Radiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand.
The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H(3) antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]1 in regions rich in H(3) receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [(11)C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [(11)C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.
Airaksinen
Anu J
AJ
Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Jablonowski
Jill A
JA
van der Mey
Margreet
M
Barbier
Ann J
AJ
Klok
Rob P
RP
Verbeek
Joost
J
Schuit
Robert
R
Herscheid
Jacobus D M
JD
Leysen
Josee E
JE
Carruthers
Nicholas I
NI
Lammertsma
Adriaan A
AA
Windhorst
Albert D
AD
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D014018:Tissue Distribution
C515396:4-(3-(4-piperidin-1-ylbut-1-ynyl)benzyl)morpholine; D002250:Carbon Radioisotopes; D006633:Histamine Antagonists; D008024:Ligands; D009025:Morpholines; D010880:Piperidines; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3