AlzeCure Pharma (Sweden)

The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand. Preclinical studies were performed using a multidimensional approach of post-mortem brain imaging techniques, radioligand binding, and biochemical studies. These experiments were followed by PET imaging in cynomolgus monkeys using [11C]KAC-50.1. [3H]KAC-50.1 displayed a KD of 35 nM toward site 2 in recombinant α-syn fibrils. Specific binding of [3H]KAC-50.1 was observed in brain tissues with abundant α-syn pathology but also in AD, PSP, and CBD cases, indicating binding to amyloid β (Aβ) and tau pathology. PET studies showed a rapid entrance of [11C]KAC-50.1 into the brain and relatively rapid washout from cortical brain regions, with slower washout in subcortical regions. [3H]KAC-50.1 is a ligand that binds to fibrillar α-syn but shows limited selectivity for α-syn versus Aβ and tau fibrils. PET studies in NHPs indicate that [11C]KAC-50.1, despite reversible kinetic properties, displays retention in white matter. Altogether, the in vitro and in vivo properties do not support further development of [11C]KAC-50.1 as a PET imaging agent.

BackgroundMajor depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process.ObjectivesThe purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo.MethodsThe effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat.ResultsThe results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, aremediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD.ConclusionsTrk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.

The aggregation of β‐amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ‐secretase–mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ‐Secretase modulators (GSMs) represent a promising class of Aβ42‐lowering anti‐amyloidogenic compounds for the treatment of AD. Gamma‐secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ‐secretase–mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ‐secretase cleavage of three γ‐secretase substrates, E‐cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ‐secretase–dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ‐secretase processing of EphA4 and EphB2 results in the release of several Aβ‐like peptides, but that only the production of Aβ‐like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ‐secretase–mediated Aβ production.

The aim of this study was to evaluate the effect of levocabastine, a new H1-blocking antihistamine for topical use, in comparison with sodium cromoglycate on conjunctival symptoms of birch pollinosis. The two drugs were compared in a randomized double-blind comparative study over 5 weeks in 37 children and adolescents (6-19 years of age) with birch pollen conjunctivitis. Nasal symptoms occurred in 31 of the children and were treated with beclomethasone dipropionate nasal spray. An oral antihistamine was offered as rescue medication for eye symptoms. Initially, the patients received placebo four times a day for a 7-day run-in period. Conjunctival symptoms were recorded daily on diary cards on a 100 mm visual analogue scale. The pollen counts indicated a short but intensive birch pollen season. There was no statistically significant difference between the two treatment groups with regard to eye symptom scores before and during active treatment. However, the patients' evaluation of the efficacy of the therapy was in favour of levocabastine (P less than 0.01). Topical levocabastine, an H1-blocker, applied twice daily, seems to protect from symptoms of allergic conjunctivities as favourably as sodium cromoglycate applied four times a day. There was no difference in number or character of reported adverse reactions between the two treatment groups.