Synthesis and In-Vivo Evaluation of [11C]p-PVP-MEMA as a PET Radioligand for Imaging Nicotinic Receptors

Frédéric Dollé; Sandrine Langle; Gaëlle Roger; Roger R. Fulton; Béatrice Lagnel-de Bruin; David J. Henderson; Françoise Hinnen; Taliesha Paine; Mark J. Coster; Heric Valette; Michel Bottlaender; Michael Kassiou

doi:10.1071/CH08083

RESEARCH ARTICLE

Synthesis and In-Vivo Evaluation of [¹¹C]p-PVP-MEMA as a PET Radioligand for Imaging Nicotinic Receptors

Frédéric Dollé ^A , Sandrine Langle ^A , Gaëlle Roger ^A , Roger R. Fulton ^B , Béatrice Lagnel-de Bruin ^A , David J. Henderson ^B , Françoise Hinnen ^A , Taliesha Paine ^C , Mark J. Coster ^D , Heric Valette ^A , Michel Bottlaender ^A and Michael Kassiou ^C ^E ^F ^G

+ Author Affiliations

- Author Affiliations

^A CEA, Service Hospitalier Frédéric Joliot, Institut d’Imagerie Biomédicale, 4 Place du Général Leclerc, F-91401 Orsay, France.

^B Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.

^C School of Chemistry, University of Sydney, NSW 2006, Australia.

^D Eskitis Institute for Cell and Molecular Therapies, Griffith University, Don Young Rd, Nathan, Qld 4121, Australia.

^E Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia.

^F Brain and Mind Research Institute, 100 Mallett St, Camperdown, NSW 2050, Australia.

^G Corresponding author. Email: m.kassiou@usyd.edu.au

Australian Journal of Chemistry 61(6) 438-445 https://doi.org/10.1071/CH08083
Submitted: 27 February 2008 Accepted: 22 April 2008 Published: 19 June 2008

Abstract

Within the class of (4-pyridinyl)vinylpyridines developed by Abbott laboratories as potent neuronal nicotinic acetylcholine receptor ligands, p-PVP-MEMA ({(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-1-methylethyl}methylamine) is the lead compound of a novel series that do not display the traditional nicotinic-like pyrrole-ring but still possessing high subnanomolar affinity (K_i 0.077 nm—displacement of [³H](–)cytisine from whole rat brain synaptic membranes). In the present study, p-PVP-MEMA and its nor-derivative ({(R)-2-[6-chloro-5-((E)-2-pyridin-4-ylvinyl)pyridin-3-yloxy]-1-methylethyl}methylamine) as precursor for labelling with the short-lived positron-emitter carbon-11 (T_1/2 20.4 min) were synthesized in 10 chemical steps from 2-hydroxy-5-nitropyridine and Boc-d-alanine. N-Alkylation of nor-p-PVP-MEMA with [¹¹C]methyl iodide afforded [¹¹C]p-PVP-MEMA (>98% radiochemically pure, specific activity of 86.4 GBq μmol^–1) in 2% (non-decay corrected and non-optimized) radiochemical yield, in 34 min (including HPLC purification and formulation). Preliminary positron emission tomography (PET) results obtained in a Papio hamadryas baboon showed that [¹¹C]p-PVP-MEMA is not a suitable PET-radioligand.

Acknowledgements

The authors thank Dr Dirk Roeda for proofreading the manuscript. This work was supported by DEST and the French Embassy in Australia under the FAST program (FR040051).

References

Synthesis and In-Vivo Evaluation of [11C]p-PVP-MEMA as a PET Radioligand for Imaging Nicotinic Receptors

Abstract

Acknowledgements

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Synthesis and In-Vivo Evaluation of [¹¹C]p-PVP-MEMA as a PET Radioligand for Imaging Nicotinic Receptors