Collier T.L.,Harvard University |
Yokell D.L.,Harvard University |
Livni E.,Harvard University |
Rice P.A.,Massachusetts General Hospital |
And 8 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2017
Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [18F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FXFN. Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [18F]fluoride (K[18F]/K222) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170-250 mCi) of [18F]MK-6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [18F]fluoride) with a specific activity of 222 ± 67 GBq/μmol (6.0 ± 1.8 Ci/μmol) at the end of synthesis (90 minutes; n = 3). [18F]MK-6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use. © 2017 John Wiley & Sons, Ltd.
Evens N.,Laboratory for Radiopharmacy |
Vandeputte C.,IMIR K.U. Leuven |
Muccioli G.G.,Leuven Drug Research Institute |
Lambert D.M.,Leuven Drug Research Institute |
And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011
The type 2 cannabinoid receptor (CB2R) is part of the endocannabinoid system and is expressed in tissues related to the immune system. As the CB2R has a very low brain expression in non-pathological conditions, but is upregulated in activated microglia, it is an interesting target for visualization of neuroinflammation using positron emission tomography with a suitable radiolabeled CB2R ligand. In this study, we radiolabelled a fluoroethyl derivative of GW405833, a well known CB2R partial agonist, with fluorine-18 (half-life 109.8 min) by alkylation of the phenol precursor with 1-bromo-2-[18F]fluoroethane. In vitro studies showed that FE-GW405833 behaved as a selective high affinity (27 nM) inverse agonist for hCB2R. [18F]FE-GW405833 showed moderate initial brain uptake in mice and rats, but a slow washout from brain and plasma due to retention of a radiometabolite. Specific binding of the tracer to human CB2R was demonstrated in vivo in a rat model with local CB 2R overexpression in the brain. Optimized derivatives of GW405833 that are less susceptible to metabolism will need to be developed in order to provide a useful tracer for CB2R quantification with PET. © 2011 Elsevier Ltd. All rights reserved.
Ly H.G.,Translational Research Center for Gastrointestinal Disorders |
Ceccarini J.,University Hospitals Leuven |
Weltens N.,Translational Research Center for Gastrointestinal Disorders |
Bormans G.,Laboratory for Radiopharmacy |
And 4 more authors.
Psychotherapy and Psychosomatics | Year: 2015
Background: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). Methods: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [18F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months). Results: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months. Conclusions: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs. © 2015 S. Karger AG, Basel.
PubMed | Laboratory for Cognitive Neurology, Nuclear Medicine and Molecular Imaging and Laboratory for Radiopharmacy
Type: | Journal: Frontiers in pharmacology | Year: 2016
Clinical trials aiming to develop disease-altering drugs for Alzheimers disease (AD), a neurodegenerative disorder with devastating consequences, are failing at an alarming rate. Poorly defined inclusion-and outcome criteria, due to a limited amount of objective biomarkers, is one of the major concerns. Non-invasive molecular imaging techniques, positron emission tomography and single photon emission (computed) tomography (PET and SPE(C)T), allow visualization and quantification of a wide variety of (patho)physiological processes and allow early (differential) diagnosis in many disorders. PET and SPECT have the ability to provide biomarkers that permit spatial assessment of pathophysiological molecular changes and therefore objectively evaluate and follow up therapeutic response, especially in the brain. A number of specific PET/SPECT biomarkers used in support of emerging clinical therapies in AD are discussed in this review.
PubMed | Laboratory for Radiopharmacy
Type: Journal Article | Journal: Current pharmaceutical design | Year: 2014
Neuroinflammation is a well-orchestrated, dynamic, multicellular process playing a major role in neurodegenerative disorders. The microglia which make up the innate immune system of the central nervous system are key cellular mediators of neuroinflammatory processes. In normal condition they exert a protective function, providing tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. Upon neuronal injury or infection, they become overactivated, thereby releasing neurotoxic substances, amplifying neuroinflammation leading to neurodegeneration. Positron emission tomography (PET) provides a sensitive non-invasive imaging technique to study and quantify receptor and enzyme expression. A radiolabeled tracer for a protein (over)expressed in neuroinflammation and more specifically for the overactivated microglia would be useful as a diagnostic tool in the follow-up of neuroinflammation progression and to study the efficacy of anti-inflammatory therapy over time. In this manuscript, an overview of potential PET tracer targets upregulated during neuroinflammation is provided together with the current radiotracers used to image these targets. In addition, lead structures to develop radiotracers for new targets are suggested.
PubMed | Laboratory for Radiopharmacy
Type: Evaluation Studies | Journal: Bioorganic & medicinal chemistry | Year: 2011
The type 2 cannabinoid receptor (CBR) is part of the endocannabinoid system and is expressed in tissues related to the immune system. As the CBR has a very low brain expression in non-pathological conditions, but is upregulated in activated microglia, it is an interesting target for visualization of neuroinflammation using positron emission tomography with a suitable radiolabeled CBR ligand. In this study, we radiolabelled a fluoroethyl derivative of GW405833, a well known CBR partial agonist, with fluorine-18 (half-life 109.8 min) by alkylation of the phenol precursor with 1-bromo-2-[F]fluoroethane. In vitro studies showed that FE-GW405833 behaved as a selective high affinity (27 nM) inverse agonist for hCBR. [F]FE-GW405833 showed moderate initial brain uptake in mice and rats, but a slow washout from brain and plasma due to retention of a radiometabolite. Specific binding of the tracer to human CBR was demonstrated in vivo in a rat model with local CBR overexpression in the brain. Optimized derivatives of GW405833 that are less susceptible to metabolism will need to be developed in order to provide a useful tracer for CBR quantification with PET.