Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants.

This corrects the article DOI: 10.1038/ejhg.2017.59.

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants.

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

Time trends of gender-based differences in lipid goal attainments during secondary prevention of coronary artery disease: results of a 5-year survey.

Coronary artery disease is the leading cause of death in both men and women worldwide. Little is known about gender-based differences in lipid goal attainment during secondary prevention of coronary artery disease. We conducted this study to analyze gender differences in low-density lipoprotein cholesterol target attainment in secondary prevention after acute myocardial infarction over a 5-year period. In this retrospective study, the electronic database of lipid clinic at a single center was used as the data source. Temporal trends and gender differences in demographics, lipid profile, and medication use were determined. Goal low-density lipoprotein (LDL) was defined per National Cholesterol Education Program ATP III guidelines.A total of 1365 patients (823 males, 542 females) constituted the study sample. Patients in 2007 were older than those in 2003 (females 68.6 ± 14 vs. 70.7 ± 11.7 years; males 63.6 ± 12 vs. 65.8 ± 11 years; P < 0.05) and had a higher body mass index (females 27.8 ± 1 vs. 28.6 ± 1 kg/m; males 27.6 ± 1 vs. 28.1 ± 1 kg/m, in 2003 and 2007 respectively, P < 0.05). Mean LDL decreased significantly overtime in both males and females. No gender difference in lipid-lowering therapy was observed. Females had a higher LDL than did males in 2003 (115.3 ± 12.3 vs. 99.7 ± 12.5 mg/dL; P < 0.05), and this difference persisted through 2007 (102.2 ± 11.7 vs. 91.3 ± 11.2 mg/dL; P < 0.05). Overall rate of achieving goal LDL improved from 76.5% (2003) to 83.02% (2007), P < 0.05, but remained lower for females than for males both in 2003 and 2007 [69.8% vs. 80.1% (2003), P < 0.05, and 77.9% vs. 85.6% (2007), P < 0.05].The trend over a recent 5-year period shows that females are less likely to achieve goal LDL than males are, and it indicates the need for more aggressive lipid-lowering strategies in females.

Suboccipital decompression enhances heart rate variability indices of cardiac control in healthy subjects.

OBJECTIVES: Osteopathic manipulative treatment (OMT) focused on the upper cervical spine is theorized to affect the function of the vagus nerve and thereby influence the parasympathetic branch of the autonomic nervous system. This study was designed to determine the acute effect of upper cervical spine manipulation on cardiac autonomic control as measured by heart rate variability. DESIGN: Nineteen healthy, young adult subjects underwent three different experimental interventions administered in random order: cervical OMT, sham manipulation, and time control. Six minutes of electrocardiographic data were collected before and after each intervention, and heart rate variability was assessed by both time-domain and frequency-domain measures. RESULTS: No differences in resting heart rate or any measure of heart rate variability were observed between the baseline periods prior to each intervention. The OMT protocol resulted in an increase in the standard deviation of the normal-to-normal intervals (0.12±0.082 seconds, p<0.01), an increase in the high frequency spectral power (p=0.03), and a decrease in the low/high frequency spectral ratio (p=0.01) relative to the sham and time control conditions. No significant differences between sham and time control were observed (p>0.11 for all variables). CONCLUSIONS: These data support the hypothesis that upper cervical spine manipulation can acutely affect measures of heart rate variability in healthy individuals.

Controlling lipids in a high-risk population with documented coronary artery disease for secondary prevention: are we doing enough?

BACKGROUND: The prevalence of high-density lipoprotein cholesterol (HDL-C) in patients who have achieved low-density lipoprotein cholesterol (LDL-C) targets in the current era of universal statin therapy remains unknown. We conducted a study to determine the prevalence of low HDL-C in patients with documented coronary artery disease, and to determine the lipid-lowering treatment patterns in secondary prevention of coronary artery disease. METHODS: In this retrospective cohort analysis, data were obtained from the electronic database of a cardiology clinic. The Joint British Society 2 criteria were used defining low HDL-C as less than 1 mmol/l in males and less than 1.2 mmol/l in females. We compared the prevalence of low HDL-C across the following categories of LDL-C: less than 2, 2-2.5, and greater than 2.5 mmol/l. RESULTS: Two thousand and eighty-seven patients with a mean age of 64.34±11.94 years constituted the study sample. About 36.6% of patients in this study were found to have low HDL-C. Irrespective of sex, low HDL-C was prevalent across all levels of LDL-C, but interestingly this was most prevalent in patients with a LDL-C less than 2 mmol/l (43.06%). HDL-C level of 1.16±0.97 mmol/l in patients with LDL-C less than 2 mmol/l was significantly lower than 1.22±0.33 mmol/l in patients with LDL-C greater than 2 mmol/l, P value less than 0.01. There was a poor correlation between levels of HDL-C and LDL-C in the study population irrespective of sex or statin therapy. CONCLUSION: This study shows widely prevalent low HDL-C levels in high-risk patients across the spectrum of LDL-C levels despite statin therapy. There was no correlation between the LDL-C and HDL-C levels implying their independent relationship and, thus, the need to treat them independently.

Antagonists of the human adenosine A2A receptor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine derivatives.

We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.

Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives.

The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.