Measurement of alpha4beta2 nicotinic acetylcholine receptors with [123I]5-I-A-85380 SPECT.
Nicotinic acetylcholine receptors (nAChRs) play an important role in tobacco dependence and a potential therapeutic role in neuropsychiatric disorders such as Alzheimer's disease. [123I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a new SPECT tracer that labels alpha4beta2 nAChRs. The purpose of this study was to assess the usefulness of this tracer to measure regional nAChR binding in baboon brain using both a bolus/kinetic paradigm and also a bolus plus constant infusion/equilibrium paradigm.


METHODS
A pair of bolus/kinetic and bolus plus constant infusion/equilibrium studies was performed in each of 3 isoflurane-anesthetized baboons. Bolus studies were performed by intravenous injection of 191-226 MBq [123I]5-I-A-85380 and image acquisition for 289-367 min. The data were analyzed with 1- and 2-tissue compartment models. Bolus plus constant infusion/equilibrium studies were performed by a bolus injection (74-132 MBq) followed by a 468- to 495-min infusion with a bolus/infusion ratio (B/I) of 4.8-5.0 h. The distribution volumes in the thalamus were measured in these 2 paradigms. To study whether the cerebellum was appropriate as a receptor-poor region, displacement studies were done in 2 baboons using the B/I paradigm with subcutaneous injection of (-)-cytisine (0.8 and 1.0 mg/kg).


RESULTS
The kinetics of this tracer was best described by the 1-tissue compartment model. The 2-compartment model showed poor identifiability of rate constants. The total (specific plus nondisplaceable compartments) distribution volumes (V(T)') agreed between bolus and B/I paradigms (average percentage difference in V(T)', 16.8%). (-)-Cytisine (0.8 and 1.0 mg/kg) displaced 70% and 72% of the radioactivity in the thalamus and 36% and 55% in the cerebellum, respectively, indicating that the latter was not appropriate as a receptor-poor region.


CONCLUSIONS
These results show the feasibility of quantifying alpha4beta2 nAChRs using [123I]5-I-A-85380 and support the use of V(T)' as an appropriate outcome measure.
Fujita
M
M
Department of Psychiatry, Yale University School of Medicine and VA Connecticut, West Haven 06516, USA.
Tamagnan
G
G
Zoghbi
S S
SS
Al-Tikriti
M S
MS
Baldwin
R M
RM
Seibyl
J P
JP
Innis
R B
RB
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001392:Azocines; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007700:Kinetics; D016018:Least-Squares Analysis; D008279:Magnetic Resonance Imaging; D010215:Papio; D011807:Quinolizines; D011978:Receptors, Nicotinic / Q000032:analysis / Q000378:metabolism*; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001384:Azetidines; D001392:Azocines; D007457:Iodine Radioisotopes; D011807:Quinolizines; D011978:Receptors, Nicotinic; C104288:A 85380; C403531:nicotinic receptor alpha4beta2; C004712:cytisine; D000093843:Quinolizidine Alkaloids