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Use of functional imaging across clinical phases in CNS drug development.

ABSTRACT: The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases across all clinical phases (I-IV) of drug development. The evolution of functional imaging and the promise it holds to contribute to drug development will require the development of standards (including good imaging practice), but, if well integrated into drug development, functional imaging can define markers of CNS penetration, drug dosing and target engagement (even for drugs that are not amenable to positron emission tomography imaging) in phase I; differentiate objective measures of efficacy and side effects and responders vs non-responders in phase II, evaluate differences between placebo and drug in phase III trials and provide insights into disease modification in phase IV trials.

SUBMITTER: Borsook D

PROVIDER: S-EPMC3731782 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Use of functional imaging across clinical phases in CNS drug development.

Borsook D D Becerra L L Fava M M

Translational psychiatry 20130716

The use of novel brain biomarkers using nuclear magnetic resonance imaging holds potential of making central nervous system (CNS) drug development more efficient. By evaluating changes in brain function in the disease state or drug effects on brain function, the technology opens up the possibility of obtaining objective data on drug effects in the living awake brain. By providing objective data, imaging may improve the probability of success of identifying useful drugs to treat CNS diseases acro ...[more]

PMID: 23860483

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Project description:PurposeA limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for in-human imaging.MethodsWe provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties.Results and conclusionsOur review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18F-MK-6240 for tau imaging, 11C-UCB-J for imaging SV2A, 11C-CURB and 11C-MK-3168 for characterisation of fatty acid amide hydrolase, 18F-FIMX for metabotropic glutamate receptor 1, and 18F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete pre-clinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

Project description:BackgroundRecent studies have reported that pulmo-neurotropic viruses can cause systemic invasion leading to acute respiratory failure and neuroinfection. The tetracycline class of secondary metabolites of microorganisms is effective against several migrating neurotropic viral disorders, as Japanese-Encephalitis (JE), Severe-Acute-Respiratory-Syndrome Coronavirus-2 (SARS-COV2), Human-Immunodeficiency-Virus (HIV), and Simian-Immunodeficiency-Virus (SIV). Another microbial secondary metabolite, cephalosporin, can be used for anti-viral combination therapy. However, a substantial public health debacle is viral resistance to such antibiotics, and, thus, one needs to explore the antiviral efficiency of other secondary metabolites, as phytochemicals. Hence, here, we investigate phytochemicals like podophyllotoxin, chlorogenic acid, naringenin, and quercetin for therapeutic efficiency in neurotropic viral infections.MethodsTo investigate the possibility of the afferent neural pathway of migrating virus in man, MRI scanning was performed on human subjects, whereby the connections between cranial nerves and the brain-stem/limbic-region were assessed by fiber-tractography. Moreover, human clinical-trial assessment (n = 140, p = 0.028) was done for formulating a quantitative model of antiviral pharmacological intervention. Furthermore, docking studies were performed to identify the binding affinity of phytochemicals toward antiviral targets as (i) host receptor [Angiotensin-converting Enzyme-2], (ii) main protease of SARS-COV2 virus (iii) NS3-Helicase/Nucleoside triphosphatase of Japanese-encephalitis-virus, and the affinities were compared to standard tetracycline and cephalosporin antibiotics. Then, network pharmacology analysis was utilized to identify the possible mechanism of action of those phytochemicals.ResultsHuman MRI-tractography analysis showed fiber connectivity, as: (a) Path-1: From the olfactory nerve to the limbic region (2) Path-2: From the peripheral glossopharyngeal nerve and vagus nerves to the midbrain-respiratory-center. Docking studies revealed comparable binding affinity of phytochemicals, tetracycline, and cephalosporin antibiotics toward both (a) virus receptors, (b) host cell receptors where virus-receptor binds. The phytochemicals effectively countered the cytokine storm-induced neuroinflammation, a critical pathogenic pathway. We also found that a systems-biology-based double-hit mathematical bi-exponential model accounts for patient survival-curve under antiviral treatment, thus furnishing a quantitative-clinical framework of secondary metabolite action on virus and host cells.ConclusionDue to the current viral resistance to antibiotics, we identified novel phytochemicals that can have clinical therapeutic application to neurotropic virus infection. Based on human MRI scanning and clinical-trial analysis, we demarcated the anatomical pathway and systems-biology-based quantitative formulation of the mechanism of antiviral action.

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Use of functional imaging across clinical phases in CNS drug development.

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Use of functional imaging across clinical phases in CNS drug development.

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