TY - JOUR
T1 - Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates
AU - Jin, Hongjun
AU - Zhang, Xiang
AU - Yue, Xuyi
AU - Liu, Hui
AU - Li, Junfeng
AU - Yang, Hao
AU - Flores, Hubert
AU - Su, Yi
AU - Parsons, Stanley M.
AU - Perlmutter, Joel S.
AU - Tu, Zhude
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (nos. NS075527 , NS061025 ), National Institute of Mental Health (no. MH092797 ) of the National Institutes of Health of U.S.A., and the U.S.A. Department of Energy (no. DES0012737 ). We would like to thank Emily Williams, Christina Zukas, Darryl Craig and John Hood for technical support. We thank Lynne Jones for her assistance in preparation of the manuscript.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Introduction: Deficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (-)-[11C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain. Methods: MicroPET brain imaging of (-)-[11C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (-)-vesamicol, or S-(-)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (-)-vesamicol. Results: Baseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (-)-[11C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (-)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (-)-[11C]TZ659. In contrast, pretreatment with the sigma-ligand (+)-pentazocine had no impact. Pretreatment with the S-(-)-eticlopride, a dopamine D2-like receptor antagonist, increased striatal uptake of (-)-[11C]TZ659. Striatal binding potential (BPND, range of 0.33-1.6 with cerebellar hemispheres as the reference region) showed good correlation (r2 = 0.97) between SRTM and LoganREF. Occupancy studies found that ~0.0057 mg/kg of (-)-vesamicol produced 50% VAChT occupancy in the striatum. Conclusion: (-)-[11C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain.
AB - Introduction: Deficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (-)-[11C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain. Methods: MicroPET brain imaging of (-)-[11C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (-)-vesamicol, or S-(-)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (-)-vesamicol. Results: Baseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (-)-[11C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (-)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (-)-[11C]TZ659. In contrast, pretreatment with the sigma-ligand (+)-pentazocine had no impact. Pretreatment with the S-(-)-eticlopride, a dopamine D2-like receptor antagonist, increased striatal uptake of (-)-[11C]TZ659. Striatal binding potential (BPND, range of 0.33-1.6 with cerebellar hemispheres as the reference region) showed good correlation (r2 = 0.97) between SRTM and LoganREF. Occupancy studies found that ~0.0057 mg/kg of (-)-vesamicol produced 50% VAChT occupancy in the striatum. Conclusion: (-)-[11C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain.
KW - (-)-[C]TZ659
KW - Binding potential
KW - Occupancy
KW - Tracer kinetics
KW - Vesicular acetylcholine transporter
UR - http://www.scopus.com/inward/record.url?scp=84958157913&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2015.11.003
DO - 10.1016/j.nucmedbio.2015.11.003
M3 - Article
C2 - 26872437
AN - SCOPUS:84958157913
SN - 0969-8051
VL - 43
SP - 131
EP - 139
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 2
ER -