Thiol‐ene Click Chemistry

Thiol‐ene click reaction was successfully employed for chemical modification of graphene oxide (GO) by one‐step synthesis. Herein, 2,2‐azobis(2‐methylpropionitrile) (AIBN) was used as thermal catalyst and cysteamine hydrochloride (HS?(CH₂)₂?NH₂HCl) was used as thiol‐containing compound, which is incorporated to GO surface upon reaction with the C=C bonds. The hydrochloride acts as protecting group for the amine, which is finally eliminated by adding sodium hydroxide. The modified GO contains both S‐ and N‐containing groups (NS‐GO). We found that NS‐GO sheets form good dispersion in water, ethanol, and ethylene glycol. These graphene dispersions can be processed into functionalized graphene film. Besides, it was demonstrated that NS‐GO was proved to be an excellent host matrix for platinum nanoparticles. The developed method paves a new way for graphene modification and its functional nanocomposites.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

Selective Anchoring of GdIII Chelates on the External Surface of Organo‐Modified Mesoporous Silica Nanoparticles: A New Chemical Strategy To Enhance Relaxivity

The optimization of the physico‐chemical properties of both Gd^III chelates and nanocarriers is of great importance for the development of effective nanosystems for magnetic resonance imaging (MRI) applications. With this aim, macrocyclic Gd^III chelates were selectively attached to the pendant amino groups exposed to the external surface of spheroidal mesoporous silica nanoparticles (MSNs). This was achieved by treating the metal complexes with MSNs that contained the templating surfactant molecules confined within the silica channels (hexadecyltrimethylammonium (CTA)/MSN), followed by extraction of the surfactant. The nanoparticles showed greatly improved ¹H relaxometric efficiency relative to corresponding systems that also feature Gd^III chelates conjugated inside the pores. A further significant relaxivity enhancement was observed after chemical transformation of the free amino groups into amides. The ionic relaxivity of the final nanoparticles (r_1p=79.1 mM ^?1 s^?1; 0.5 T, 310 K) is one of the highest reported so far.     

Importance of Outer‐Sphere and Aggregation Phenomena in the Relaxation Properties of Phosphonated Gadolinium Complexes with Potential Applications as MRI Contrast Agents

A series composed of a tetra‐, a tris‐ and a bisphosphonated ligand based on a pyridine scaffold ( L⁴ , L³ and L² , respectively) was studied within the frame of lanthanide (Ln) coordination. The stability constants of the complexes formed with lanthanide cations (Ln=La, Nd, Eu, Gd, Tb, Er and Lu) were determined by potentiometry in aqueous solutions (25.0 °C, 0.1 M NaClO₄), showing that the tetraphosphonated complexes are among the most stable Ln^III complexes reported in the literature. The complexation of L⁴ was further studied by different titration experiments using mass spectrometry and various spectroscopic techniques including UV/Vis absorption, and steady state and time‐resolved luminescence (Ln=Eu and Tb). Titration experiments confirmed the formation of highly stable [Ln L⁴ ] complexes. ³¹P NMR experiments of the Lu L⁴ complex revealed an intramolecular interconversion process which was studied at different temperatures and was rationalized by DFT modelling. The relaxivity properties of the Gd^III complexes were studied by recording their ¹H NMRD profiles at various temperatures, by temperature dependent ¹⁷O NMR experiments (Gd L⁴ ) and by pH dependent relaxivity measurements at 0.47 T (Gd L³ and Gd L² ). In addition to the high relaxivity values observed for all complexes, the results showed an important second‐sphere contribution to relaxivity and pH dependent variations associated with the formation of aggregates for Gd L² and Gd L³ . Finally, intravenous injection of Gd L⁴ to a mouse was followed by dynamic MRI imaging at 1.5 T, which showed that the complex can be immediately found in the blood stream and rapidly eliminated through the liver and in large part through the kidneys.     

Dual‐Modal Magnetic Resonance/Fluorescent Zinc Probes for Pancreatic β‐Cell Mass Imaging

Despite the contribution of changes in pancreatic β‐cell mass to the development of all forms of diabetes mellitus, few robust approaches currently exist to monitor these changes prospectively in vivo. Although magnetic‐resonance imaging (MRI) provides a potentially useful technique, targeting MRI‐active probes to the β cell has proved challenging. Zinc ions are highly concentrated in the secretory granule, but they are relatively less abundant in the exocrine pancreas and in other tissues. We have therefore developed functional dual‐modal probes based on transition‐metal chelates capable of binding zinc. The first of these, Gd ?1 , binds Zn^II directly by means of an amidoquinoline moiety (AQA), thus causing a large ratiometric Stokes shift in the fluorescence from λ_em=410 to 500 nm with an increase in relaxivity from r₁=4.2 up to 4.9 mM ^?1 s^?1. The probe is efficiently accumulated into secretory granules in β‐cell‐derived lines and isolated islets, but more poorly by non‐endocrine cells, and leads to a reduction in T₁ in human islets. In vivo murine studies of Gd ?1 have shown accumulation of the probe in the pancreas with increased signal intensity over 140 minutes.