Pharmacological evaluation of a Br-76 analog of epibatidine: a potent ligand for studying brain nicotinic acetylcholine receptors.
[(76)Br]-Norchlorobromoepibatidine ([(76)Br]BrPH) is a specific and high affinity radioligand for the nicotinic acetylcholine receptors (nAChRs). In vitro, on rat thalamus membranes [(76)Br]BrPH bound to two sites with apparent affinities of 8 pM and 3 nM. The density of binding sites were 1.9 and 70 fmol/mg protein, respectively. In vivo, in biodistribution and autoradiographic studies in rats the regional distribution of [(76)Br]BrPH paralleled the neuroanatomical localization of nAChRs. Two hours postinjection, the highest concentration in the brain was found in thalamus and colliculi (4% ID/g). Competition experiments with specific nicotinic, muscarinic, dopaminergic, and serotoninergic drugs confirmed that the in vivo binding of [(76)Br]BrPH was consistent with neuronal nicotinic receptors. PET imaging of [(76)Br]BrPH in baboon demonstrated a rapid and high uptake in the brain. Peak uptake occurred at 30-40 min for the thalamus. Due to the constant washout in the cerebellum, the thalamus to cerebellum ratio was 5 at 2 h postinjection. Subcutaneous injection of cytisine (1 mg/kg), 3 h postinjection of [(76)Br]BrPH reduced the radioactivity concentration in thalamus and cortex by 58 and 50%, respectively, as observed 1 h later. Cytisine pretreatment (5 mg/kg s.c.) inhibited completely the radioligand accumulation in the thalamus. Chronic MPTP pretreatment resulted in reduction of [(76)Br]BrPH uptake in all brain regions except in cerebellum. These preliminary results suggest that [(76)Br]BrPH has the potential to be a useful radioligand for studying the pharmacology of nicotinic acetylcholine receptors in preclinical experiments.
Department of PET and Nuclear Medicine, Royal Prince Alfred Hospital, Camperdown NSW 2050 Australia. mkassiou@med.usyd.edu.au
Michael
M
Kassiou
Michel
M
Bottlaender
Christian
C
Loc'h
Frederic
F
Dolle
John L
JL
Musachio
Christine
C
Coulon
Michele
M
Ottaviani
Robert F
RF
Dannals
Bernard
B
Maziere
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001392:Azocines; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D015259:Dopamine Agents / Q000494:pharmacology; D004611:Ellipticines / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000037:antagonists & inhibitors; D018722:Nicotinic Agonists / Q000378:metabolism / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D011807:Quinolizines; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors; D014055:Tomography, Emission-Computed; D000093843:Quinolizidine Alkaloids
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015259:Dopamine Agents; D004611:Ellipticines; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C049509:BR 76; C082748:epibatidine