Synthesis of carbon-11-, fluorine-18-, and iodine-125-labeled GABAA-gated chloride ion channel blockers: substituted 5-tert-butyl-2-phenyl-1,3-dithianes and -dithiane oxides.
A series of substituted 5-tert-butyl-2-phenyl-1,3-dithianes and 5-tert-butyl-2-phenyl-1,1,3,3-tetraoxo-1,3-dithianes was synthesized as ligands for the GABAA receptor complex-associated neuronal chloride ion channels. The in vitro binding affinities of these compounds for the GABA-gated chloride ion channel were determined by their ability to compete with [3H]TBOB for binding to rat brain slices. Of the eight compounds tested, trans-5-tert-butyl-2-(4-cyanophenyl)-2-methyl-1,1,3,3-tetraoxo+ ++-1,3-dithiane, 9b, trans-5-tert-butyl-2-(4-fluorophenyl)-1,1,3,3-tetraoxo-1,3-dithian e, 10, and trans-5-tert-butyl-2-(4-iodophenyl)-2-methyl-1,1,3,3-tetraoxo-1,3- dithiane, 11, showed moderately high binding affinities (Ki = 41, 180, and 105 nM, respectively). Four radioligand candidates from this series, 5-tert-butyl-2-(4-cyanophenyl)-2-[11C]methyl-1,3-dithiane, [11C]6, 5-tert-butyl-2-(4-[18F]fluorophenyl)-1,3-dithiane, [18F]7, 5-tert-butyl-2-(4-[18F]-fluorophenyl)-1,1,3,3-tetraoxo-1,3- dithiane, [18F]10, and 5-tert-butyl-2-(4-[125I]iodophenyl)-2-methyl-1,1,3,3- tetraoxo-1,3-dithiane, [125I]11, have been successfully prepared for evaluation as in vivo imaging agents useful for positron emission tomography and single photon emission computed tomography. Preliminary in vivo studies indicate significant uptake into mouse brain for [18F]7, [18F]10, and [125I]11.
Snyder
S E
SE
Division of Nuclear Medicine, University of Michigan Medical School, Ann Arbor, USA.
Kume
A
A
Jung
Y W
YW
Connor
S E
SE
Sherman
P S
PS
Albin
R L
RL
Wieland
D M
DM
Kilbourn
M R
MR
D000818:Animals; D001921:Brain / Q000187:drug effects; D002247:Carbon Isotopes; D018118:Chloride Channels / Q000037:antagonists & inhibitors*; D005260:Female; D005461:Fluorine; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D015640:Ion Channel Gating / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002247:Carbon Isotopes; D018118:Chloride Channels; D006571:Heterocyclic Compounds; D007457:Iodine Radioisotopes; D011963:Receptors, GABA-A; D013450:Sulfones; D005461:Fluorine