[18F]FPhEP and [18F]F2PhEP, two new epibatidine-based radioligands: evaluation for imaging nicotinic acetylcholine receptors in baboon brain.

The radioligand 2-[(18)F]fluoro-A-85380 has been developed for imaging alpha(4)beta(2) nAChRs with PET. However, it has slow kinetics and a large fraction of bound activity is nondisplaceable. In an attempt to address these problems, two epibatidine-based alpha(4)beta(2) nicotinic antagonists, coded FPhEP and F(2)PhEP, were evaluated in vivo in baboons. They were radiolabeled with fluorine-18 from the corresponding N-Boc-protected bromo-derivatives and the no-carrier-added K[(18)F]F-Kryptofix(222) complex. Radiochemically pure [(18)F]FPhEP or [(18)F]F(2)PhEP was obtained in 80 min in amounts of 1.11-2.22 GBq (111-185 GBq/micromol). After injection of 215 MBq of [(18)F]FPhEP or [(18)F]F(2)PhEP, dynamic PET data were acquired. Thalamic radioactivity peaked at 20 min (4.9% +/- 0.2% ID/100 mL tissue) for [(18)F]FPhEP. For [(18)F]F(2)PhEP, the peak was at 45 min (3.3% +/- 0.1% ID/100 mL tissue). Regional distribution of both radiotracers was in accordance with the known distribution of nAChRs. In presaturation experiments, nicotine, cytosine, or FPhEP reduced brain radioactivity of [(18)F]FPhEP. In a displacement experiment with nicotine only a small amount of [(18)F]F(2)PhEP was dislodged. In spite of a moderate to high in vitro affinity, both ligands do not fulfill the widely adopted criteria for a PET radioligand.