Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles.
Purpose: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first...
| Publicado en: | Molecular Imaging & Biology Vol. 22; no. 1; pp. 173 - 181 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Springer Nature
Feb2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=141727737&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 141727737 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 15361632 KJU jtl: Molecular Imaging & Biology issn: 15361632 maglogo: N pubinfo: dt: Feb2020 vid: 22 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 141727737 141727737 NLM31111397 141727737 10.1007/s11307-019-01367-w NLM31111397 141727737 ppf: 173 ppct: 8 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles. aug: au: Koole, Michel Lohith, Talakad G. Valentine, John L. Bennacef, Idriss Declercq, Ruben Reynders, Tom Riffel, Kerry Celen, Sofie Serdons, Kim Bormans, Guy Ferry-Martin, Sandrine Laroque, Philippe Walji, Abbas Hostetler, Eric D. Briscoe, Richard J. de Hoon, Jan Sur, Cyrille Van Laere, Koen Struyk, Arie affil: Division of Nuclear Medicine, Leuven University Hospitals and UZ Leuven, Leuven, Belgium sug: subj: Neurons Pathology Radiometry Methods Isoquinolines Pharmacokinetics Fluorine Radioisotopes Pharmacokinetics Alzheimer's Disease Pathology Diagnostic Imaging Methods Female Male Human Alzheimer's Disease Metabolism Rats Alzheimer's Disease Radiopharmaceuticals Pharmacokinetics Patient Safety Neurons Metabolism Animal Studies Research Subjects Validation Studies Comparative Studies Evaluation Research Multicenter Studies Female Male ab: Purpose: [18F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [18F]MK-6240 for its potential application in human brain imaging studies.Procedures: MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [18F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose).Results: MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [18F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands.Conclusions: Microdoses of [18F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [18F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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