Synthesis and brain distribution of carbon-11 labeled analogs of antagonists for the NMDA receptor coupled PCP-binding site

Abstract

Two phencyclidine (PCP) analogs, 3 and 4, and one thienylcyclohexyl‐piperidine (TCP) analog, (±)6, were labeled with positron emitter carbon‐11. These compounds displayed higher in vitro binding affinities than PCP itself for the PCP‐binding site located inside the ion channel on the N‐methyl‐D‐aspartate (NMDA) receptors. Brain distribution studies in mice showed different uptake characteristics between the PCP and TCP analogs, indicating their different in vivo interactions with the brain components including the PCP‐binding site probably due to the different physicochemical properties of the molecules. © 1998 John Wiley & Sons, Ltd.

trans-4-[4-(Methoxyphenyl)cyclohexyl]-1-arylpiperazines: A New Class of Potent and Selective 5-HT1A Receptor Ligands as Conformationally Constrained Analogues of 4-[3-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]-1- arylpiperazines

“…Partition Coefficient. The experimental partition coefficient of trans- 8a was measured with the shake-flask method as described in the literature . 1-Octanol saturated with water buffer and water buffer (50 mM sodium phosphate buffer, pH 7.4) saturated with 1-octanol were used.…”

Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting N-Methyl-d-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors

“…Two PCP derivatives [ 11 C] 1 (log P = 1.92) and [ 11 C] 2 (Figure , log P = 2.13) were labeled with carbon-11, and both tracers could readily enter the rat brain with the brain uptakes of 1.45% ([ 11 C] 1 ) and 1.38% ID/g ([ 11 C] 2 ) in cerebral cortex at 1 min postinjection (p.i. ), but unfortunately, the distribution was uniform in different brain regions, indicating nonspecific binding in the brain . The radiolabeling of TCP derivatives generated seven 18 F-labeled and one 11 C-labeled PET tracers .…”

“…), but unfortunately, the distribution was uniform in different brain regions, indicating nonspecific binding in the brain. 26 The radiolabeling of TCP derivatives generated seven 18 F-labeled and one 11 C-labeled PET tracers. 10 Among them, [ 18 combined measure describing the ultimate binding force of a receptor to its ligand, and values greater than 5−10 are usually observed for successful radiotracers; 10,27−29 B max denotes the density of available binding sites in a sample of tissue, and K d is for equilibrium dissociation constant of a radioligand) measured with [ 3 H]3 in different rat brain regions were <15.…”

PET and SPECT Imaging of the NMDA Receptor System: An Overview of Radiotracer Development

“…evere adverse effects, especially postoperative psychoses, precluded its clinical use. Two methoxy derivatives [ 11 C]2 and [ 11 C]3 were labelled with carbon-11 by O-[ 11 C]-methylation of the corresponding phenols with a specific radioactivity higher than 41 GBq/ mol [33]. [ 11 C]2 and [ 11 C]3 freely entered into the rat brain and showed similar regional cerebral distributions with a slightly higher uptake in the hippocampus and striatum than for the other regions studied.…”

“…[ 11 C]2 and [ 11 C]3 freely entered into the rat brain and showed similar regional cerebral distributions with a slightly higher uptake in the hippocampus and striatum than for the other regions studied. The NMDAR-rich regions (hippocampus, striatum, cerebral cortex) to cerebellum ratio for [ 11 C]2 and [ 11 C]3 did not exceed 1.2 and suggested high non specific interactions with other brain regions [33].…”