Synthesis of a [2-Pyridinyl-18F]-labelled fluoro derivative of (−)-Cytisine as a candidate radioligand for brain nicotinic α4β2 receptor imaging with PET

In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the α4β2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (−)-cytisine (1), namely (−)-9-(2-fluoropyridinyl)cytisine (3, Ki values of 24 and 3462 nM for the α4β2 and α7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (−)-cytisine and labelled with fluorine-18 (T1/2: 119.8 min) using an efficient two-step radiochemical process [(a) nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b) TFA removal of the Boc protective group]. Typically, 20–45 mCi (0.74–1.67 GBq) of (−)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3, 2–3 Ci/μmol or 74–111 GBq/μmol) were easily obtained in 70–75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [18F]fluoride production batch (20–45% non decay-corrected yield based on the starting [18F]fluoride). The in vivo pharmacological profile of (−)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive β-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (−)-[3H]cytisine. Moreover, competition studies with (−)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (−)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) does not have the required properties for imaging nAChRs using PET. [Copyright &y& Elsevier]