Optimization of a 1,4,7-Triazacyclononane-1,4-diacetic acid (NODA) Derivative Radiofluorination by Al18 F Complexation Using a Design of Experiments Approach.

Fluorine-18 (18 F) is the most favorable positron emitter for radiolabeling Positron Emission Tomography (PET) probes. However, conventional 18 F labeling through covalent C-F bond formation is challenging, involving multiple steps and stringent conditions unsuitable for sensitive biomolecular probes whose integrity may be altered. Over the past decade, an elegant new approach has been developed involving the coordination of an aluminum fluoride {Al18 F} species in aqueous media at a late-stage of the synthetic process. The objective of this study was to implement this method and to optimize radiolabeling efficiency using a Design of Experiments (DoE). To assess the impact of various experimental parameters on {Al18 F} incorporation, a pentadentate chelating agent NODA-MP-C4 was prepared as a model compound. This model carried a thiourea function present in the final conjugates resulting from the grafting of the chelating agent onto the probe. The formation of the radioactive complex Al18 F-NODA-MP-C4 was studied to achieve the highest radiochemical conversion. A complementary "cold" series study using the natural isotope 19 F was also conducted to guide the radiochemical operating conditions. Ultimately, Al18 F-NODA-MP-C4 was obtained with a reproducible and satisfactory radiochemical conversion of 79±3.5 % (n=5).

Self-Sensitized Photooxidation of Naphthols to Naphthoquinones and the Use of Naphthoquinones as Visible Light Photocatalysts in Batch and Continuous Flow Reactors.

Visible light photooxidation of naphthols to produce naphthoquinones, such as the natural product juglone, has been known for decades and has been widely utilized to benchmark the performances of a variety of photocatalytic systems. We discovered that these transformations can occur without the help of a photocatalyst and, even more intriguingly, that the photocatatyst-free process provides higher yields compared to control experiments utilizing state-of-the-art photocatalysts. In addition, we demonstrate that naphthoquinones and their corresponding naphthol precursors can act as alternatives to commonly used organic and organometallic photocatalysts with applications to challenging targets, such as the antimalarial drug artemisinin. This approach was finally transposed in continuous flow reactors where high photocatalyst stability and process efficiency are demonstrated with a 23× improvement in the space-time yield.

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization.

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM-1·s-1, at 1.41 T and 37 °C).

19F molecular MR imaging for detection of brain tumor angiogenesis: in vivo validation using targeted PFOB nanoparticles.

Molecular imaging with magnetic resonance imaging (MRI) targeted contrast agents has emerged as a promising diagnostic approach in cancer research to detect associated biomarkers. In this work, the potential of (19)F MRI was investigated to detect angiogenesis with α(ν)ß(3)-targeted perfluorooctylbromide nanoparticles (PFOB NP) in a U87 glioblastoma mouse model at 7 Tesla. Mice were injected intravenously with targeted or non-targeted NP and (19)F images were immediately acquired for 90 min using a PFOB-dedicated MRI sequence. Mice infused with targeted NP exhibited higher concentrations in tumors than mice of the control group, despite the presence of nonspecific signal originating from the blood. Imaging results were corroborated by histology and fluorescence imaging, suggesting specific binding of targeted NP to α(ν)ß(3) integrin. Two other groups of mice were injected 24 h before imaging to allow blood clearance but no significant differences were found between both groups, probably due to a loss of specificity of PFOB NP. This is the first demonstration of the ability of (19)F MRI to detect α(ν)ß(3)-integrin endothelial expression in brain tumors in vivo.

In vivo CEST MR imaging of U87 mice brain tumor angiogenesis using targeted LipoCEST contrast agent at 7 T.

LipoCEST are liposome-encapsulating paramagnetic contrast agents (CA) based on chemical exchange saturation transfer with applications in biomolecular MRI. Their attractive features include biocompatibility, subnanomolar sensitivity, and amenability to functionalization for targeting biomarkers. We demonstrate MR imaging using a targeted lipoCEST, injected intravenously. A lipoCEST carrying Tm(III)-complexes was conjugated to RGD tripeptide (RGD-lipoCEST), to target integrin α(ν)ß(3) receptors involved in tumor angiogenesis and was compared with an unconjugated lipoCEST. Brain tumors were induced in athymic nude mice by intracerebral injection of U87MG cells and were imaged at 7 T after intravenous injection of either of the two contrast agents (n = 12 for each group). Chemical exchange saturation transfer-MSME sequence was applied over 2 h with an average acquisition time interval of 13.5 min. The chemical exchange saturation transfer signal was ∼1% in the tumor and controlateral regions, and decreased to ∼0.3% after 2 h; while RGD-lipoCEST signal was ∼1.4% in the tumor region and persisted for up to 2 h. Immunohistochemical staining revealed a persistent colocalization of RGD-lipoCEST with α(ν)ß(3) receptors in the tumor region. These results constitute an encouraging step toward in vivo MRI imaging of tumor angiogenesis using intravenously injected lipoCEST.

Development of a magnetic resonance imaging protocol for the characterization of atherosclerotic plaque by using vascular cell adhesion molecule-1 and apoptosis-targeted ultrasmall superparamagnetic iron oxide derivatives.

OBJECTIVE: Acute ischemic events are often caused by the disruption of lipid-rich plaques, which are frequently not angiographically visible. Vascular cell adhesion molecule-1 and apoptotic cell-targeted peptides studied during our previous work were conjugated to ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-R832 for vascular cell adhesion molecule-1 targeting; USPIO-R826 for apoptosis targeting) and assessed by magnetic resonance imaging. METHODS AND RESULTS: Apolipoprotein E knockout mice were injected with 0.1 mmol Fe/kg body weight and were imaged on a 4.7-T Bruker magnetic resonance imaging until 24 hours after contrast agent administration. Aortic samples were then harvested and examined by histochemistry, and the magnetic resonance images and histological micrographs were analyzed with ImageJ software. The plaques enhanced by USPIO-R832 contained macrophages concentrated in the cap and a large necrotic core, whereas USPIO-R826 produced a negative enhancement of plaques rich in macrophages and neutral fats concentrated inside the plaque. Both USPIO derivatives colocalized with their target on histological sections and were able to detect plaques with a vulnerable morphology, but each one is detecting a specific environment. CONCLUSIONS: Our vascular cell adhesion molecule-1 and apoptotic cell targeted USPIO derivatives seem to be highly promising tools for atherosclerosis imaging contributing to the detection of vulnerable plaques. They are able to attain their target in low doses and as fast as 30 minutes after administration.

Evaluation of relative efficiency of PDT photosensitizers in producing hydroxyl radicals and singlet oxygen in aqueous media using a UV-visible spectroscopy pNDA dosage.

In order to improve the performance of PDT, it is important to develop new photosensitizers that induce the formation of both hydroxyl radicals and singlet oxygen. In this work, we developed and validated the experimental conditions and reproducibility for the evaluation of relative efficiency of hydroxyl radicals and singlet oxygen production by studying the bleaching of p-nitrosoaniline (pNDA) using a continuous flow UV-visible spectroscopy method in presence of photosensitizers in PBS media. Rapid data sampling made possible to analyze the kinetics of the bleaching by using a mathematical modeling. The pNDA dosage is specific of hydroxyl radicals' production without l-histidine and of singlet oxygen production in presence of l-histidine. A statistical approach is used to precisely evaluate the reliability of the results and to be able to compare different photosensitizers between them such as Methylene Blue and Brillant Blue G.

High sensitivity 19F MRI of a perfluorooctyl bromide emulsion: application to a dynamic biodistribution study and oxygen tension mapping in the mouse liver and spleen.

We have recently developed an optimized multi-spin echo (MSE) sequence dedicated to perfluorooctyl bromide (PFOB) imaging yielding an excellent sensitivity in vitro. The aim of the present study was to apply this sequence to quantitative measurements in the mouse liver and spleen after intravenous (i.v.) injection of PFOB emulsions. We first performed oxygenation maps 25.5 min after a single infusion of emulsion and, contrary to previous studies, shortly after injection. The signal-to-noise ratio (SNR) in the liver and spleen was as high as 45 and 120, respectively, for 3-min images with 11.7-µL pixels. Values of oxygen tension tended to be slightly higher in the spleen than in the liver. Dynamic biodistribution experiments were then performed immediately after intravenous (i.v.) injection of PFOB emulsions grafted with different quantities of polyethylene glycol (PEG) for stealth. Images were acquired every 7 min for 84 min and the SNR measured in the liver and spleen was at least four from the first time point. Uptake rates could be assessed for each PEG amount and, in spite of high standard deviations (SDs) owing to interanimal variability, our data confirmed that increasing quantities of PEG allow more gradual uptake of the emulsion particles by the liver and spleen. In conclusion, our method seems to be a powerful tool to non-invasively perform accurate in vivo quantitative measurements in the liver and spleen using (19)F MRI.

In vivo imaging of folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugates.

The overexpression of the folate receptor (FR) in a variety of malignant tumors, along with its limited expression in healthy tissues, makes it an attractive tumor-specific molecular target. Noninvasive imaging of FR using radiolabeled folate derivatives is therefore highly desirable. Given the advantages of positron emission tomography (PET) and the convenience of (68)Ga production, the aim of our study was to develop a new (68)Ga-folate-based radiotracer for clinical application. The chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) was conjugated to folic acid and to 5,8-dideazafolic acid using 1,2-diaminoethane as a spacer, resulting in two novel conjugates, namely, P3246 and P3238, respectively. Both conjugates were labeled with (68/67)Ga. In vitro internalization, efflux, and saturation binding studies were performed using the FR-positive KB cell line. Biodistribution and small-animal PET imaging studies were performed in nude mice bearing subcutaneous KB xenografts. Both conjugates were labeled with (68)Ga at room temperature within 10 min in labeling yields >95% and specific activity ~30 GBq/µmol. The K(d) values of (68/67)Ga-P3246 (5.61 ± 0.96 nM) and (68/67)Ga-P3238 (7.21 ± 2.46 nM) showed high affinity for the FR. (68/67)Ga-P3246 showed higher cell-associated uptake in vitro than (68/67)Ga-P3238 (approximately 72 and 60% at 4 h, respectively, P < 0.01), while both radiotracers exhibited similar cellular retention up to 4 h (approximately 76 and 71%, respectively). Their biodistribution profile is characterized by high tumor uptake, fast blood clearance, low hepatobiliary excretion, and almost negligible background. Tumor uptake was already high at 1 h for both (68)Ga-P3246 and (68)Ga-P3238 (16.56 ± 3.67 and 10.95 ± 2.12% IA/g, respectively, P > 0.05) and remained at about the same level up to 4 h. Radioactivity also accumulated in the FR-positive organs, such as kidneys (91.52 ± 21.05 and 62.26 ± 14.32% IA/g, respectively, 1 h pi) and salivary glands (9.05 ± 2.03 and 10.39 ± 1.19% IA/g, respectively, 1 h pi). The specificity of the radiotracers for the FR was confirmed by blocking experiments where tumor uptake was reduced by more than 85%, while the uptake in the kidneys and the salivary glands was reduced by more than 90%. Reduction of the kidney uptake was achieved by administration of the antifolate pemetrexed 1 h prior to the injection of the radiotracers, which resulted in an improvement of tumor-to-kidney ratios by more than a factor of 3. In line with the biodistribution results, small-animal PET images showed high uptake in the kidneys, clear visualization of the tumor, accumulation of radioactivity in the salivary glands, and no uptake in the gastrointestinal tract. (68)Ga-P3246 and (68)Ga-P3238 showed very high tumor-to-background contrast in PET images; however, the tumor-to-kidney ratio remained low. The new radiotracers, especially (68)Ga-P3246, are promising as PET imaging probes for clinical application due to their facile preparation and improved in vivo profile as compared to the other folate-based PET radiotracers.

Ultrasmall iron oxide nanoparticles for biomedical applications: improving the colloidal and magnetic properties.

A considerable increase in the saturation magnetization, M(s) (40%), and initial susceptibility of ultrasmall (<5 nm) iron oxide nanoparticles prepared by laser pyrolysis was obtained through an optimized acid treatment. Moreover, a significant enhancement in the colloidal properties, such as smaller aggregate sizes in aqueous media and increased surface charge densities, was found after this chemical protocol. The results are consistent with a reduction in nanoparticle surface disorder induced by a dissolution-recrystallization mechanism.

Hydrogels incorporating GdDOTA: towards highly efficient dual T1/T2 MRI contrast agents.

Do not tumble dry: Gadolinium-DOTA encapsulated into polysaccharide nanoparticles (GdDOTA NPs) exhibited high relaxivity (r(1) =101.7 s(-1) mM(-1) per Gd(3+) ion at 37 °C and 20 MHz). This high relaxation rate is due to efficient Gd loading, reduced tumbling of the Gd complex, and the hydrogel nature of the nanoparticles. The efficacy of the nanoparticles as a T(1)/T(2) dual-mode contrast agent was studied in C6 cells.

Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates.

PURPOSE: A number of (111)In- and (99m)Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A (68)Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of (68)Ga from a generator. The aim of the study was to develop a new (68)Ga-folate-based PET radiotracer. METHODS: Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with (67/68)Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule (111)In-DTPA-folate ((111)In-P3139). RESULTS: The K(d) values of (67/68)Ga-P3026 (4.65 ± 0.82 nM) and (67/68)Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order (67/68)Ga-P3026 > (67/68)Ga-P1254 > (111)In-P3139, while almost double cellular retention was found for (67/68)Ga-P3026 and (67/68)Ga-P1254, compared to (111)In-P3139. The biodistribution data of (67/68)Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to (111)In-P3139. PET/CT images, performed with (68)Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. CONCLUSION: The DOTA-folate conjugates can be efficiently labelled with (68)Ga in labelling yields and specific activities which allow clinical application. The characteristics of the (67/68)Ga-DOTA-folates are comparable to (111)In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers for FR-positive tumours.

The role of phosphate on Omniscan(®) dechelation: an in vitro relaxivity study at pH 7.

Nephrogenic systemic fibrosis (NSF), a disease occurring in patients with severe renal failure, may be linked to injections of gadolinium chelates, contrast agents used for magnetic resonance imaging. A hypothesis frequently proposed to explain NSF is dissociation of Gd(3+) from its chelate, possibly from a deep storage compartment. Numerous in vivo and in vitro studies have been performed in an attempt to determine the extent of this dechelation and to understand its mechanism. Proton-assisted dechelation and transmetallation are the most widely described mechanisms of dechelation. This study investigated the possible ligand exchange role played by phosphate in the dechelation mechanism. Omniscan(®) dechelation was monitored in vitro by relaxivity measurements performed at physiological pH with different concentrations of phosphate buffer and in the presence of endogenous cations. Dechelation experiments performed on phosphate buffer alone showed that phosphate may induce gadolinium release by ligand exchange when the phosphate concentration in the buffer is higher than 130 mM for an Omniscan(®) concentration of 1.25 mM. This corresponds to a Gd/phosphate ratio of 10(-2). This ratio could be reached in vivo, especially in deep compartments such as bone. The presence of endogenous cations (Zn(2+), Cu(2+) or Ca(2+)) has also been demonstrated to accelerate the kinetics of gadolinium release, either by catalysing ligand exchange or by inducing a transmetallation mechanism. The Omniscan(®) formulation was also tested and the added Ca-DTPA-BMA was shown to increase dechelation kinetics in these experiments. This striking result may question the value of the Omniscan(®) formulation in the context of NSF.

Medical Applications of Metallic Bismuth Nanoparticles.

Recent reviews described the efficient syntheses of metallic bismuth nanoparticles. Nevertheless, few studies have been published on the medical applications of these nanoparticles compared to the number of studies on the well-documented clinical use of the bismuth(III) complex. An analysis of the literature revealed the significant potential of metallic bismuth nanoparticles in different theranostic applications. In the diagnostic field, preclinical proofs of concept have been demonstrated for X-ray, photoacoustic and fluorescence imaging. In the therapeutic field, several preclinical studies have shown the potential of bismuth nanoparticles as X-ray radiosensitizers for use in radiotherapy and as photothermal agents for applications in near infrared phototherapy. The properties of these metallic bismuth nanoparticles as bactericidal, fungicidal, antiparasitic and antibiofilm agents have also been studied. Although information concerning the toxic effects of these nanoparticles has been collected, these data are insufficient when considering the immediate clinical use of these new nanoparticles.

Data of the quantification of the influence of DMSO concentration on the kinetic of interaction between TNFα and SPD304.

The data presented here are related to the article entitled "New contributions to the drug profile of TNFα inhibitor SPD304: affinity, selectivity ADMET considerations" published in the European Journal of pharmacology. As DMSO is usually used as a co-solvent to dissolve low aqueous soluble small molecules, such as SPD304, we have investigated the influence of its concentration on the kinetic of interaction between tumor necrosis factor α (TNF-α) and its inhibitor, SPD304. The presented data, acquired using a surface acoustic wave sensor, can be used in further biological studies to compare the kinetic of interaction between proteins/small molecules in general and TNFα/inhibitors in particular. The estimated dissociation constant can be compared to other ones to statute on the degree of affinity between a protein and a given molecule.

New contributions to the drug profile of TNFα inhibitor SPD304: Affinity, selectivity and ADMET considerations.

Tumor necrosis factor alpha (TNFα) is a relevant clinical target for the treatment of chronic inflammatory diseases. Currently, only few small molecules are known as direct inhibitors of TNFα. To date, none of these molecules has shown both an efficient activity and a low toxicity to be considered for clinical trials. The SPD304 is considered as a reference of direct inhibitors of TNFα because of its well demonstrated mechanism (He et al., 2005). Herein, we provide new insights regarding the drug profile, selectivity and absorption, distribution, metabolism, excretion and toxicity (ADMET) considerations of SPD304 to evaluate its potential as a hit for the structure-based design of novel TNFα inhibitors. ELISA experiments confirmed the inhibition of TNFα/TNF receptor 1 binding (IC50 = 12 µM). Cellular-based assays highlighted the cytotoxicity of SPD304, as well as its ability to inhibit TNFα signaling pathways at non-cytotoxic concentrations. A surface acoustic wave (SAW) experiment highlighted only one binding site with a dissociation constant of 6.1 ± 4.7 nM. SPD304 inhibited the binding of the cytokines like interleukins (IL)-4 and IL-13 to their receptors and showed no direct inhibition on proteins involved in the TNFα pathway. Finally, the thermodynamic solubility and Caco-2 cells permeability of SPD304 were experimentally evaluated and ADMET in silico predictions are also discussed. The physicochemical, pharmacological and ADMET studies of SPD304 have shown that is not an ideal hit for a drug optimization program based on its chemical structure.

A new paradigm for high-sensitivity 19F magnetic resonance imaging of perfluorooctylbromide.

In the present work, the NMR properties of perfluorooctylbromide are revisited to derive a high-sensitivity fluorine MRI strategy. It is shown that the harmful effects of J-coupling can be eliminated by carefully choosing the bandwidth of the 180 degrees pulses in a spin-echo sequence. The T(2) of the CF(3) resonance of the molecule is measured using a multispin-echo sequence and shown to dramatically depend on the interpulse delay. Following these observations, an optimized multispin-echo imaging sequence is derived and compared with short TE/pulse repetition time gradient echo and chemical shift imaging sequences. The unparalleled sensitivity yielded by the multispin-echo sequence is promising for future applications, in particular for targeted contrast agents such as perfluorooctylbromide nanoparticles.

Comparison of the high relaxivity Gd chelates P1152 and Gd-BOPTA for contrast-enhanced MR angiography in rabbits at 1.5 Tesla and 3.0 Tesla.

PURPOSE: To compare signal-enhancing properties of the high relaxivity Gd chelates P1152 and Gd-BOPTA for contrast-enhanced MR angiography (CE-MRA) in rabbits at 1.5 Tesla (T) and 3.0T. MATERIALS AND METHODS: Three-dimensional CE-MRA of the abdominal vasculature was performed in six rabbits using both contrast agents at a dose of 0.1 mmol/kg. Data acquisition was carried out during first pass and up to 10 min after contrast material administration. CNR was determined in aorta, vena cava, and renal cortex. Image quality (5-point scale, 5 = best) of first pass MR angiograms was rated by two radiologists. RESULTS: During first pass CNR of the aorta was 55.1 +/- 5.8 (P1152) and 40.3 +/- 3.9 (Gd-BOPTA) at 1.5T (P < 0.05), and 114.9 +/- 9.9 (P1152) and 73.5 +/- 8.1 (Gd-BOPTA) at 3.0T (P < 0.05). Both contrast agents showed a comparable decline of CNR within 10 min. Image quality was rated 4.8 +/- 0.40 (P1152) and 4.5 +/- 0.50 (Gd-BOPTA) at 1.5T (P = 0.17), and 4.8 +/- 0.37 (P1152) and 4.7 +/- 0.47 (Gd-BOPTA) at 3.0T (P = 0.61). CONCLUSION: The high relaxivity Gd-chelate P1152 offers potential to improve image contrast for CE-MRA compared with a clinically approved high relaxivity contrast agent.

Molecular Imaging of Galectin-1 Expression as a Biomarker of Papillary Thyroid Cancer by Using Peptide-Functionalized Imaging Probes.

Thyroid cancers are the most frequent endocrine cancers and their incidence is increasing worldwide. Thyroid nodules occur in over 19-68% of the population, but only 7-15% of them are diagnosed as malignant. Diagnosis relies on a fine needle aspiration biopsy, which is often inconclusive and about 90% of thyroidectomies are performed for benign lesions. Galectin-1 has been proposed as a confident biomarker for the discrimination of malignant from benign nodules. We previously identified by phage display two peptides (P1 and P7) targeting galectin-1, with the goal of developing imaging probes for non-invasive diagnosis of thyroid cancer. The peptides were coupled to ultra-small superparamagnetic particles of iron oxide (USPIO) or to a near-infrared dye (CF770) for non-invasive detection of galectin-1 expression in a mouse model of papillary thyroid cancer (PTC, as the most frequent one) by magnetic resonance imaging and fluorescence lifetime imaging. The imaging probes functionalized with the two peptides presented comparable image enhancement characteristics. However, those coupled to P7 were more favorable, and showed decreased retention by the liver and spleen (known for their galectin-1 expression) and high sensitivity (75%) and specificity (100%) of PTC detection, which confirm the aptitude of this peptide to discriminate human malignant from benign nodules (80% sensitivity, 100% specificity) previously observed by immunohistochemistry.

Role of thermodynamic and kinetic parameters in gadolinium chelate stability.

In recent years there has been a renewed interest in the physicochemical properties of gadolinium chelates (GC). The aim of this review is to discuss the physicochemical properties of marketed GC with regard to possible biological consequences. GC can be classified according to three key molecular features: 1) the nature of the chelating moiety: either macrocyclic molecules in which Gd(3+) is caged in the preorganized cavity of the ligand, or linear, open-chain molecules; 2) ionicity: the ionicity of the molecule varies from neutral to tri-anionic agents; and 3) the presence or absence of an aromatic lipophilic moiety, which has a profound impact on the biodistribution of the GC. These parameters can also explain why GC differ considerably with regard to their thermodynamic stability constants and kinetic stability, as demonstrated by numerous studies. The concept of thermodynamic and kinetic stability is critically discussed, as it remains somewhat controversial, especially in predicting the amount of free gadolinium that may result from decomplexation of chelates in physiologic or pathologic situations. This review examines the possibility that the high kinetic stability provided by the macrocyclic structure combined with a high thermodynamic stability (reinforced by ionicity for macrocyclic chelates) can minimize the amount of free Gd(3+) released in the body. J. Magn. Reson. Imaging 2009;30:1249-1258. (c) 2009 Wiley-Liss, Inc.