Biomarkers of Brain Structure and Function for Neurodegenerative Disorders: Are They Adequate for Go/No Go Decisions in Drug Development?

Wz, Potter

doi:10.1002/cpt.196

Cited by 3 publications

(2 citation statements)

References 8 publications

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“…Effective symptomatic and disease‐modifying pharmacotherapy is a public health priority and collaboration between the academic, government, and industrial interests is a necessity to achieve the goals. This issue devotes much space to the current state of understanding of the mechanistic basis of these diseases, clinical tools and trial designs in this field, as well a comprehensive review of promising targets for neurodegenerative diseases . Finally, as the discipline of clinical pharmacology spans the continuum of drug development through utilization, a pair of companion pieces are included on the role of pharmacovigilance science in characterizing progressive multifocal leukoencephalopathy (PML) associated with drugs for neurological conditions …”

Section: Neuroscience At the Tipping Pointmentioning

confidence: 99%

Pharmacotherapy for Neurodegenerative Diseases: Are We Approaching the Tipping Point?

Honig¹

2015

Clin Pharma and Therapeutics

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Neurodegenerative diseases continue to represent major unmet medical and public health needs and will increasingly strain the healthcare system as people live longer due to medical advances in other diseases. Hopefully the emergence of increased understanding of the biology of these conditions coupled with novel clinical pharmacology tools, clinical trial designs, and regulatory innovation will allow the emergence of highly effective symptomatic and disease modifying pharmacotherapies.

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Section: Neuroscience At the Tipping Pointmentioning

confidence: 99%

Pharmacotherapy for Neurodegenerative Diseases: Are We Approaching the Tipping Point?

Honig¹

2015

Clin Pharma and Therapeutics

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“…The observation suggests that the atypical antipsychotic profile of the drug is due, at least in part, to dopaminergic activity of the metabolite [4]. The role of imaging in drug development for neurodegeneration has been discussed [5] and a recent review, focused on the role of PET in the development of new drugs to treat heart failure [6], exemplifies the power of molecular imaging in this regard. The extensive biomedical advances made possible by radiopharmaceuticals and nuclear imaging are exemplified by over 150 books and review articles within the last three years.…”

Section: Introductionmentioning

confidence: 99%

Tactics for preclinical validation of receptor-binding radiotracers

Lever

Fan

Lever

2017

Nuclear Medicine and Biology

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Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was observed for both radioligands in vivo, [125I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [125I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ1 receptor radioligands lead to major differences in binding properties in vitro and in vivo.

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Stress-Related Blood Biomarkers

Szczepek

Mazurek

2017

Tinnitus and Stress

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Biomarkers of Brain Structure and Function for Neurodegenerative Disorders: Are They Adequate for Go/No Go Decisions in Drug Development?

Cited by 3 publications

References 8 publications

Pharmacotherapy for Neurodegenerative Diseases: Are We Approaching the Tipping Point?

Pharmacotherapy for Neurodegenerative Diseases: Are We Approaching the Tipping Point?

Tactics for preclinical validation of receptor-binding radiotracers

Stress-Related Blood Biomarkers

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