Involvement of the basal ganglia in refractory epilepsy: an 18F-fluoro-L-DOPA PET study using 2 methods of analysis.

Studies in animal models and epileptic patients have led to the suggestion that the basal ganglia (BG) are involved in seizures. PET with 6-18F-L-3,4-fluorodihydroxyphenylalanine (18F-fluoro-L-DOPA) has recently demonstrated a reduction of striatal dopamine uptake in drug-resistant epileptic patients with ring chromosome 20 (r20) using a multiple-time graphical analysis. The aim of the present study was to evaluate the involvement of dopamine in other epileptic syndromes using a multiple-time graphical analysis and the all-brain statistical parametric mapping (SPM) analysis. METHODS: Patients with drug-resistant epilepsy were divided into 3 groups: group 1, with r20 epilepsy (n = 16; mean age +/- SD, 21.5 +/- 5.4 y); group 2, with resistant generalized "absence-like" epilepsy (n = 10; mean age, 32.3 +/- 11.4 y); and group 3, with drug-resistant temporal lobe epilepsy with hippocampal sclerosis (n = 9; mean age, 35.2 +/- 10.3 y). We compared 2 strategies of analysis of the 18F-fluoro-L-DOPA uptake constant (K(i), min(-1)) in BG using a multiple-time graphical analysis using regions of interest (the gold-standard method) and an SPM analysis using a voxel-by-voxel statistical t test to avoid a priori hypotheses in the analysis. Each epileptic group was compared with a group of healthy volunteers (n = 10; mean age, 45.1 +/- 16.5 y). RESULTS: A decrease of the mean K(i) value was observed in the striatum in all groups of patients with both types of analysis. With multiple-time graphical analysis, the reduction was evident using the averaged K(i) values over both hemispheres in each BG. Unilateral decreases in each BG were detected in SPM analysis. A ratio of decrease of 18F-fluoro-L-DOPA uptake was observed in the 3 groups of patients. Only the SPM analysis showed a decrease of 18F-fluoro-L-DOPA uptake ipsilateral to the seizure side in patients with temporal lobe epilepsy. Moreover, the all-brain SPM analysis showed a decrease of 18F-fluoro-L-DOPA uptake in the substantia nigra bilaterally (P < 0.001). CONCLUSION: This result confirms the involvement of dopamine neurotransmission in seizure control related to the type of epileptic syndrome. The difference in epileptic types may depend in part on the seizure frequency.     

Assessment of 11C-PE2I binding to the neuronal dopamine transporter in humans with the high-spatial-resolution PET scanner HRRT.

The high-resolution research tomograph (HRRT), dedicated to brain imaging, may offer new perspectives for identifying small brain nuclei that remain neglected by the spatial resolution of conventional scanners. However, the use of HRRT for neuroimaging applications still needs to be fully assessed. The present study aimed at evaluating the HRRT for measurement of the dopamine transporter (DAT) binding to validate its quantification and explore the gain induced by the increased spatial resolution in comparison with conventional PET scanners. METHODS: Fifteen and 11 healthy subjects were examined using the selective DAT radioligand (11)C-PE2I with HRRT and HR+ scanners, respectively. Quantification of the DAT binding was assessed by the calculation of binding potential (BP) values using the simplified reference tissue model in anatomic regions of interest (ROIs) defined on the dorsal striatum and in a standardized ROI defined on the midbrain. RESULTS: Quantification of (11)C-PE2I binding to the DAT measured in the midbrain and striatum with both scanners at the same spatial resolution (smoothed HRRT images) exhibited similar BP values and intersubject variability, thus validating the quantification of DAT binding on the HRRT. For age-paired comparison, BP values of subjects examined with HRRT were significantly higher than those of the subjects examined with HR+. The increase ranged from 29% in the caudate and 35% in the putamen to 92% in the midbrain. The decline in DAT binding with age in the striatum was in good agreement between both scanners and literature, whereas no significant decrease in DAT binding with age was observed in the midbrain with either HRRT or HR+. CONCLUSION: HRRT allows quantitative measurements of neurotransmission processes in small brain nuclei and allows recovering higher values as compared with coarser spatial resolution PET scanners. High-spatial-resolution PET appears promising for a more accurate detection of neurobiologic modifications and also for the exploration of subtle modifications in small and complex brain structures largely affected by the partial-volume effect.     

Novel 6-[(hetero)arylamino]thieno[3,2-b]pyridines: synthesis and antitumoral activities

Several novel 6-[(hetero)arylamino]thieno[3,2-b]pyridines were prepared by palladium-catalyzed C-N Buchwald-Hartwig coupling of the methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate with aryl and heteroarylamines, using different reaction conditions. The antitumoral activity of the di(hetero)arylamines obtained was evaluated against three representative human tumor cell lines, namely breast adenocarcinoma (MCF-7), melanoma (A375-C5), and non-small cell lung cancer (NCI-H460) and some structure-activity relationships were established within each series. The most promising compounds were shown to be a benzothiazole derivative with GI50 3.5-6.9 μM followed by an indole derivative with GI50 13-21 μM.     

Efficient synthesis of 6-(hetero)arylthieno[3,2-b]pyridines by Suzuki-Miyaura coupling. Evaluation of growth inhibition on human tumor cell lines, SARs and effects on the cell cycle

A wide variety of new bi(hetero)aryl derivatives of the thieno[3,2-b]pyridine skeleton was obtained in high to excellent yields (65-91%) by Suzuki-Miyaura cross-coupling of the methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate, recently reported by us, with aryl or heteroaryl pinacolboranes or potassium trifluoroborates. The coupling products obtained were evaluated for their growth inhibitory effect on three human tumor cell lines, representing different tumor models, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma) and NCI-H460 (non-small cell lung cancer). Some of the compounds showed an interesting activity against the tested cell lines, with GI50 values in the μM range, and it was possible to establish some structure-activity relationships (SARs). Several compounds presented GI50 values below 15 μM, particularly a bithiophene and an o-aniline thienopyridine derivative. The first presented selectivity for MCF-7 and NCI-H460 cell lines, with very low GI50 values (0.7-1.0 μM), while the latter was active against the three cell lines tested in this study, also presenting very low GI50 values (2.5-4.2 μM). The effect of these two compounds on cell cycle progression was analyzed in the NCI-H460 cell line. Results showed that both compounds interfered with the normal cell cycle distribution.     

When Is Congruency Helpful? Interactive Effects of Frame,Motivational Orientation,and Perceived Message Quality on Fruit and Vegetable Consumption

Health messages framed to be congruent with people’s motivational orientation have been shown to be generally effective in promoting health behavior change, but some inconsistencies have been found. This study tested whether the perceived quality of a health message moderated the congruency effect in the domain of fruit and vegetable (FV) consumption. Undergraduate participants (N = 109) read a health message promoting FV intake in which the frame (gain vs. loss) was either congruent or incongruent with their approach/avoidance motivational orientation. Perceived message quality and intention to increase FV intake were assessed after message exposure, and self-reported FV intake was assessed one week later. A significant interaction between congruency and perceived message quality was found on both intention and FV intake. When messages were congruent, higher intentions and FV intake were observed when perceived message quality was high, but the reverse pattern was observed when perceived message quality was low. The findings support the potential utility of using congruently-framed messages to promote fruit and vegetable consumption, while also underscoring the necessity of using high-quality messages in order for congruency to influence health-related behaviors.     

Analysis of natural allelic variation in Arabidopsis using a multiparent recombinant inbred line population

To exploit the diversity in Arabidopsis thaliana, eight founder accessions were crossed to produce six recombinant inbred line (RIL) subpopulations, together called an Arabidopsis multiparent RIL (AMPRIL) population. Founders were crossed pairwise to produce four F1 hybrids. These F1s were crossed according to a diallel scheme. The resulting offspring was then selfed for three generations. The F4 generation was genotyped with SNP and microsatellite markers. Data for flowering time and leaf morphology traits were determined in the F5 generation. Quantitative trait locus (QTL) analysis for these traits was performed using especially developed mixed-model methodology, allowing tests for QTL main effects, QTL by background interactions, and QTL by QTL interactions. Because RILs were genotyped in the F4 generation and phenotyped in the F5 generation, residual heterozygosity could be used to confirm and fine-map a number of the QTLs in the selfed progeny of lines containing such heterozygosity. The AMPRIL population is an attractive resource for the study of complex traits.     

Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation

IntroductionThe translocator protein 18 kDa (TSPO), although minimally expressed in healthy brain, is up-regulated in pathological conditions, coinciding with microglial activation. It is thereby a suitable in vivo biomarker of neuroinflammation for detection, evaluation and therapeutic monitoring of brain diseases. We aimed to estimate the radiation dosimetry of the positron emission tomography (PET) TSPO radioligand [¹⁸F]DPA-714, and we evaluated in healthy volunteers its whole-body uptake and cerebral kinetics.MethodsBiodistribution data from mice were used for the prediction of radiation dosimetry. In human studies, a 90-min dynamic PET scan was performed in seven healthy volunteers after injection of [¹⁸F]DPA-714 (245±45 MBq). Arterial and venous samples were collected from two subjects, and two additional subjects were submitted to whole-body acquisition. Regions of interest were defined over cerebral structures to obtain mean time–activity curves and to estimate the distribution volume ratios by Logan graphical analysis, and over peripheral organs to obtain standard uptake values.ResultsThe effective dose estimated from biodistribution in mice was 17.2 μSv/MBq. Modeling of regional brain and plasma data showed good in vivo stability of [¹⁸F]DPA-714 in humans, with only 20% of blood metabolites 20 min postinjection (p.i.). Maximum cerebral uptake was observed 5 min p.i., followed by two decreasing phases: a rapid washout (5–30 min) followed by a slower phase for the remainder of PET acquisition. Whole-body images demonstrate high activity in the gallbladder, heart, spleen and kidneys.ConclusionsThis initial study in humans shows that [¹⁸F]DPA-714 is a promising PET radioligand with excellent in vivo stability and biodistribution, and acceptable effective dose estimation. Therefore, [¹⁸F]DPA-714 could provide a sensitive measure of neuroinflammatory changes in subsequent clinical investigations.     

Synthesis and evaluation of tumor cell growth inhibition of methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates. Structure-activity relationships, effects on the cell cycle and apoptosis

The methyl 3-amino-6-bromothieno[3,2-b]pyridine-2-carboxylate, recently reported by some of us, was reacted in Sonogashira couplings with several (hetero)arylacetylenes. The growth inhibitory activity of the novel methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates obtained was evaluated on three human tumor cell lines (MCF-7, NCI-H460, A375-C5). The para-methoxyphenyl and the ortho- and para-aminophenyl derivatives were the most promising compounds, and their effects were further studied regarding alterations in the normal cell cycle distribution and induction of apoptosis in the NCI-H460 cell line. All three compounds altered cell cycle distribution and the ortho-aminophenyl derivative was further shown to induce apoptosis in the same cell line.