Assessment of [(125)I]WYE-230949 as a Novel Histamine H(3) Receptor Radiopharmaceutical

Histamine H(3) receptor therapeutics have been proposed for several diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease and obesity. We set out to evaluate the novel compound, [(125)I]WYE-230949, as a potential radionuclide imaging agent for the histamine H(3) receptor in brain. [(125)I]WYE-230949 had a high in vitro affinity for the rat histamine H(3) receptor (K(d) of 6.9 nM). The regional distribution of [(125)I]WYE-230949 binding sites in rat brain, demonstrated by in vitro autoradiography, was consistent with the known distribution of the histamine H(3) receptor. Rat brain uptake of intravenously injected [(125)I]WYE-230949 was low (0.11 %ID/g) and the ratio of specific: non-specific binding was less than 1.4, as determined by ex vivo autoradiography. In plasma, metabolism of [(125)I]WYE-230949 into a less lipophilic species occurred, such that less than 38% of the parent compound remained 30 minutes after injection. Brain uptake and metabolism of [(125)I]WYE-230949 were increased and specific binding was reduced in anaesthetised compared to conscious rats. [(125)I]WYE230949 is not a potential radiotracer for imaging rat histamine H(3) receptors in vivo due to low brain uptake, in vivo metabolism of the parent compound and low specific binding.