Synthesis andPreclinical Evaluation of Fluorinated5-Azaindoles as CB2 PET Radioligands

Annukka Kallinen; Karine Mardon; Samuel Lane; Andrew P. Montgomery; Rajiv Bhalla; Damion H.R. Stimson; Muneer Ahamed; Gary J. Cowin; David Hibbs; Eryn L. Werry; Roger Fulton; Mark Connor; Michael Kassiou

doi:10.1021/acschemneuro.3c00345

Synthesis andPreclinical Evaluation of Fluorinated5-Azaindoles as CB2 PET Radioligands

Annukka Kallinen, Karine Mardon, Samuel Lane, Andrew P. Montgomery, Rajiv Bhalla, Damion H.R. Stimson, Muneer Ahamed, Gary J. Cowin, David Hibbs, Eryn L. Werry, Roger Fulton, Mark Connor, Michael Kassiou

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Severalclasses of cannabinoid receptor type 2 radioligandshavebeen evaluated for imaging of neuroinflammation, with successful clinicaltranslation yet to take place. Here we describe the synthesis of fluorinated5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM)and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorinationwith non-decay-corrected radiochemical yields of 15 ± 6% and18 ± 2% over 85 and 80 min, respectively, with high radiochemicalpurities (>97%) and molar activities (140-416 GBq/μmol).In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific bindingin CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptakeat later time points in a murine model of neuroinflammation comparedwith a healthy control group. The results suggest further evaluationof azaindole based CB2 radioligands is warranted in other neuroinflammationmodels.

Original language	English
Pages (from-to)	2902-2921
Number of pages	20
Journal	ACS Chemical Neuroscience
Volume	14
Issue number	16
DOIs	https://doi.org/10.1021/acschemneuro.3c00345
Publication status	Published or Issued - 16 Aug 2023
Externally published	Yes

Keywords

CB2 radioligand
Cu-mediatedfluorination
LPS
aryl boronate
fluorine-18
neuroinflammation

ASJC Scopus subject areas

Cognitive Neuroscience
Biochemistry
Physiology
Cell Biology

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10.1021/acschemneuro.3c00345

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title = "Synthesis andPreclinical Evaluation of Fluorinated5-Azaindoles as CB2 PET Radioligands",

abstract = "Severalclasses of cannabinoid receptor type 2 radioligandshavebeen evaluated for imaging of neuroinflammation, with successful clinicaltranslation yet to take place. Here we describe the synthesis of fluorinated5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM)and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorinationwith non-decay-corrected radiochemical yields of 15 ± 6% and18 ± 2% over 85 and 80 min, respectively, with high radiochemicalpurities (>97%) and molar activities (140-416 GBq/μmol).In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific bindingin CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptakeat later time points in a murine model of neuroinflammation comparedwith a healthy control group. The results suggest further evaluationof azaindole based CB2 radioligands is warranted in other neuroinflammationmodels.",

keywords = "CB2 radioligand, Cu-mediatedfluorination, LPS, aryl boronate, fluorine-18, neuroinflammation",

author = "Annukka Kallinen and Karine Mardon and Samuel Lane and Montgomery, {Andrew P.} and Rajiv Bhalla and Stimson, {Damion H.R.} and Muneer Ahamed and Cowin, {Gary J.} and David Hibbs and Werry, {Eryn L.} and Roger Fulton and Mark Connor and Michael Kassiou",

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doi = "10.1021/acschemneuro.3c00345",

language = "English",

volume = "14",

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T1 - Synthesis andPreclinical Evaluation of Fluorinated5-Azaindoles as CB2 PET Radioligands

AU - Kallinen, Annukka

AU - Mardon, Karine

AU - Lane, Samuel

AU - Montgomery, Andrew P.

AU - Bhalla, Rajiv

AU - Stimson, Damion H.R.

AU - Ahamed, Muneer

AU - Cowin, Gary J.

AU - Hibbs, David

AU - Werry, Eryn L.

AU - Fulton, Roger

AU - Connor, Mark

AU - Kassiou, Michael

PY - 2023/8/16

Y1 - 2023/8/16

N2 - Severalclasses of cannabinoid receptor type 2 radioligandshavebeen evaluated for imaging of neuroinflammation, with successful clinicaltranslation yet to take place. Here we describe the synthesis of fluorinated5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM)and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorinationwith non-decay-corrected radiochemical yields of 15 ± 6% and18 ± 2% over 85 and 80 min, respectively, with high radiochemicalpurities (>97%) and molar activities (140-416 GBq/μmol).In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific bindingin CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptakeat later time points in a murine model of neuroinflammation comparedwith a healthy control group. The results suggest further evaluationof azaindole based CB2 radioligands is warranted in other neuroinflammationmodels.

AB - Severalclasses of cannabinoid receptor type 2 radioligandshavebeen evaluated for imaging of neuroinflammation, with successful clinicaltranslation yet to take place. Here we describe the synthesis of fluorinated5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM)and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorinationwith non-decay-corrected radiochemical yields of 15 ± 6% and18 ± 2% over 85 and 80 min, respectively, with high radiochemicalpurities (>97%) and molar activities (140-416 GBq/μmol).In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific bindingin CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptakeat later time points in a murine model of neuroinflammation comparedwith a healthy control group. The results suggest further evaluationof azaindole based CB2 radioligands is warranted in other neuroinflammationmodels.

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KW - Cu-mediatedfluorination

KW - LPS

KW - aryl boronate

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Synthesis andPreclinical Evaluation of Fluorinated5-Azaindoles as CB2 PET Radioligands

Abstract

Keywords

ASJC Scopus subject areas

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