Preliminary in vivo and ex vivo evaluation of the 5-HT2A imaging probe [(18)F]MH.MZ.
BACKGROUND
The 5-HT(2A) receptor is one of the most interesting targets within the serotonergic system because it is involved in a number of important physiological processes and diseases.


METHODS
[(18)F]MH.MZ, a 5-HT(2A) antagonistic receptor ligand, is labeled by (18)F-fluoroalkylation of the corresponding desmethyl analogue MDL 105725 with 2-[(18)F]fluoroethyltosylate ([(18)F]FETos). In vitro binding experiments were performed to test selectivity toward a broad spectrum of neuroreceptors by radioligand binding assays. Moreover, first micro-positron emission tomography (microPET) experiments, ex vivo organ biodistribution, blood cell and protein binding and brain metabolism studies of [(18)F]MH.MZ were carried out in rats.


RESULTS
[(18)F]MH.MZ showed a K(i) of 3 nM toward the 5-HT(2A) receptor and no appreciable affinity for a variety of receptors and transporters. Ex vivo biodistribution as well as microPET showed highest brain uptake at approximately 5 min p.i. and steady state after approximately 30 min p.i. While [(18)F]MH.MZ undergoes extensive first-pass metabolism which significantly reduces its bioavailability, it is insignificantly metabolized within the brain. The binding potential in the rat frontal cortex is 1.45, whereas the cortex to cerebellum ratio was determined to be 2.7 after approximately 30 min.


CONCLUSIONS
Results from microPET measurements of [(18)F]MH.MZ are in no way inferior to data known for [(11)C]MDL 100907 at least in rats. [(18)F]MH.MZ appears to be a highly potent and selective serotonergic PET ligand in small animals.
Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, D-55128 Mainz, Germany. herthm@uni-mainz.de
Matthias M
MM
Herth
Markus
M
Piel
Fabian
F
Debus
Ulrich
U
Schmitt
Hartmut
H
Lüddens
Frank
F
Rösch
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000166:cytology / Q000378:metabolism; D005464:Fluorobenzenes / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D010880:Piperidines / Q000097:blood / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011851:Radioactivity; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000032:analysis / Q000378:metabolism*; D014018:Tissue Distribution
C528727:2-(18F)fluoro-ethoxy-3-methoxyphenyl)-1-(2-(4-fluoro-phenyl)ethyl-4-piperidine-methanol; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A