Synthesis and in-vivo evaluation of C-11 p-PVP-MEMA as a PET radioligand for imaging nicotinic receptors

Within the class of (4-pyridinyl)vinyl-pyridines developed by Abbott laboratories as potent neuronal nicotinic acetylcholine receptor ligands, p-PVP-MEMA ({oro-5-((E)-2-pyridin-4-yl-vinyl) pyridin-3-yloxy]-1-methylethyl} is the lead compound of a novel series that do not display the traditional nicotinic-like pyrrole-ring but still possessing high sub-nanomolar affinity (K-i 0.077 nm-displacement of [H-3](-)cytisine from whole rat brain synaptic membranes). In the present study, p-PVP-MEMA and its nor-derivative ({oro-5-((E)-2-pyridin-4- yl-vinyl) pyridin-3-yloxy]-1-methylethyl} as precursor for labelling with the short-lived positron-emitter carbon-11 (T1/2 = 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 [C-11] methyl iodide afforded [C-11]p-PVP-MEMA (≥ 98% radiochemically pure, specific activity of 86.4 GBq μ mol-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 [C-11] p-PVP-MEMA is not a suitable PET-radioligand. (authors)