Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain.
Jonas MalmquistKatarina VarnäsMarie SvedbergFrédéric ValléeJeffrey S AlbertSjoerd J FinnemaMagnus SchouPublished in: ACS chemical neuroscience (2017)
Positron emission tomography (PET), together with a suitable radioligand, is one of the more prominent methods for measuring changes in synaptic neurotransmitter concentrations in vivo. The radioligand of choice for such measurements on the cholinergic system is the muscarinic receptor antagonist N-[1-11C]propyl-3-piperidyl benzilate (PPB). In an effort to overcome the shortcomings with the technically cumbersome synthesis of [11C]PPB, we designed and synthesized four structurally related analogues of PPB, of which (S,R)-1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate (1) was found to bind muscarinic receptors with similar affinity as PPB (3.5 vs 7.9 nM, respectively). (S,R)-1 was radiolabeled via N-11C-methylation at high radiochemical purity (>99%) and high specific radioactivity (>130 GBq/μmol). In vitro studies by autoradiography on human brain tissue and in vivo studies by PET in nonhuman primates demonstrated excellent signal-to-noise ratios and a kinetic profile in brain comparable to that of [11C]PBB. (S,R)-[11C]1 is a promising candidate for measuring changes in endogenous acetylcholine concentrations.
Keyphrases
- positron emission tomography
- computed tomography
- pet ct
- pet imaging
- white matter
- resting state
- small molecule
- case control
- air pollution
- cerebral ischemia
- photodynamic therapy
- dna methylation
- mass spectrometry
- genome wide
- gene expression
- multiple sclerosis
- blood brain barrier
- subarachnoid hemorrhage
- structure activity relationship