Juan J. Vaquero

NEMA NU 4-2008 Comparison of Preclinical PET Imaging Systems

The National Electrical Manufacturers Association (NEMA) standard NU 4-2008 for performance measurements of small-animal tomographs was recently published. Before this standard, there were no standard testing procedures for preclinical PET systems, and manufacturers could not provide clear specifications similar to those available for clinical systems under NEMA NU 2-1994 and 2-2001. Consequently, performance evaluation papers used methods that were modified ad hoc from the clinical PET NEMA standard, thus making comparisons between systems difficult. Methods: We acquired NEMA NU 4-2008 performance data for a collection of commercial animal PET systems manufactured since 2000: microPET P4, microPET R4, microPET Focus 120, microPET Focus 220, Inveon, ClearPET, Mosaic HP, Argus (formerly eXplore Vista), VrPET, LabPET 8, and LabPET 12. The data included spatial resolution, counting-rate performance, scatter fraction, sensitivity, and image quality and were acquired using settings for routine PET. Results: The data showed a steady improvement in system performance for newer systems as compared with first-generation systems, with notable improvements in spatial resolution and sensitivity. Conclusion: Variation in system design makes direct comparisons between systems from different vendors difficult. When considering the results from NEMA testing, one must also consider the suitability of the PET system for the specific imaging task at hand.

Identification of intermediates and assessment of ecotoxicity in the oxidation products generated during the ozonation of clofibric acid.

The degradation of an aqueous solution of clofibric acid was investigated during catalytic and non-catalytic ozonation. The catalyst, TiO(2), enhanced the production of hydroxyl radicals from ozone and raised the fraction or clofibric acid degraded by hydroxyl radicals. The rate constant for the reaction of clofibric acid and hydroxyl radicals was not affected by the presence of the catalyst. The toxicity of the oxidation products obtained during the reaction was assessed by means of Vibrio fischeri and Daphnia magna tests in order to evaluate the potential formation of toxic by-products. The results showed that the ozonation was enhanced by the presence of TiO(2,) the clofibric acid being removed completely after 15 min at pH 5. The evolution of dissolved organic carbon, specific ultraviolet absorption at 254 nm and the concentration of carboxylic acids monitored the degradation process. The formation of 4-chlorophenol, hydroquinone, 4-chlorocatechol, 2-hydroxyisobutyric acid and three non-aromatic compounds identified as a product of the ring-opening reaction was assessed by exact mass measurements performed by liquid chromatography coupled to time-of-flight mass spectrometry (LC-TOF-MS). The bioassays showed a significant increase in toxicity during the initial stages of ozonation following a toxicity pattern closely related to the formation of ring-opening by-products.

Synthesis and Structure of New Pyrido[2,3-d]pyrimidine Derivatives with Calcium Channel Antagonist Activity

We gratefully acknowledge to ALTER S. A. for studentship (to A. P and R. A.) and financial support

Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence.

Marijuana consumption during adolescence has been proposed to be a stepping-stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self-administration (1 mg/kg), food-reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food-restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [18F]-fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP-treated rats showed a higher rate of cocaine self-administration as compared to vehicle-treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food-reinforced operant task, pointing to the cocaine-specific nature of the effect seen in self-administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP-treated females when compared to their vehicle-treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo-entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self-administration, in a sex-specific fashion. This increased susceptibility could be related to the changes in brain metabolic activity induced by cannabinoids during adolescence.

Assessment of a New High-Performance Small-Animal X-Ray Tomograph

We have developed a new X-ray cone-beam tomograph for in vivo small-animal imaging using a flat panel detector (CMOS technology with a microcolumnar CsI scintillator plate) and a microfocus X-ray source. The geometrical configuration was designed to achieve a spatial resolution of about 12 lpmm with a field of view appropriate for laboratory rodents. In order to achieve high performance with regard to per-animal screening time and cost, the acquisition software takes advantage of the highest frame rate of the detector and performs on-the-fly corrections on the detector raw data. These corrections include geometrical misalignments, sensor non-uniformities, and defective elements. The resulting image is then converted to attenuation values. We measured detector modulation transfer function (MTF), detector stability, system resolution, quality of the reconstructed tomographic images and radiated dose. The system resolution was measured following the standard test method ASTM E 1695 -95. For image quality evaluation, we assessed signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) as a function of the radiated dose. Dose studies for different imaging protocols were performed by introducing TLD dosimeters in representative organs of euthanized laboratory rats. Noise figure, measured as standard deviation, was 50 HU for a dose of 10 cGy. Effective dose with standard research protocols is below 200 mGy, confirming that the system is appropriate for in vivo imaging. Maximum spatial resolution achieved was better than 50 micron. Our experimental results obtained with image quality phantoms as well as with in-vivo studies show that the proposed configuration based on a CMOS flat panel detector and a small micro-focus X-ray tube leads to a compact design that provides good image quality and low radiated dose, and it could be used as an add-on for existing PET or SPECT scanners.

A V-shaped cationic dye for nonlinear optical bioimaging

A symmetric cationic molecule with D-π-A(+)-π-D architecture was synthesized with high two-photon absorption cross-section (σ(2) ≈ 1140 GM). Application as a marker in fluorescence microscopy of living cells revealed its presence inside the cell staining vesicular shape organelles in the cytoplasm. Fluorescence lifetime imaging microscopy shows that it is also able to penetrate within the nucleus.

A new approach to the synthesis of 2-aminoimidazo[1,2-a]pyridine derivatives through microwave-assisted N-alkylation of 2-halopyridines

Abstract A microwave (focused waves) assisted N-alkylation of 2-halopyridines provides a convenient entry to 2-amino-imidazo[1,2-a]pyridine derivatives after reaction of the alkylated substrates with cyanamide under basic conditions.

Synthesis and chromatographic separation of the stereoisomers of furnidipine

Abstract The four stereoisomers of methyl tetrahydrofuran-2-ylmethyl 2,6-dimethyl-4-(o-nitrophenyl)-1,4-dihydro-pyridine-3,5-dicarboxilate (furnidipine), have been synthesized and separated by chiral chromatography using D-phenylglycine as chiral stationary phase. Enantiomeric purity of stereoisomers is determined by HPLC-CSP technique and configurations deduced via X-ray crystallography.

Design and performance evaluation of a coplanar multimodality scanner for rodent imaging

This work reports on the development and performance evaluation of the VrPET/CT, a new multimodality scanner with coplanar geometry for in vivo rodent imaging. The scanner design is based on a partial-ring PET system and a small-animal CT assembled on a rotatory gantry without axial displacement between the geometric centers of both fields of view (FOV). We report on the PET system performance based on the NEMA NU-4 protocol; the performance characteristics of the CT component are not included herein. The accuracy of inter-modality alignment and the imaging capability of the whole system are also evaluated on phantom and animal studies. Tangential spatial resolution of PET images ranged between 1.56 mm at the center of the FOV and 2.46 at a radial offset of 3.5 cm. The radial resolution varies from 1.48 mm to 1.88 mm, and the axial resolution from 2.34 mm to 3.38 mm for the same positions. The energy resolution was 16.5% on average for the entire system. The absolute coincidence sensitivity is 2.2% for a 100-700 keV energy window with a 3.8 ns coincident window. The scatter fraction values for the same settings were 11.45% for a mouse-sized phantom and 23.26% for a rat-sized phantom. The peak noise equivalent count rates were also evaluated for those phantoms obtaining 70.8 kcps at 0.66 MBq/cc and 31.5 kcps at 0.11 MBq/cc, respectively. The accuracy of inter-modality alignment is below half the PET resolution, and the image quality of biological specimens agrees with measured performance parameters. The assessment presented in this study shows that the VrPET/CT system is a good performance small-animal imager, while the cost derived from a partial ring detection system is substantially reduced as compared with a full-ring PET tomograph.

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin.

Trabectedin (Yondelis; ET-743) is a potent anticancer drug that binds to DNA by forming a covalent bond with a guanine in one strand and one or more hydrogen bonds with the opposite strand. Using a fluorescence-based melting assay, we show that one single trabectedin-DNA adduct increases the thermal stability of the double helix by >20°C. As deduced from the analysis of phosphorylated H2AX and Rad51 foci, we observed that clinically relevant doses of trabectedin induce the formation of DNA double-strand breaks in human cells and activate homologous recombination repair in a manner similar to that evoked by the DNA interstrand cross-linking agent mitomycin C (MMC). Because one important characteristic of this drug is its marked cytotoxicity on cells lacking a functional Fanconi anemia (FA) pathway, we compared the response of different subtypes of FA cells to MMC and trabectedin. Our data clearly show that human cells with mutations in FANCA, FANCC, FANCF, FANCG, or FANCD1 genes are highly sensitive to both MMC and trabectedin. However, in marked contrast to MMC, trabectedin does not induce any significant accumulation of FA cells in G2-M. The critical relevance of FA proteins in the response of human cells to trabectedin reported herein, together with observations showing the role of the FA pathway in cancer suppression, strongly suggest that screening for mutations in FA genes may facilitate the identification of tumors displaying enhanced sensitivity to this novel anticancer drug. [Mol Cancer Ther 2008;7(5):1309–18]