Synthesis and preclinical evaluation of fluorinated 5-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 and preclinical evaluation of fluorinated 5-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^*

^*Corresponding author for this work

Macquarie Medical School

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

2 Citations (Scopus)

Abstract

Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation 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 K_i = 96.5 nM)and [¹⁸F]9 (hCB2 K_i = 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 radiochemical purities (>97%) and molar activities (140-416 GBq/μmol). In PET imaging studies in rats, both [¹⁸F]2 and [¹⁸F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [¹⁸F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.

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 - 16 Aug 2023

Keywords

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

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10.1021/acschemneuro.3c00345

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title = "Synthesis and preclinical evaluation of fluorinated 5-azaindoles as CB2 PET radioligands",

abstract = "Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation 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 radiochemical purities (>97%) and molar activities (140-416 GBq/μmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.",

keywords = "aryl boronate, CB2 radioligand, Cu-mediatedfluorination, fluorine-18, LPS, 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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T1 - Synthesis and preclinical evaluation of fluorinated 5-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

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N2 - Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation 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 radiochemical purities (>97%) and molar activities (140-416 GBq/μmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.

AB - Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation 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 radiochemical purities (>97%) and molar activities (140-416 GBq/μmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833.Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.

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Synthesis and preclinical evaluation of fluorinated 5-azaindoles as CB2 PET radioligands

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