18F-ZW-104: A New Radioligand for Imaging Neuronal Nicotinic Acetylcholine Receptors-In Vitro Binding Properties and PET Studies in Baboons

An extensive series of radioligands has been developed for imaging central nicotinic acetylcholine receptors (nAChRs) with PET. Two halogeno-derivatives of A-85380 are being used in humans. Nevertheless, these derivatives still display too-slow brain kinetics and low signal-to-noise ratio. Methods: A novel nAChR radio-ligand, 5-(6-fluorohexyn-1-yl)-3-[2(S)-2-azetidinylmethoxy] pyridine (ZW-104), was characterized in vitro using competition binding assays (nAChR subtypes heterologously expressed in HEK 293 cells and in native alpha 4 beta 2 nAChRs from rat brain). F-18-ZW-104 was prepared as follows: no-carrier-added nucleophilic aliphatic radiofluorination of the corresponding N-Boc-protected tosyloxy derivative 5-(6-tosyloxyhexyn-1-yl)-3-[ 2(S)-(N-(tert-butoxycarbonyl))2-azetidinylmethoxy] pyridine) with the activated 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[ 8,8,8]hexacosane (K-F-18-F-Kryptofix 222 [K-222] complex), followed by quantitative trifluoroacetic acid-induced removal of the N-Boc protective group. F-18-ZW-104 was then studied in baboons using PET. Results: ZW-104 showed high binding affinities for rat alpha 4 beta 2 nAChRs (K-i, 0.2 nM) and other subtypes containing the beta 2 subunit but much lower affinities for rat alpha 3 beta 4 nAChRs (Ki, 5,500 nM) and other subtypes containing the beta 4 subunit. The regional radioactivity distribution in the baboon brain matched that of the alpha 4 beta 2 nAChR, which was similar to that of 2-F-18-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-18-A-85380), a radioligand used in humans. Comparison between F-18-ZW-104 and 2-F-18-A-85380 demonstrated better in vivo binding properties of the new radioligand: a substantially greater amount of radioactivity accumulated in the brain, and the occurrence of peak uptake in the thalamus was earlier than that of 2-F-18-A-85380 and was followed by washout. Distribution volume values in different brain regions were 2-fold higher for F-18-ZW-104 than for 2-F-18-A85380. Displacement by nicotine or unlabeled ZW-104 demonstrated a lower nonspecific binding than that of 2-F-A-85380. Conclusion: These results suggest that F-18-ZW-104 is a promising PET radioligand for studying nAChRs containing the beta 2 subunits in humans.