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

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 (Ki 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 (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 [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.

A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research

“…Additionally, similar radiotracers have been labeled with 11 C, such as [ 11 C]p-PVP-MEMA ([ 11 C]54; RCP > 98%, RCY = 2% (non-decay-corrected and non-optimized), A m = 86.4 GBq/ μmol, K i = 77 pM). 277,278 Among all of these, [ 18 F]51 has shown the most utility to date for human studies, 273,279,280 with better imaging properties than [ 11 C]46. Furthermore, [ 18 F]NS10743 ([ 18 F]55; RCY = 32.2 ± 7%, RCP ≥ 99%, A m = 571 ± 17 GBq/μmol, K i > 10 μM) 281,282 has also been reported with high affinity for α4β2 nACh receptors.…”

“…amine with [ 11 C]CH 3 OTf. 277 [ 18 F]55 was synthesized through 18 F displacement of a nitro group from 2-((1s,5s)-1,4diazabicyclo[3.2.2]nonan-4-yl)-5-(4-nitrophenyl)-1,3,4-oxadiazole. 281 The mammalian nACh receptor is composed of five subunits, selected from α (α2−α7, α9, α10) and β (β2−β4) peptides, which allows for a vast number of combinations.…”

Development of radioligands with optimized imaging properties for quantification of nicotinic acetylcholine receptors by positron emission tomography

“…Among the most interesting recent radioligands with rapid brain kinetics are (±)-[ 11 C]NMI-EPI (Ding et al 2006), [ 18 F]nifene (Pichika et al 2006; Easwaramoorthy et al 2007), [ 11 C] p -PVP-MEMA (Dolle et al 2008), [ 18 F]FPhEP and [ 18 F]F2PhEP(Roger et al 2006; Valette et al 2007), [ 18 F](−)NCFHEB (Deuther-Conrad et al 2004; Brust et al 2008; Deuther-Conrad et al 2008) and two JHU series (Gao et al 2007a; Gao et al 2007b; Gao et al 2007c; Gao et al 2008b). These will be discussed below.…”

“…( R,E )-1-(6-chloro-5-(2-(pyridin-4-yl)vinyl)pyridin-3-yloxy)-N-methylpropan-2-amine (Figure 5), a nAChR ligand with K i = 77 pM (Lin et al 2002), was chosen for radiolabeling with 11 C (Dolle et al 2008) because of the structural similarity of this compound to the previously developed [ 11 C]Me-PVC (Brown et al 2002), a high affinity nAChR radioligand (K i = 28 pM) with rapid brain kinetics in the monkey brain (Brown et al 2004). ( R,E )-1-(6-chloro-5-(2-(pyridin-4-yl)vinyl)pyridin-3-yloxy)-N-[ 11 C]methylpropan-2-amine ([ 11 C] p -PVP-MEMA) was prepared by radiomethylation of the corresponding desmethyl precursor (Dolle et al 2008).…”

“…( R,E )-1-(6-chloro-5-(2-(pyridin-4-yl)vinyl)pyridin-3-yloxy)-N-[ 11 C]methylpropan-2-amine ([ 11 C] p -PVP-MEMA) was prepared by radiomethylation of the corresponding desmethyl precursor (Dolle et al 2008). Dynamic PET studies in baboon showed that [ 11 C] p -PVP-MEMA entered the brain with maximal uptake value of 0.4–0.6 %ID/100 mL at 2 min after injection.…”