Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging.
BACKGROUND
The 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/mumol and 270 GBq/mumol, 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.


RESULTS
All 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.


CONCLUSIONS
The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).
Syvänen
Stina
S
Uppsala Imanet, GE Healthcare, Uppsala, Sweden. stina.syvanen@uppsala.imanet.se
Eriksson
Jonas
J
Genchel
Tove
T
Lindhe
Orjan
O
Antoni
Gunnar
G
Långström
Bengt
B
D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015195:Drug Design; D005240:Feasibility Studies; D006168:Guinea Pigs; D006847:Hydrocarbons, Iodinated / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D010865:Pilot Projects; D010880:Piperidines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013777:Tetrazoles / Q000493:pharmacokinetics; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D006847:Hydrocarbons, Iodinated; D010880:Piperidines; D019275:Radiopharmaceuticals; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; C103207:vofopitant; C509670:propyl iodide