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Synthesis and precl...
Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
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- Eriksson, Jonas (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Roy, Tamal (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Sawadjoon, Supaporn (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Bachmann, Kim (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Sköld, Christian (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Larhed, Mats (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi
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- Weis, Jan, 1956- (author)
- Uppsala universitet,Radiologi
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- Selvaraju, Ramkumar (author)
- Uppsala universitet,Plattformen för Preklinisk PET-MRI
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- Korsgren, Olle (author)
- Uppsala universitet,Klinisk immunologi
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- Eriksson, Olof (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Odell, Luke R. (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- English.
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In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 71, s. 1-10
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Abstract
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- Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Eriksson, Jonas
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Roy, Tamal
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Sawadjoon, Supap ...
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Bachmann, Kim
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Sköld, Christian
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Larhed, Mats
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show more...
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Weis, Jan, 1956-
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Selvaraju, Ramku ...
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Korsgren, Olle
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Eriksson, Olof
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Odell, Luke R.
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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Nuclear Medicine ...
- By the university
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Uppsala University