Synthesis and Pharmacological Evaluation of [¹¹C]Granisetron and [¹⁸F]Fluoropalonosetron as PET Probes for 5-HT₃ Receptor Imaging

Abstract

Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril®) and palonosetron (Aloxi®), belong to a family of drugs (the 'setrons') that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15)

Positron Emission Tomography (PET) Imaging Tracers for Serotonin Receptors

“… , This radioligand showed rapid initial brain uptake in rats and baboons, however, with negligible specific binding to 5-HT 3 receptors, which may be caused by its high lipophilicity. In the following, several other antagonist PET ligands are reported, including [ 11 C]­L683877, [ 11 C]­Y-25130, [ 11 C]­YM060, [ 11 C]­KF17643, [ 11 C]­granisetron, , and [ 18 F]­fluoropalonosetron ([ 11 C] 120 – 124 and [ 18 F] 125 , respectively, Figure ). Except for [ 11 C] 120 , the brain kinetics of the other radioligands have been evaluated in mice or rats.…”

“…[ 11 C]Y-25130,390 [ 11 C]YM060,390 [ 11 C]-KF17643, 3 9 1 [ 1 1 C]granisetron, 3 9 2 , 3 9 3 and [1 8 F]fluoropalonosetron393 ([ 11 C]120−124 and [ 18 F]125, respectively, Figure19). Except for [ 11 C]120, the brain kinetics of the other radioligands have been evaluated in mice or rats.…”

Radiotracers for the Central Serotoninergic System

“…The second “setron” drug developed in 2016 was a fluorine analogue of the clinically used palonosetron which also contained the 3-aminoquinuclidinyl moiety. In vitro autoradiography showed specific labeling in rodent brain slices, but in vivo PET studies in rats with [ 18 F]Fluoropalonosetron gave low and homogeneous radiotracer signals [ 178 ]. This could be related to the low expression of 5-HT 3 R in the brain combined with the low lipophilicity of the radioligand and could explain why [ 18 F]Fluoropalonosetron is not suitable for in vivo PET imaging of 5-HT 3 receptors.…”

Mapping the Orthosteric Binding Site of the Human 5-HT3 Receptor Using Photo-cross-linking Antagonists

“…We have previously developed fluorescent − and PET 5-HT 3 receptor ligands derived from the high-affinity competitive antagonist granisetron (Kytril, Figure d) and used these probes to study these receptors in cells and live animals. Here we extend these studies of biophysical probes by synthesizing a series of photo-cross-linking probes that were created by appending various photoreactive moieties to three different positions of the granisetron core.…”