18F-ZW-104: A new radioligand for imaging neuronal nicotinic acetylcholine receptors - In vitro binding properties and PET studies in baboons

Héric Valette, Yingxiang Xiao, Marie Anne Peyronneau, Annelaure Damont, Alan P. Kozikowski, Zhi Liang Wei, Michael Kassiou, Kenneth J. Kellar, Frédéric Dollé, Michel Bottlaender

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 radioligand, 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 α4β2 nAChRs from rat brain). 18F-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- 18F-F-Kryptofix 222 [K222] complex), followed by quantitative trifluoroacetic acid-induced removal of the N-Boc protective group. 18F-ZW-104 was then studied in baboons using PET. Results: ZW-104 showed high binding affinities for rat α4β2 nAChRs (Ki, 0.2 nM) and other subtypes containing the β2 subunit but much lower affinities for rat α3β4 nAChRs (Ki, 5,500 nM) and other subtypes containing the β4 subunit. The regional radioactivity distribution in the baboon brain matched that of the α4β2 nAChR, which was similar to that of 2-18F-fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-18F-A-85380), a radioligand used in humans. Comparison between 18F-ZW-104 and 2-18F-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 2-18F-A-85380 and was followed by washout. Distribution volume values in different brain regions were 2-fold higher for 18F-ZW-104 than for 2-18F-A-85380. Displacement by nicotine or unlabeled ZW-104 demonstrated a lower nonspecific binding than that of 2-F-A-85380. Conclusion: These results suggest that 18F-ZW- 104 is a promising PET radioligand for studying nAChRs containing the β2 subunits in humans.

Original languageEnglish (US)
Pages (from-to)1349-1355
Number of pages7
JournalJournal of Nuclear Medicine
Issue number8
StatePublished - Aug 1 2009
Externally publishedYes


  • Central nicotinic receptors
  • In vitro binding
  • Positron emission tomography
  • β2 subunit

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging


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