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 su...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.展开更多
Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD...Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.Methods:KLK levels in cerebrospinal fluid(CSF),as determined by ELISA,were compared between 32 AD patients stratified to A/T/(N)system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers.Associations between KLK levels and clinical severity,CSF and positron emission tomography(PET)based AD biomarkers were tested for.Results:Levels of KLK6 and KLK10 were significantly increased in AD.KLK6 differed significantly between AD A+/T+/N+and AD A+/T−/N+or NC with an AUC of 0.922.CSF pTau and tTau levels were significantly associated with KLK6 in AD.Conclusions:KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.展开更多
文摘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.
基金This work was supported by the German Research Foundation(DFG)and the Technical University of Munich(TUM)in the framework of the Open Access Publishing Program.
文摘Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.Methods:KLK levels in cerebrospinal fluid(CSF),as determined by ELISA,were compared between 32 AD patients stratified to A/T/(N)system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers.Associations between KLK levels and clinical severity,CSF and positron emission tomography(PET)based AD biomarkers were tested for.Results:Levels of KLK6 and KLK10 were significantly increased in AD.KLK6 differed significantly between AD A+/T+/N+and AD A+/T−/N+or NC with an AUC of 0.922.CSF pTau and tTau levels were significantly associated with KLK6 in AD.Conclusions:KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.
