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Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (A?) in Alzheimer's Disease.

ABSTRACT: Fluselenamyl (5), a novel planar benzoselenazole shows traits desirable of enabling noninvasive imaging of A? pathophysiology in vivo; labeling of both diffuse (an earlier manifestation of neuritic plaques) and fibrillar plaques in Alzheimer's disease (AD) brain sections, and remarkable specificity for mapping A? compared with biomarker proteins of other neurodegenerative diseases. Employing AD homogenates, [¹⁸F]-9, a PET tracer demonstrates superior (2-10 fold higher) binding affinity than approved FDA tracers, while also indicating binding to high affinity site on A? plaques. Pharmacokinetic studies indicate high initial influx of [¹⁸F]-9 in normal mice brains accompanied by rapid clearance in the absence of targeted plaques. Following incubation in human serum, [¹⁸F]-9 indicates presence of parental compound up to 3h thus indicating its stability. Furthermore, in vitro autoradiography studies of [¹⁸F]-9 with AD brain tissue sections and ex vivo autoradiography studies in transgenic mouse brain sections show cortical A? binding, and a fair correlation with A? immunostaining. Finally, multiphoton- and microPET/CT imaging indicate its ability to penetrate brain and label parenchymal plaques in transgenic mice. Following further validation of its performance in other AD rodent models and nonhuman primates, Fluselenamyl could offer a platform technology for monitoring earliest stages of A? pathophysiology in vivo.

SUBMITTER: Sundaram GS

PROVIDER: S-EPMC5090206 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer's Disease.

Sundaram G S M GS Dhavale Dhruva D DD Prior Julie L JL Yan Ping P Cirrito John J Rath Nigam P NP Laforest Richard R Cairns Nigel J NJ Lee Jin-Moo JM Kotzbauer Paul T PT Sharma Vijay V

Scientific reports 20161102

Fluselenamyl (5), a novel planar benzoselenazole shows traits desirable of enabling noninvasive imaging of Aβ pathophysiology in vivo; labeling of both diffuse (an earlier manifestation of neuritic plaques) and fibrillar plaques in Alzheimer's disease (AD) brain sections, and remarkable specificity for mapping Aβ compared with biomarker proteins of other neurodegenerative diseases. Employing AD homogenates, [<sup>18</sup>F]-9, a PET tracer demonstrates superior (2-10 fold higher) binding affinit ...[more]

PMID: 27805057

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Project description:BACKGROUND:We previously investigated low doses (105 or 225?mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-? by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200?mg every 4?weeks on amyloid-? plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD). METHODS:A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90?years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10?months) with a target gantenerumab dose of 1200?mg every 4?weeks. The main endpoint of this substudy was change in amyloid-? plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. RESULTS:Sixty-seven of the 89 patients initially enrolled had ??1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2?years at 225?mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-? plaque levels below the amyloid-? positivity threshold. CONCLUSION:Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200?mg resulted in robust amyloid-? plaque removal at 2?years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-? plaques in 51% of patients after 2?years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

Dataset Information

Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (A?) in Alzheimer's Disease.

Publications

Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer's Disease.

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