Development of 5-HT1A receptor radioligands to determine receptor density and changes in endogenous 5-HT.
[(18)F]FCWAY and [(18)F]FPWAY, analogues of the high affinity 5-HT(1A) receptor (5-HT(1A)R) antagonist WAY100635, were evaluated in rodents as potential radiopharmaceuticals for determining 5-HT(1A)R density and changes in receptor occupancy due to changes in endogenous serotonin (5-HT) levels. The in vivo hippocampus specific binding ratio [(hippocampus(uptake)/cerebellum(uptake))-1] of [(18)F]FPWAY was decreased to 32% of the ratio of [(18)F]FCWAY, indicating that [(18)F]FPWAY has lower affinity than [(18)F]FCWAY. The 5-HT(1A)R selectivity of [(18)F]FPWAY was confirmed using ex vivo autoradiography studies with 5-HT(1A)R knockout, heterozygous, and wildtype mice.Pre- or post-treatment of awake rodents in tissue dissection studies with paroxetine had no effect on hippocampal binding of [(18)F]FCWAY or [(18)F]FPWAY compared to controls, indicating neither tracer was sensitive to changes in endogenous 5-HT. In mouse ex vivo autoradiography studies in which awake mice were treated with fenfluramine following the [(18)F]FPWAY, a significant decrease was not observed in the hippocampus specific binding ratios. In rat dissection studies with fenfluramine administered following [(18)F]FPWAY or [(18)F]FBWAY ([(18)F]-MPPF) in awake or urethane-anesthetized rats, no significant differences in the specific binding ratios of the hippocampus were observed compared to their respective controls. [(18)F]FPWAY and [(18)F]FBWAY uptakes in all brain regions were increased variably in the anesthetized group (with the greatest increase in the hippocampus) vs. the awake group, but were decreased in the fenfluramine-treated anesthetized group vs. the anesthetized group. These data are best explained by changes in blood flow caused by urethane and fenfluramine, which varies from region to region in the brain.
Jagoda
Elaine M
EM
Positron Emission Tomography PET Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. ejagoda@mail.nih.gov
Lang
Lixin
L
Tokugawa
Joji
J
Simmons
Ashlie
A
Ma
Ying
Y
Contoreggi
Carlo
C
Kiesewetter
Dale
D
Eckelman
William C
WC
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D003510:Cyclohexanes / Q000493:pharmacokinetics; D004347:Drug Interactions; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000032:analysis* / Q000737:chemistry* / Q000172:deficiency; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
D003510:Cyclohexanes; D005462:Fluorine Radioisotopes; D008024:Ligands; C493883:N-(2-(4-(2-methoxyphenyl)piperazino))-N-(2-pyridinyl) trans-4-fluorocyclohexanecarboxamide; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide