In vivo measurement of nicotinic acetylcholine receptors with [18F]norchloro-fluoro-homoepibatidine

Functional changes of nicotinic acetylcholine receptors (nAChR) are important during age-related neuronal degeneration. Recent studies demonstrate the applicability of the nAChR ligand 2-[(18)F]F-A-85380 for neuroimaging of patients with dementias. However, its binding kinetics demands a 7-h acquisition time limiting its practicality for clinical PET studies. Thus, the authors developed [(18)F]norchloro-fluoro-homoepibatidine ([(18)F]NCFHEB) for nAChR imaging. The kinetics of the two enantiomers of [(18)F]NCFHEB were compared with 2-[(18)F]F-A85380 in porcine brain to evaluate their potential for human neuroimaging. Twenty-four juvenile female pigs were studied with PET using [(18)F]NCFHEB. Nine animals received an additional i.v. injection (1 mg/kg) of the nAChR agonist A81418 before radiotracer administration followed by infusion (2 mg/kg/7h) thereafter. Several compartment models were applied for quantification. (-)- and (+)-[(18)F]NCFHEB showed a twofold to threefold higher brain uptake than 2-[(18)F]F-A-85380. All three radiotracers displayed spatially heterogeneous binding kinetics in regions with high, moderate, or low specific binding. The equilibrium of specific binding of (-)-[(18)F]NCFHEB was reached earlier than that of (+)-[(18)F]NCFHEB or 2-[(18)F]F-A85380. Continuous administration of the nAChR agonist A81418 inhibited the specific binding of (-)- and (+)-[(18)F]NCFHEB but not of 2-[(18)F]F-A85380. The peripheral metabolism of (+)-[(18)F]NCFHEB proceeded somewhat slower than that of the other radiotracers. Both enantiomers of [(18)F]NCFHEB are appropriate radiotracers for neuroimaging of nAChR in pigs. Their binding profile in vivo appears to be more selective than that of 2-[(18)F]F-A85380. (-)-[(18)F]NCFHEB offers a faster equilibrium of specific binding than 2-[(18)F]F-A85380.