Radiosynthesis and Preclinical Evaluation of an 18F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A).

The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cascades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an interesting therapeutic and diagnostic target for neurodegenerative and neuropsychiatric diseases as well as for cancer. Aiming at specific imaging of this enzyme in the brain with positron emission tomography (PET), a new triazolopyridopyrazine-based derivative (11) was identified as a potent PDE2A inhibitor (IC50, PDE2A = 1.99 nM; IC50, PDE10A ~2000 nM) and has been radiofluorinated for biological evaluation. In vitro autoradiographic studies revealed that [18F]11 binds with high affinity and excellent specificity towards PDE2A in the rat brain. For the PDE2A-rich region nucleus caudate and putamen an apparent KD value of 0.24 nM and an apparent Bmax value of 16 pmol/mg protein were estimated. In vivo PET-MR studies in rats showed a moderate brain uptake of [18F]11 with a highest standardized uptake value (SUV) of 0.97. However, no considerable enrichment in PDE2A-specific regions in comparison to a reference region was detectable (SUVcaudate putamen = 0.51 vs. SUVcerebellum = 0.40 at 15 min p.i.). Furthermore, metabolism studies revealed a considerable uptake of radiometabolites of [18F]11 in the brain (66% parent fraction at 30 min p.i.). Altogether, despite the low specificity and the blood−brain barrier crossing of radiometabolites observed in vivo, [18F]11 is a valuable imaging probe for the in vitro investigation of PDE2A in the brain and has potential as a lead compound for further development of a PDE2A-specific PET ligand for neuroimaging.

Associations Between Personality Functioning, Childhood Trauma and Non-adherence in Cardiovascular Disease: A Psychodynamically-Informed Cross-Sectional Study.

Objective: Although treatment adherence and lifestyle changes significantly improve the prognosis of cardiovascular disease, many patients do not comply with clinician recommendations. Personality functioning appears to be of importance and is hypothesized to be superior to symptom-based measures in explaining individual differences in non-adherence. Methods: 194 cardiology inpatients (mean age = 70.6 years, 60% male) were assessed using self-report measures in a cross-sectional design. Patients were assessed using the short version of the Operationalized Psychodynamic Diagnosis Structure Questionnaire (OPD-SQS) to measure personality functioning, as well as the Childhood Trauma Screener (CTS), the Patient Health Questionnaire (PHQ-9) for symptoms of depression, and the Generalized Anxiety Disorder Scale-7 (GAD-7). To assess non-adherence we introduced a brief, novel scale. Results: Non-adherence correlated significant with personality functioning (r = 0.325), childhood trauma (r = 0.204) and depressiveness (r = 0.225). In a stepwise multiple regression analysis with socio-demographic variables inputted into the model, higher deficits in personality functioning, higher levels of childhood trauma, and male gender were associated with non-adherence (adjusted R2 = 0.149, F (3,190) = 12.225, p < 0.01). Level of depressive symptoms, anxiety, age, education, and income showed no significant additional predictive value and were excluded from the model. Conclusion: In cardiovascular disease, personality functioning, childhood trauma and male gender are associated with non-adherence and appear to be more important than symptom reports of depression and anxiety. This highlights the relevance of basic impairments in intra- and interpersonal functioning in chronic disease, where the patient's adherence is central.

Hybrid Peptides Based on α-Aminoxy Acids as Antimicrobial and Anticancer Foldamers.

α-Aminoxy peptides represent an interesting group of peptidomimetics with high proteolytic stability and the ability to fold into specific, predictable secondary structures. Here, we present a series of hybrid peptides consisting of α-aminoxy acids and α-amino acids with cationic and aromatic, hydrophobic side chains in an alternating manner synthesized using an efficient protocol that combines solution- and solid-phase synthesis. 2D ROESY experiments with a representative hexamer suggested the presence of a 7/8 helical conformation in solution. Biological evaluation revealed a significant impact of the peptide chain length and the N-terminal cap on the antimicrobial and anticancer properties of this series of hybrid peptides. The Fmoc-capped peptide 6e displayed the most potent antimicrobial activity against a panel of Gram-negative and Gram-positive bacterial strains (e. g. against E. Coli: MIC=8 mg/L; S. aureus: MIC=4 mg/L).

Derivatization of Methylglyoxal for LC-ESI-MS Analysis-Stability and Relative Sensitivity of Different Derivatives.

The great research interest in the quantification of reactive carbonyl compounds (RCCs), such as methylglyoxal (MGO) in biological and environmental samples, is reflected by the fact that several publications have described specific strategies to perform this task. Thus, many reagents have also been reported for the derivatization of RCCs to effectively detect and quantify the resulting compounds using sensitive techniques such as liquid chromatography coupled with mass spectrometry (LC-MS). However, the choice of the derivatization protocol is not always clear, and a comparative evaluation is not feasible because detection limits from separate reports and determined with different instruments are hardly comparable. Consequently, for a systematic comparison, we tested 21 agents in one experimental setup for derivatization of RCCs prior to LC-MS analysis. This consisted of seven commonly employed reagents and 14 similar reagents, three of which were designed and synthesized by us. All reagents were probed for analytical responsiveness of the derivatives and stability of the reaction mixtures. The results showed that derivatives of 4-methoxyphenylenediamine and 3-methoxyphenylhydrazine-reported here for the first time for derivatization of RCCs-provided a particularly high responsiveness with ESI-MS detection. We applied the protocol to investigate MGO contamination of laboratory water and show successful quantification in a lipoxidation experiment. In summary, our results provide valuable information for scientists in establishing accurate analysis of RCCs.

[A psychometric view on the applicability of the BDI-II in non-clinical populations]. / Die Anwendbarkeit des BDI-II in klinischen und nichtklinischen Populationen aus psychometrischer Sicht. Eine vergleichende Analyse mit dem Rasch-Modell.

BACKGROUND: The revised version of the Beck Depression Inventory (BDI-II) is a broadly used instrument for assessing the severity of depression of adolescents of at least 13 years of age and adults. The self-assessment questionnaire contains 21 polytomous items and follows the criteria for a major depression specified in the DSM-IV. Clinical samples have often been used to analyze the psychometric properties of the instrument primarily with factor analytic methods. METHODS: The present study performs a psychometric analysis in a non-clinical sample in order to ascertain, whether the instrument performs equally well with the different kinds of samples. A clinical sample and a sample of students filled in the questionnaire. A partial credit model was applied and parameter estimates and model fit of the two samples were compared. RESULTS: Threshold parameters and model fit largely agreed, however some items exhibited characteristic deviations. Nevertheless, person parameter estimates notably agreed in both samples. CONCLUSIONS: These results indicate that the BDI-II performs in clinical and non-clinical samples comparably well, only some items show characteristic deviations in the non-clinical sample.