A novel radioligand, 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2- fluoropyridin-4-yl)pyridine (NIDA522131), for imaging extrathalamic nicotinic acetylcholine receptors (nAChRs) was characterized in vitro and in vivo using positron emission tomography. The Kd and T1/2 of dissociation of NIDA522131 binding measured at 37°C in vitro were 4.9 ± 0.4 pmol/L and 81 ± 5 min, respectively. The patterns of radioactivity distribution in monkey brain in vivo was similar to that of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2FA), a radioligand that has been successfully used in humans, and matched the α 4β2* nAChRs distribution. Comparison between [18F]NIDA522131 and 2FA demonstrated better in vivo binding properties of the new radioligand and substantially greater radioactivity accumulation in brain. Consistent with [18F]NIDA522131 elevated affinity for nAChRs and its increased lipophilicity, both, the total and non-displaceable distribution volumes were substantially higher than those of 2FA. Estimated binding potential values in different brain regions, characterizing the specificity of receptor binding, were 3-4 fold higher for [18F]NIDA522131 than those of 2FA. Pharmacological evaluation in mice demonstrated a toxicity that was comparable to 2FA and is in agreement with a 2300 fold higher affinity at α4β2* versus α3β4* nAChRs. These results suggest that [18F]NIDA522131 is a promising positron emission tomography radioligand for studying extrathalamic nAChR in humans.
- Nicotinic acetylcholine receptors
- Positron emission tomography
- Receptor binding
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience