An attempt to visualize baboon brain nicotinic receptors with N-[11C]ABT-418 and N-[11C]methyl-cytisine

Nicotinic acetylcholine receptor imaging for dementia

“…Among the cortices, the uptakes in the occipital lobes were lower than those in other cortices. The DV values of Group A, Group T and Group C were 10 2 at the basal ganglia, respectively. In all regions, the mean values of DV are the lowest in Group A, the middle in Group T and the highest in Group C. The mean values of DV of Group A were significantly lower than those of Group C at the frontal, parietal, occipital cortices, thalamus and pons ( p b 0.05).…”

“…Therefore the development of suitable radioligand for in vivo imaging of nAChRs, which has 1) high and selective affinity to a4h2 receptors, 2) less non-specific binding, and 3) slow metabolism and slow wash-out from the brain. Initially, [ 11 C]cytisine, [ 11 C]ABT418 or N-[ 11 C]metylcytisine were investigated [10], however, their disadvantages, such as human toxicity, have been disclosed respectively, and have not been applied to human studies. Saji et al [11] has developed a radioligand for imaging neuronal nAChR with SPECT, 5-Iodo-3-(2(S)-azetidinylmethoxy) pyridine (5IA), an A-85380 analog iodinated at the 6-position of the pyridine ring.…”

Nicotinic receptors as targets for therapeutic discovery

“…The azetidine derivative compound ( 3) demonstrates specific binding in vivo , but decomposes rapidly. Cytisine and its N-methyl derivative compound (4) cross the blood -brain barrier more slowly than nicotine and show a homogeneous distribution in monkey brain [166] . A few synthesized [ 3 H]-, [ 18 F]-, [ 125 I]-and [ 11 C]-labeled analogs of epibatidine ( 5 ) are highly toxic and could not achieve a safety margin that is appropriate for radiopharmaceuticals [161] .…”

Nicotinic Acetylcholine Receptors and Imaging

“…Grünwald ABT-418 was characterized by rapid association and dissociation (T 1/2(ass) = 1.4 ± 0.3 min, T 1/2(diss) = 2.9 ± 0.4 min and T 1/2(ass) = 0.5 ± 0.22/12.7 ± 2.5 min, T 1/2(diss) = 1.49 ± 0.53/7.1 ± 1.5 min, respectively). As ABT-418 has high affinity for brain nAChRs and the safety index for ABT-418 is high reflecting low toxicity, N-[ 11 C]ABT-418 was synthesized and administered in baboon [37]. N-[ 11 C]ABT-418 was synthesized by methylation of its precursor A-79814 using [ 11 C]methyliodide.…”

“…In addition, the regional distribution of radioactivity in the brain following injection of N-[ 11 C]ABT-418 was not consistent with the distribution of nicotinic receptors as measured by autoradiography using different ligands ([ 3 H]ABT-418 or [ 3 H]cytisine). The lactam derivative A-87770 [37], the predominant metabolite of ABT-418, has very low affinity and should not cross the blood-brain barrier influencing the results of the imaging study. It is…”