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

¹ CEA, I2BM, Service Hospitalier Frédéric Joliot, LIME, Orsay, France; ² Department of Pharmacology, Georgetown University School of Medicine, Washington, DC; ³ Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; ⁴ School of Chemistry, University of Sydney, Sydney, New South Wales, Australia; ⁵ Discipline of Medical Radiation Sciences, University of Sydney, Sydney, New South Wales, Australia; and ⁶ Brain and Mind Research Institute, University of Sydney, Camperdown, New South Wales, Australia

Correspondence: For correspondence or reprints contact: Héric Valette, Service Hospitalier Frédéric Joliot, CEA, I2BM/LIME, F-91401 Orsay, France.E-mail: heric.valette{at}cea.fr

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 4β2 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 4β2 nAChRs (K_i, 0.2 nM) and other subtypes containing the β2 subunit but much lower affinities for rat 3β4 nAChRs (K_i, 5,500 nM) and other subtypes containing the β4 subunit. The regional radioactivity distribution in the baboon brain matched that of the 4β2 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.

Key Words: positron emission tomography • central nicotinic receptors • in vitro binding • β2 subunit

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