Development of a Novel [11C]CO-Labeled Positron Emission Tomography Radioligand [11C]BIO-1819578 for the Detection of O-GlcNAcase Enzyme Activity

Imaging O-GlcNAcase OGA by positron emission tomography (PET) could provide information on the pathophysiological pathway of neurodegenerative diseases and important information on drug-target engagement and be helpful in dose selection of therapeutic drugs. Our aim was to develop an efficient synthetic method for labeling BIO-1819578 with carbon-11 using 11CO for evaluation of its potential to measure levels of OGA enzyme in non-human primate (NHP) brain using PET. Radiolabeling was achieved in one-pot via a carbon-11 carbonylation reaction using [11C]CO. The detailed regional brain distribution of [11C]BIO-1819578 binding was evaluated using PET measurements in NHPs. Brain radioactivity was measured for 93 min using a high-resolution PET system, and radiometabolites were measured in monkey plasma using gradient radio HPLC. Radiolabeling of [11C]BIO-1819578 was successfully accomplished, and the product was found to be stable at 1 h after formulation. [11C]BIO-1819578 was characterized in the cynomolgus monkey brain where a high brain uptake was found (7 SUV at 4 min). A pronounced pretreatment effect was found, indicating specific binding to OGA enzyme. Radiolabeling of [11C]BIO-1819578 with [11C]CO was successfully accomplished. [11C]BIO-1819578 binds specifically to OGA enzyme. The results suggest that [11C]BIO-1819578 is a potential radioligand for imaging and for measuring target engagement of OGA in the human brain.

[1]  C. Halldin,et al.  Synthesis and biological evaluation of a novel radioligand [11C] BIO-1790735 for detection of O-GlcNAcase (OGA) enzyme activity , 2022, Nuclear Medicine and Biology.

[2]  M. Schou,et al.  One‐Pot Synthesis of 11C‐Labelled Primary Benzamides via Intermediate [11C]Aroyl Dimethylaminopyridinium Salts , 2021, Chemistry.

[3]  N. Vasdev,et al.  Radiosynthesis of a Bruton's Tyrosine Kinase Inhibitor, [11 C]Tolebrutinib, via Palladium-NiXantphos-Mediated Carbonylation. , 2020, Journal of labelled compounds & radiopharmaceuticals.

[4]  S. Zoghbi,et al.  PET ligands [18F]LSN3316612 and [11C]LSN3316612 quantify O-linked-β-N-acetyl-glucosamine hydrolase in the brain , 2020, Science Translational Medicine.

[5]  Mohammad B. Haskali,et al.  PET quantification of brain O-GlcNAcase with [18F]LSN3316612 in healthy human volunteers , 2020, EJNMMI Research.

[6]  C. Halldin,et al.  Sample preparation techniques for radiometabolite analysis of positron emission tomography radioligands; trends, progress, limitations and future prospects , 2019, TrAC Trends in Analytical Chemistry.

[7]  B. Permanne,et al.  PHASE 1 STUDY IN HEALTHY VOLUNTEERS OF THE O-GLCNACASE INHIBITOR ASN120290 AS A NOVEL THERAPY FOR PROGRESSIVE SUPRANUCLEAR PALSY AND RELATED TAUOPATHIES , 2018, Alzheimer's & Dementia.

[8]  L. McMahon,et al.  O-GlcNAcylation and neurodegeneration , 2017, Brain Research Bulletin.

[9]  G. Antoni,et al.  Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11 C-Acetylation of Peptides. , 2017, Angewandte Chemie.

[10]  David S. Miller,et al.  Tau: From research to clinical development , 2016, Alzheimer's & Dementia.

[11]  T. Arendt,et al.  Tau and tauopathies , 2016, Brain Research Bulletin.

[12]  Dawn M. Toolan,et al.  PHARMACOKINETICS AND PHARMACODYNAMICS TO SUPPORT CLINICAL STUDIES OF MK-8719: AN O-GLCNACASE INHIBITOR FOR PROGRESSIVE SUPRANUCLEAR PALSY , 2016, Alzheimer's & Dementia.

[13]  G. Antoni,et al.  Efficient 11C-carbonylation of isolated aryl palladium complexes for PET: application to challenging radiopharmaceutical synthesis. , 2015, Journal of the American Chemical Society.

[14]  D. Vocadlo,et al.  O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. , 2014, Chemical Society reviews.

[15]  L. McIntosh,et al.  O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers. , 2014, Journal of molecular biology.

[16]  L. Wells,et al.  Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology , 2014, Critical reviews in biochemistry and molecular biology.

[17]  C. Halldin,et al.  Palladium-Mediated [11C]Carbonylation at Atmospheric Pressure: A General Method Using Xantphos as Supporting Ligand , 2013 .

[18]  R. Erasmus,et al.  Exploring leukocyte O-GlcNAcylation as a novel diagnostic tool for the earlier detection of type 2 diabetes mellitus. , 2012, The Journal of clinical endocrinology and metabolism.

[19]  B. Gulyás,et al.  Synthesis of three novel fluorine-18 labeled analogues of L-deprenyl for positron emission tomography (PET) studies of monoamine oxidase B (MAO-B). , 2011, Journal of medicinal chemistry.

[20]  Division on Earth.  Guide for the Care and Use of Laboratory Animals: Eighth Edition -- Tamil Version , 2011 .

[21]  R. Webb,et al.  O-GlcNAcylation: a novel post-translational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension. , 2009, Journal of the American Society of Hypertension : JASH.

[22]  J. Hanover,et al.  O-GlcNAc cycling: implications for neurodegenerative disorders. , 2009, The international journal of biochemistry & cell biology.

[23]  Christer Halldin,et al.  Advancement in PET quantification using 3D-OP-OSEM point spread function reconstruction with the HRRT , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[24]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  G. Hart,et al.  Dynamic O-Glycosylation of Nuclear and Cytosolic Proteins , 2002, The Journal of Biological Chemistry.

[26]  B. Gulyás,et al.  PET studies with carbon-11 radioligands in neuropsychopharmacological drug development. , 2001, Current pharmaceutical design.

[27]  C. Halldin,et al.  Brain radioligands--state of the art and new trends. , 2001, The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology.

[28]  Andrew N. Rowan.  Guide for the Care and Use of Laboratory Animals , 1996 .

[29]  C. Carlson,et al.  Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. , 2012, Physiological genomics.

[30]  G. V. Van Hoesen,et al.  The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. , 1991, Cerebral cortex.