¹⁸F-Niofene: A novel PET/SPECT imaging agent for nicotinic receptors

Objectives Down-regulation of α4β2 nicotinic acetylcholine receptors (nAChRs) within the brain is indicative of various neurodegenerative diseases. We have developed Niofene (2-fluoro-5-iodo-3-[2-(S)-3-dehydropyrrolinylmethoxy]pyridine) as a potential PET/SPECT imaging agent for nAChRs with faster kinetics relative to 5-¹²³I-A85380 (5-IA) and 2-¹⁸F-A85380 (2-FA). We report the synthesis, radiolabeling, and in vivo evaluation of ¹⁸F-Niofene with an initial focus on PET applications.

Methods The Niofene precursor (SAK1) was produced under Mitsunobu conditions (Pandey et al., 2012). ³H-cytisine binding affinity studies in rat brain were carried out. ¹⁸F-labeling of SAK1 (2 mg) was carried out at 120°C for 30 mins (Kryptofix/K₂CO₃/DMSO 0.1 cc-CH₃CN 0.2 cc), purified by RP HPLC, and deprotected (Hillmer et al., 2012). PET studies in rats, injected iv 0.5 mCi, were carried out in Inveon PET for 2 hrs.

Results Subnanomolar affinity of Niofene results from its structural features resembling that of Nifene and Niodene (Pandey et al., 2012). Radiolabeling of ¹⁸F-Niofene was achieved in 10-15% radiochemical yield in high specific activities >2 Ci/μmol. In vivo PET in rats showed rapid uptake in the brain and selective localization in receptor regions (thalamus, TH). Using cerebellum (CB) as reference, pseudoequilibrium was achieved in 30-40 mins with TH/CB >2. Time to reach pseudoequilibrium for ¹⁸F-Niofene was similar to ¹⁸F-Nifene (30-40 mins) and shorter when compared to 5-IA and 2-FA (>4-6 hrs) while TH/CB ratio is similar to 5-IA.

Conclusions ¹⁸F-Niofene was synthesized in high radiochemical yields and showed rapid in vivo kinetics similar to ¹⁸F-Nifene. For SPECT, ¹²³I-Niofene is expected to have in vivo kinetic properties similar to ¹⁸F-Niofene and would be faster compared to current SPECT agent 5-IA. ¹⁸F-Niofene, an antagonist, has the potential to compliment our ongoing studies with ¹⁸F-Nifene, an agonist, for studies of α4β2 nAChRs in various animal models and human studies.

Research Support NIH AG029479 (JM)