Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging

Abstract

BackgroundThe previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171.Methods[1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171.ResultsAll ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171.ConclusionThe propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…In contrast, NK-1 receptor antagonists are intensively investigated for a variety of neuronal diseases including epilepsy. Consequently, non-peptide small molecule antagonists are available including CP-122,721 [176], GR205171 [177], and MK-869 [178] as shown in (Fig. 4).…”

Low‐Pressure Radical 11C‐Aminocarbonylation of Alkyl Iodides through Thermal Initiation

“…Positron Emission Tomography (PET) is a molecular imaging modality with diverse applications in biomedical research and clinical diagnostics such as the monitoring of disease progression In recent years, a growing number of 11 C‐labelled compounds derived from [ 11 C]CO have been prepared for preclinical imaging based on well‐established carbonylative transformations. For instance, [ 11 C]phenytoin has advanced to clinical studies as a P‐glycoprotein PET tracer .…”

“…Other structures that have been obtained directly from [ 11 C]CO by using palladium include aldehydes,, carboxylic acids,, , esters,, , , hydrazides, imides, ketones,, thioesters, and ureas . There are also a few examples of compounds obtained from multi‐step synthesis starting with 11 C‐carbonylation; these include 11 C‐labelled hydroxamic acid from esters, and alkyl iodides, from aldehydes/carboxylic acids through olefin carbonylation. However, palladium‐mediated carbonylation is restricted to organic halides lacking beta‐hydrogen atoms; methyl, aryl, benzyl, and alkenyl iodides are good examples of such species , .…”

“…In syntheses involving 11 C-labelled precursors, small reaction vessels are ideal for achieving high reagent concentrations and thereby sustaining fast reaction kinetics without the need for large amounts of reagents, which may increase cost and compromise purification processes. However, the low solubility of [ 11 C]CO in most solvents, [19] in combination with degassing and venting of the vessel headspace by poorly soluble transfer gases (e.g.…”

“…However, the low solubility of [ 11 C]CO in most solvents, [19] in combination with degassing and venting of the vessel headspace by poorly soluble transfer gases (e.g. helium) render efficient transfer of [ 11 C]CO to small volume reaction vessels difficult, thus hampering its use in limited to the preparation of 11 C-labelled compounds lacking beta-hydrogen atoms. The use of AIBN as a radical initiator and a low-pressure xenon-[ 11 C]CO delivery unit represents a simple and convenient alternative to previous radical 11 C-carbonylation methodologies burdened with the need for a proprietary high pressure reactor connected to a light source.…”