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Development and Evaluation of Deuterated [18F]JHU94620 Isotopologues for the Non-invasive Assessment of the Cannabinoid Type 2 Receptor in Brain
  • +8
  • Daniel Gündel,
  • Mudasir Maqbool,
  • Rodrigo Teodoro,
  • Friedrich Ludwig,
  • Anne Heerklotz,
  • Magali Toussaint,
  • Winnie Deuther-Conrad,
  • Guy Bormans,
  • Peter Brust,
  • Klaus Kopka,
  • Rareş Moldovan
Daniel Gündel
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung

Corresponding Author:[email protected]

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Mudasir Maqbool
National Institutes of Health
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Rodrigo Teodoro
Life Molecular Imaging GmbH
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Friedrich Ludwig
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Anne Heerklotz
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Magali Toussaint
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Winnie Deuther-Conrad
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Guy Bormans
KU Leuven
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Peter Brust
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Klaus Kopka
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Rareş Moldovan
Helmholtz-Zentrum Dresden-Rossendorf Institut für Radiopharmazeutische Krebsforschung
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Abstract

Background and Purpose: The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [18F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood-brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing d4 and -d8 deuterated isotopologues of [18F]JHU94620. Experimental Approach: [18F]JHU94620-d8 was further evaluated to characterize its binding properties, metabolic stability, formation of BBB-penetrant radiometabolites and biodistribution in mice and rats. Key Results: The deuterated [18F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with KD values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [18F]JHU94620-d8 in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats. Conclusion and Implications: These results support further investigations of [18F]JHU94620-d8 in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.