The effects of lobeline on α4β2* nicotinic acetylcholine receptor binding and uptake of [(18)F]nifene in rats.
Lobeline is a potential smoking cessation drug with affinity for the α4β2 nicotinic acetylcholine receptor and may inhibit the blood-brain barrier (BBB) amine transporter. The goal of this work was to use PET imaging to evaluate the effects of lobeline on the kinetic properties of [(18)F]nifene in the rat brain.


METHODS
Direct α4β2* competition of lobeline with [(18)F]nifene was evaluated using imaging experiments with both displacing and blocking doses of lobeline (1mg/kg, i.v.) given between two injections of [(18)F]nifene separated by 50min. Inhibition of the BBB amine transporter was examined using a separate imaging protocol with three injections of [(18)F]nifene, first at baseline, then following (-)nicotine blocking, and finally following lobeline blocking.


RESULTS
Rapid displacement of [(18)F]nifene was observed in the α4β2*-rich thalamus following lobeline administration, suggesting direct competition of the drug at α4β2* sites. Slight decreases in BBB transport of [(18)F]nifene were observed when the α4β2* system was first saturated with (-)nicotine and then given lobeline. This perturbation may be due to inhibition of the BBB amine transporter by lobeline or reductions in blood flow. Significant cerebellar displacement of [(18)F]nifene was found following the administration of both lobeline and (-)nicotine, indicating detectable specific binding in the rat cerebellum.


CONCLUSIONS
The competition of lobeline with [(18)F]nifene is largely dominated at the α4β2* binding site and only small perturbations in BBB transport of [(18)F]nifene are seen at the 1mg/kg dose. Similar experiments could be used to study other drugs as therapeutic agents for smoking cessation with PET.
Department of Medical Physics, University of Wisconsin-Madison, 1111 Highland Avenue, Room 1005, Madison, WI 53705, United States. ahillmer@wisc.edu
Ansel T
AT
Hillmer
Dustin W
DW
Wooten
Mohammed
M
Farhoud
Todd E
TE
Barnhart
Jogeshwar
J
Mukherjee
Bradley T
BT
Christian
D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D008120:Lobeline / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
D018722:Nicotinic Agonists; D011725:Pyridines; D011758:Pyrroles; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C515562:nifene; D008120:Lobeline