Clinical Perspective and Recent Development of PET Radioligands for Imaging Cerebral Nicotinic Acetylcholine Receptors

Abstract

IMAGING NICOTINIC ACETYLCHOLINE RECEPTORS WITH PET IN HUMAN SUBJECTSThere have been a number of attempts to study the nicotinic cholinergic system in the human brain and the only successful approaches have been for the α 4 β 2 subtype of the nicotinic acetylcholine receptor (nAChR), the main cerebral nAChR subtype. The first and perhaps the most straightforward approach was to study the active and less active isomers of [ 11 C]nicotine [(−)-enantiomers ( Fig. 1) and (+)-enantiomers, respectively]. 1 These were among the earliest PET tracers to be used in human beings because of the known toxicology of nicotine and their ease of radiolabeling. Several efforts have been made to quantify In subsequent years, fluorinated derivatives of A-85380 labeled in both the 2 and the 6 position of the pyridine ring have been considered as promising radiotracers for imaging α 4 β 2 -nAChRs (see Fig. 1 A number of attempts have been made to simplify the 2-[ 18 F]FA studies. For example, a simplified distribution volume determined by the ratio of the tissue to the metabolite corrected plasma and using a single 90-to 120-minute PET acquisition appeared to correlate reasonably well with graphical methods and two compartmental models in cortical regions. Lower correlations were found in regions with higher binding of nicotinic cholinergic receptors, such as the thalamus. This lower correlation in higher binding regions is not unexpected because the time to achieve steady-state conditions is even slower than in the lower binding regions. 13

PET Imaging of High-Affinity α4β2 Nicotinic Acetylcholine Receptors in Humans with 18F-AZAN, a Radioligand with Optimal Brain Kinetics

“…The kinetic drawbacks of existing nAChR radioligands (2-18 F-FA and 6-18 F-FA) prompted the development of radioligands with faster brain kinetics by our group and others (8)(9)(10)(11)(12)14,15,29). Studies in our labs on the radioligand structureimaging properties relationship (17,(30)(31)(32) led us to synthesize 18 F-AZAN, an a4b2-nAChR antagonist with rapid brain kinetics and high binding potential values in mice and baboons (17,18).…”

“…Available radioligands for the quantitative PET imaging of nAChR in humans, 2-18 F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-18 F-FA) (7) and 6-18 F-fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-18 F-FA), exhibit slow distribution kinetics in primates, requiring hours of scanning (3,(8)(9)(10)(11)(12)(13)(14)(15). Even the bolusplus-infusion approach, which allows a shorter scanning time, does not resolve the problem completely because of the long postinjection waiting period of more than 6 h (16).…”

PET Imaging of Nicotinic Acetylcholine Receptors in Baboons with 18F-AZAN, a Radioligand with Improved Brain Kinetics

“…Because of the relatively low density of a4b2-nAChR, the main nAChR subtype in the human brain, the development of a quality PET radioligand for a4b2-nAChRs with high specific binding and sufficiently rapid brain kinetics is a challenge (2,(5)(6)(7)(8)(9)24,25). More than 100 a4b2-nAChR PET radioligands have been developed.…”

“…The kinetic drawbacks of 2-18 F-FA and 6-18 F-FA have prompted the development of radioligands with faster brain kinetics by our group and others (6,8,9). The studies on the relationship between radioligand structure and imaging properties (11,12) led us to synthesize 18 F-AZAN ((2)-2-(6-18 F-fluoro-2,39-bipyridin-59-yl)-7-methyl-7-azabicyclo [2.2.1]heptane), an a4b2-nAChR antagonist with rapid brain kinetics and desirably high binding potential values (11).…”

“…The only currently available radioligands for quantitative PET nAChR in humans, 2-18 F-FA and the less commonly used 6-18 F-FA, exhibit slow distribution kinetics in both monkey and human brains and require many hours of PET scanning (2,(5)(6)(7)(8)(9). Even the bolus-plus-infusion approach (10), which allows shortening the scanning time, does not resolve the problem completely because of the long postinjection waiting period (which remains more than 6 h).…”