Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants ported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of “feeding receptors” at the interface between neuroendocrine and mental diseases.

Small-Molecule Ligands as Challenge for Positron Emission Tomography of Peptide Receptors in Neurons and Microglia of the Brain

Neuropeptide and chemokine receptors of the G protein-coupled receptor (GPCR) family belong to different classes and subgroups providing different docking sites and special binding behavior at extracellular and also transmembrane domains for small molecules potentially suitable for positron emission tomography (PET). The contribution gives an overview updating developments of small-molecule, nonpeptide ligands at a selection of peptide and chemokine receptors, expressed in neurons and microglia of the brain, regarding the last five years. Orexin 1 and orexin 2 receptors (OX1R;OX2R) and neuropeptide Y1 and Y2 receptors (NPY1R, NPY2R) were chosen as representatives of Class A neuropeptide receptors, chemokine receptor CX3C (CX3CR1) as Class A, protein-activated receptor, highly expressed in activated microglia, and corticotropin releasing factor receptor 1 (CRFR1) as representative Class B1 receptor. Structural differences between binding domains and their endogenous ligands as well as parallel expression in different types of cells and generally low density of these receptors in brain tissue are factors making the search for selective and sensitive ligands more difficult than for classical GPCR receptors. Main progress in ligand development is observed for NPY receptor antagonists and orexin receptor antagonists. For orexin receptors, search for suitable ligands can be supported with modelling approaches, as recently the complete molecular structure of these receptors is available. Small molecules, binding at CRFR1, as for other Class B1 receptor ligands, in PET and investigations of pharmacodynamics revealed rather allosteric binding modes, although, the complete crystal structure of CRFR1 as prototype of Class B1 provides, hitherto, improved possibilities for understanding binding mechanisms. Highly specific as a marker of microglia among?the GPCRs, CX3CR1 is focused as target of PET during inflammation of brain and spinal cord.

Functional hyperconnectivity related to brain disease:maladaptive process or element of resilience?

Neuroimaging techniques such as magnetic resonance imaging(MRI)and positron emission tomography provide unique in vivo data to analyze structural and functional connectivity of the whole brain.Recent advances in small animal neuroimaging have opened new opportunities for the study of structure-function interactions in healthy and diseased brain networks,which are essential to develop therapies targeting network reorganization associated with functional improvement.

Structural integrity and remodeling underlying functional recovery after stroke

Stroke is the second leading cause of death worldwide with about 50% of survivors being chronically disabled(Donkor,2018).The behavioral improvement seen in stroke patients in the first weeks after a stroke is contributed by behavioral compensation, reorganization in somatotopic maps and activity in peri-infarct but also distant regions which are connected to the stroke area as supported by animal studies.

Small Molecule-Assisted PET: Approaches to Imaging of Conformational Diseases of the Brain

PET (positron emission tomography) in vivo imaging of cerebral conformational diseases is essentially based on non-peptide small molecule ligands used to detect early alterations in peptide secondary structures and subsequent accumulation of aberrant oligomers and protein deposits involved in progressive neurodegeneration, cognitive and movement disorders. In this article, an overview is given about tracers currently available and lead structures of potential PET probes for detection of?β-amyloid (Aβ), tau protein, α-synuclein, constitutive (PrPc) and infectious isoforms (PrPsc) of prions (proteinaceous infectious particles) as imaging targets. Whereas the styrylpyridine derivative florbetapir, approved for clinical applications, the stilbene derivative florbetaben and the benzoxazole derivative BF227 show high affinity binding to Aβ, preclinical investigations promise improved pharmacokinetics for benzoimidazothiazoles, aryloxazoles and benzofuran derivatives. Tau protein imaging based clinically, presently, on the pyridine-pyridoindole T807 has got new incentives following identification of a series of pyrrolopyridine quinolines and pharmacokinetic improvements of fluoropropoxy quinolines including for instance THK-5351. The pyridine isoquinoline MK6240 is involved now in clinical trials. Most forward-looking efforts apply to small molecule ligands of α-synuclein, which are expected to permit a breakthrough in differential diagnostics of Parkinson-related dementia and Lewy body diseases. However, at the moment the proposed lead structures are in affinity and blood brain barrier delivery properties below the possibilities of Aβ?and tau protein ligands. This is the case also for potential tracers of prion proteins.

Joint Multi-modal Parcellation of the Human Striatum:Functions and Clinical Relevance

The human striatum is essential for both lowand high-level functions and has been implicated in the pathophysiology of various prevalent disorders,including Parkinson's disease(PD)and schizophrenia(SCZ).It is known to consist of structurally and functionally divergent subdivisions.However,previous parcellations are based on a single neuroimaging modality,leaving the extent of the multi-modal organization of the striatum unknown.Here,we investigated the organization of the striatum across three modalities—resting-state functional connectivity,probabilistic diffusion tractography,and structural covariance—to provide a holistic convergent view of its structure and function.We found convergent clusters in the dorsal,dorsolateral,rostral,ventral,and caudal striatum.Functional characterization revealed the anterior striatum to be mainly associated with cognitive and emotional functions,while the caudal striatum was related to action execution.Interestingly,significant structural atrophy in the rostral and ventral striatum was common to both PD and SCZ,but atrophy in the dorsolateral striatum was specifically attributable to PD.Our study revealed a cross-modal convergent organization of the striatum,representing a fundamental topographical model that can be useful for investigating structural and functional variability in aging and in clinical conditions.

In vivo bioluminescence imaging to elucidate stem cell graft differentiation

Neurological disorders including neurodegeneration(e.g.,Alzheimer’s disease and Parkinson’s disease)and acute injuries(e.g.,stroke and traumatic brain injury)are the leading cause group of disability-adjusted life years and the second leading cause group of deaths.Different to other tissues,the adult brain retains only a very limited repair potential.Adult neurogenesis,the lifelong generation of new neurons,declines with age and in degenerative diseases,such as Alzheimer’s disease.Nevertheless,independently of age,the proliferation and migration of endogenous stem cells is stimulated after brain injuries and might be related to recovery processes(Adamczak et al.,2017).The limited number of endogenous stem cells during adulthood is one of the major limitations for an efficient regeneration of the injury affected brain regions.Therefore,the transplantation of neural stem or progenitor cells(NSCs/NPCs)is extensively studied in mouse models and applied in first clinical trials with the aim to replace dysfunctional or lost neural cells and thus to restore brain function.

单节段慢性颈髓病变病人局部颈髓^(18)F-FDG摄取的减低

目的本前瞻性研究的目的是应用FDG-PET评价慢性脊髓压迫症病人的颈髓葡萄糖代谢水平。

Non-cell-autonomous manner of AAV administration to attenuate cardiomyocyte hypertrophy by targeting paracrine signaling on ECM to reduce viral dosage

Dear Editor,Adeno-associated virus(AAV)is one of the most powerful vectors for exogenous gene delivery.1 However,the risks associated with the high dosages of AAV administration that are required to achieve meaningful effects limit the applicability of this method.Generally,AAV only presents cell autonomous manner in infected cells.Besides,mosaic genetic editing or gene therapy would trigger global biological function restore by above 30–40%infective ratio in heart diseases.

Hemispheric Specialization of the Primate Inferior Parietal Lobule

Hemispheric asymmetries can be seen as one of the evolutionary adaptations that allowed the human brain to muster more complex cognitive processes than other primates.In this vein,the study published by Cheng et al.[1]presents a pivotal investigation of both the regional and connectional asymmetries within the inferior parietal lobule(IPL)in human,chimpanzee,and macaque.By investigating 4 sub-divisions of the IPL across the three species,Cheng and colleagues showed that the macroanatomical and connectional architecture of the IPL became more asymmetric throughout the primate lineage.While macaques show little to no structural asymmetries,chimpanzees display a more asymmetric architecture but with both leftward and rightward asymmetries in various connections.In contrast,the human IPL displayed the highest number of asymmetries among the three species with a clear tendency towards more lateralization.This evolutionary trend towards a more lateralized organization of the IPL may have accompanied an improved command of tool-use,stronger forelimb asymmetries,and the increasing complexity of communicative behavior.