Correction: Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study
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Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study
Positron emission tomography (PET) is frequently used to obtain target occupancy (%TO) of central nervous system (CNS) drug candidates during clinical development. Obtaining %TO with PET can be particularly powerful when the %TO associated with efficacy is known for a protein target. Using the radiotracer [18F]AV-133, the relationship between plasma concentration (PK) and %TO of NBI-750142, an experimental inhibitor of the vesicular monoamine transporter type 2 (VMAT2) was obtained in both nonhuman primate (NHP) and human. This work established [18F]AV-133 PET as capable of providing a VMAT2 inhibitor PK-%TO relationship that translated from NHP to human. To establish the VMAT2%TO benchmark, PET was performed in NHP with NBI-98782, the main active metabolite of valbenazine, and this PK-%TO relationship was used to estimate VMAT2%TO at NBI-98782 exposures associated with valbenazine therapeutic effects in the treatment of tardive dyskinesia (TD). This work defined 85–90% as the VMAT2%TO achieved by exposures associated with daily dosing with 80 mg valbenazine, a dosing regimen known to exhibit a large effect size in the treatment of TD and in the treatment of chorea associated with Huntington’s Disease. NBI-750142 was estimated to achieve 36–78% VMAT2 target occupancy at acceptable doses, indicating potential inferiority in conferring clinical benefit compared to valbenazine. It is recommended that the %TO benchmark of valbenazine derived from [18F]AV-133 PET serve as a gold standard biomarker to evaluate novel VMAT2 inhibitors undergoing clinical development.
Synaptic vesicle characterization of iPSC-derived dopaminergic neurons provides insight into distinct secretory vesicle pools
The dysfunction of dopaminergic (DA) neurons is central to Parkinson’s disease. Distinct synaptic vesicle (SV) populations, differing in neurotransmitter content (dopamine vs. glutamate), may vary due to differences in trafficking and exocytosis. However, the structural organization of these vesicles remains unclear. In this study, we examined axonal varicosities in human iPSC-derived DA and glutamatergic neurons (i3Neurons). i3Neurons primarily contained small, clear SVs (40–50 nm), whereas DA neurons contained larger, pleiomorphic vesicles including dense core and empty vesicles, in addition to the classical SVs. VMAT2-positive vesicles in DA neurons, which load dopamine, were spatially segregated from VGLUT1/2-positive vesicles in an SV-like reconstitution system. These vesicles also colocalized with SV markers (e.g., VAMP2, SV2C), and can be clustered by synapsin. Moreover, DA axonal terminals in mouse striata showed similar vesicle pool diversity. These findings reveal structural differences in DA neurons’ vesicles, highlighting iPSC-derived neurons as effective models for studying presynaptic structures.
Clinical applications of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET)
The discovery of fibroblast activation protein inhibitor positron emission tomography (FAPI-PET) has paved the way for a new class of PET tracers that target the tumor microenvironment (TME) rather than the tumor itself. Although 18F-fluorodeoxyglucose (FDG) is the most common PET tracer used in clinical imaging of cancer, multiple studies have now shown that the family of FAP ligands commonly outperform FDG in detecting cancers, especially those known to have lower uptake on FDG-PET. Moreover, FAPI-PET will have applications in benign fibrotic or inflammatory conditions. Thus, even while new FAPI-PET tracers are in development and applications are yet to enter clinical guidelines, a significant body of literature has emerged on FAPI-PET, suggesting it will have important clinical roles. This article summarizes the current state of clinical FAPI-PET imaging as well as potential uses as a theranostic agent.
A positron emission tomography tracer for the imaging of oxidative stress in the central nervous system
Reactive oxygen and nitrogen species (RONS) contribute to the pathogenesis of neurodegeneration, but the inability to detect RONS in vivo in the central nervous system has confounded the interpretation of results of clinical trials of antioxidants. Here we report the synthesis and characterization of a positron emission tomography (PET) probe, [18F]fluoroedaravone ([18F]FEDV), for the in vivo quantification of oxidative stress. Derived from the antioxidant edaravone, the probe can diffuse through the blood–brain barrier and is stable in human plasma. In mice, PET imaging with [18F]FEDV allowed for the detection of RONS after intrastriatal injection of sodium nitroprusside, in the middle cerebral artery after stroke by photothrombosis, and in brains with tauopathy. When using dynamic PET imaging coupled with parametric mapping, the sensitivity of [18F]FEDV-PET to RONS allowed for the detection of increased oxidative stress. [18F]FEDV-PET could be used to quantify RONS longitudinally in vivo and to assess the results of clinical studies of antioxidants.
The role of [18F]FDG-PET/CT in Staphylococcus aureus bacteremia: A clinical perspective
Staphylococcus aureus bacteremia (SAB) is a severe infectious disease with a heterogenous clinical presentation. To diagnose possible metastatic infection and to start early adequate management including antimicrobial treatment and adequate source control as soon as possible, guidelines recommend additional imaging such as [18F]FDG-PET/CT. In this clinical perspective, we describe the current evidence of [18F]FDG-PET/CT in SAB and we share our view on the value of [18F]FDG-PET/CT in specific SAB patients.
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