TY - JOUR
T1 - In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter
AU - Padakanti, Prashanth K.
AU - Zhang, Xiang
AU - Jin, Hongjun
AU - Cui, Jinquan
AU - Wang, Ruike
AU - Li, Junfeng
AU - Flores, Hubert P.
AU - Parsons, Stanley M.
AU - Perlmutter, Joel S.
AU - Tu, Zhude
N1 - Funding Information:
Acknowledgments. This work was supported by NIH grants NS061025, NS075527, and MH092797. The authors thank John Hood, Christina Zukas, and Darryl Craig for their assistance with the nonhuman primate microPET studies.
Publisher Copyright:
© 2014, World Molecular Imaging Society.
PY - 2014/11/18
Y1 - 2014/11/18
N2 - Purpose: The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective 11C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.Procedures: For both (−)-[11C]2 and (−)-[11C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (−)-[11C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.Results: The resolved enantiomers (−)-2 and (−)-6 were very potent and selective for VAChT in vitro (Ki < 5 nM for VAChT with >35-fold selectivity for VAChT vs. σ receptors); both radioligands, (−)-[11C]2 and (−)-[11C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (−)-[11C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550 ± 0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (−)-[11C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (−)-[11C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (−)-[11C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.Conclusions: The radioligand (−)-[11C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.
AB - Purpose: The vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective 11C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.Procedures: For both (−)-[11C]2 and (−)-[11C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (−)-[11C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.Results: The resolved enantiomers (−)-2 and (−)-6 were very potent and selective for VAChT in vitro (Ki < 5 nM for VAChT with >35-fold selectivity for VAChT vs. σ receptors); both radioligands, (−)-[11C]2 and (−)-[11C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (−)-[11C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550 ± 0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (−)-[11C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (−)-[11C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (−)-[11C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.Conclusions: The radioligand (−)-[11C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects.
KW - Alzheimer’s disease
KW - PET imaging
KW - Radiotracer
KW - VAChT
KW - Vesamicol
UR - http://www.scopus.com/inward/record.url?scp=84911976960&partnerID=8YFLogxK
U2 - 10.1007/s11307-014-0749-9
DO - 10.1007/s11307-014-0749-9
M3 - Article
C2 - 24865402
AN - SCOPUS:84911976960
SN - 1536-1632
VL - 16
SP - 773
EP - 780
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
IS - 6
ER -