Positron emission tomographic studies of central cholinergic nerve terminals

Development of novel PET probe [11C](R,R)HAPT and its stereoisomer [11C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

“…In addition, the reversible‐type kinetic property of [ 11 C]( R , R )HAPT could be beneficial in terms of insensitivity to changes in the cerebral blood flow in the living brain (Farde et al, ; Logan et al, ). Taken together, these results demonstrate that the reversible‐type kinetic property of [ 11 C]( R , R )HAPT should be more appropriate and useful as a PET probe than previously reported [ 18 F]FMV (Widen et al, ), ( − )‐[ 18 F]FEOBV (Mulholland et al, ; Kilbourn et al, ), and (–)‐[ 11 C]OMV (Kawamura et al, ; Shiba et al, ) for quantitative VAChT analysis in the living brain using PET.…”

“…Preadministration of SA4503, a specific sigma‐1 receptor agonist ( K i = 50.2 and 4.4 nM for VAChT and sigma‐1 receptors, respectively) (Shiba et al, ), resulted in no significant changes in the PET images and kinetics of [ 11 C]( R , R )HAPT in the monkey brain, suggesting the potential of this PET probe for specific VAChT imaging in the living brain using PET. In addition, [ 11 C]( R , R )HAPT showed a pseudoequilibrium state of radioactivity within 30 min after the injection in all regions of monkey brain, in contrast to [ 18 F]FMV (Widen et al, ), ( − )‐[ 18 F]FEOBV (Kilbourn et al, ), and (–)‐[ 11 C]OMV (Kawamura et al, ; Shiba et al, ), all of which did not reach the equilibrium state within 90 min of injection. It has been suggested that quantitative measurement of in vivo binding to a target molecule using PET probes with a slow dissociation rate is difficult because they require a long equilibration time of several hours or more (Koeppe et al, ).…”

“…(+)‐ p ‐[ 18 F]Fluorobenzyl spirotrozamicol ((+)‐[ 18 F]spiro‐FBT) was reported to accumulate preferentially in the regions containing high to moderate densities of cholinergic terminals in rat brain; however, owing to rapid metabolism, no preferential accumulation of (+)‐[ 18 F]spiro‐FBT was observed in corresponding regions of monkey brain (Efange et al, ). (1 R ,2 R , 4S )−4‐([ 18 F]Fluoromethyl)−2‐(4‐phenylpiperidin‐1‐yl)cyclohexanol ([ 18 F]FMV) showed rapid and high brain uptake followed by a slow decrease, reaching a plateau 70 min after the injection in rat (Widen et al, ). Although preadministration of vesamicol prior to [ 18 F]FMV injection demonstrated a decrease in brain uptake, the retained radioactivity could not be displaced by postadministration of vesamicol, suggesting its irreversible binding of [ 18 F]FMV (Widen et al, ).…”

“…(1 R ,2 R , 4S )−4‐([ 18 F]Fluoromethyl)−2‐(4‐phenylpiperidin‐1‐yl)cyclohexanol ([ 18 F]FMV) showed rapid and high brain uptake followed by a slow decrease, reaching a plateau 70 min after the injection in rat (Widen et al, ). Although preadministration of vesamicol prior to [ 18 F]FMV injection demonstrated a decrease in brain uptake, the retained radioactivity could not be displaced by postadministration of vesamicol, suggesting its irreversible binding of [ 18 F]FMV (Widen et al, ). The authors concluded that the quantification of VAChT would be difficult due to the influence of the cerebral blood flow on the regional distribution pattern.…”

Positron emission tomography imaging of (2R,3R)-5-[18F]fluoroethoxybenzovesamicol in rat and monkey brain: a radioligand for the vesicular acetylcholine transporter

“…Successful imaging of the VAChT in the human brain, including losses in disease including Alzheimer’s, has been reported using a SPECT radioiodinated ligand 5-[ 123 I]iodobenzovesamicol ((-)-5-IBVM) [4,5,6,7]. For potential use in PET, radioligands labeled with the positron-emitting radionuclides carbon-11 and fluorine-18 were reported as early as 1990 [8,9] and there has been continued interest in further evaluation of both SPECTand PET radioligands for imaging of the VAChT binding site in the human brain [10,11]. …”