Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation

Abstract

Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase 10A (PDE10A) with IC 50 values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [ 11 C]papaverine and the in vitro and in vivo evaluation of [ 11 C]papaverine as a potential PET radiotracer for imaging PDE10A in the CNS. The radiosynthesis of papaverine with 11 C was achieved by O-methylation of the corresponding desmethyl precursor with [ 11 C]methyl iodide. [ 11 C]papaverine was obtained with ~70% radiochemical yield and a specific activity > 10 Ci/μmol (EOB). In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [ 11 C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [ 11 C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. microPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [ 11 C]papaverine from brain. Our initial evaluation suggests that despites papaverine's utility for in vitro studies and as a pharmaceutical tool, [ 11 C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.

The Use of PDE10A and PDE9 Inhibitors for Treating Schizophrenia

“…9). The first PET tracer was [ 11 C]-papaverine 9 [63]. Consistent with earlier reports, this radioligand exclusively labelled the striatum in ex vivo rat brain slices.…”

In Vivo Assessment and Dosimetry of 2 Novel PDE10A PET Radiotracers in Humans: 18F-MNI-659 and 18F-MNI-654

“…Potential ligands for PET imaging of PDE10A have been reported (19)(20)(21)(22)(23)(24). Papaverine, a widely used inhibitor of PDE10A activity, lacked suitable imaging characteristics when 11 C-labeled (22).…”

“…Papaverine, a widely used inhibitor of PDE10A activity, lacked suitable imaging characteristics when 11 C-labeled (22). 11 C-MP-10, another PDE10A inhibitor, was found to have good imaging qualities (19,24) despite a radiolabeled metabolite capable of penetrating the blood-brain barrier (24).…”

Quantification of 18F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

“…11 C-MP-10 has been evaluated in nonhuman primates (2,12), but although it showed good affinity and high selectivity for PDE10A, a lipophilic radiolabeled metabolite hampered further human application. The preclinical evaluation of 11 C-papaverine in rhesus macaques showed low retention (13). We previously evaluated 18 F-JNJ41510417 in PDE10A knockout and wild-type mice and in rodents (14).…”