ABSTRACT
We have synthesized three 123I-labeled histamine H3 receptor ligands, i.e., [123I]GR 190028, [123I]FUB 271, and [123I]iodoproxyfan, in moderate to good radiochemical yields via a Cu+-assisted I-for-123I exchange method. Biodistribution in the rat of these compounds revealed high hepatic and pulmonary uptake. Brain uptake was moderate, but for [123I]iodoproxyfan, brain uptake was high enough for a pilot single photon emission computed tomography (SPECT) study in the rabbit. However, for this compound, the cerebral uptake could not be blocked by a pretreatment with [R]-alpha-methylhistamine, a selective, high-affinity histamine H3 receptor agonist, both in the SPECT study in the rabbit and in the biodistribution study in the rat. Apparently, [123I]iodoproxyfan is binding to a non-H3 receptor binding site. None of the three investigated compounds is suitable for use as a SPECT ligand for the H3 receptor in the brain.
Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacokinetics , Iodine Radioisotopes/pharmacokinetics , Receptors, Histamine H3/analysis , Tomography, Emission-Computed, Single-Photon , Animals , Cerebellum/diagnostic imaging , Cerebellum/metabolism , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/metabolism , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Iodobenzenes/chemical synthesis , Iodobenzenes/pharmacokinetics , Male , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacokinetics , Rabbits , Radioligand Assay , Rats , Rats, Wistar , Tissue DistributionABSTRACT
Presynaptic cholinergic markers could be used for estimating the integrity of the cholinergic systems in the human brain with brain imaging techniques such as Single-photon emission computed tomography (SPECT). Vesamicol, an inhibitor of the vesicular acetylcholine transporter, and some of its derivatives have been suggested as potential ligands for this purpose. However, vesamicol binds not only to acetylcholine transporters but also to sigma binding sites. In the present study, we estimated the contribution of sigma site labelling to [3H](-)-vesamicol binding in different rat brain regions by selectively labelling the acetylcholine transporter, using [3H](-)-vesamicol in the presence of the sigma-ligand 1,3-di(2-tolyl)guanidine to occlude the sigma binding sites. The contribution of sigma site labelling was substantial in all brain regions and ranged from 25% in the striatum to 60% in the medulla. In addition, we investigated, in various experimental set ups, the affinities of several vesamicol derivatives for acetylcholine transporters and sigma binding sites. All vesamicol derivatives used displayed a higher affinity for the sigma1 site than for the acetylcholine transporter and also displayed a high sigma2 site affinity. This poor selectivity limits the usefulness of these compounds as selective cholinergic markers for brain imaging studies.
Subject(s)
Acetylcholine/metabolism , Brain Chemistry/physiology , Carrier Proteins/metabolism , Membrane Transport Proteins , Neuromuscular Depolarizing Agents , Piperidines , Vesicular Transport Proteins , Animals , Anticonvulsants/pharmacology , Binding, Competitive/drug effects , Cells, Cultured , Female , Guanidines/pharmacology , Guinea Pigs , In Vitro Techniques , Kinetics , Ligands , Rats , Rats, Wistar , Receptors, sigma/metabolism , Vesicular Acetylcholine Transport ProteinsABSTRACT
Removal of free radioiodide from *I-radiopharmaceuticals was easily performed by using a pure metallic silver membrane, placed in a screwable holder. Well-known radiopharmaceuticals such as 3-iodobenzylguanidine, Hippuran, iomazenil and fatty acids were treated successfully, and gave reproducible results. Only a trace of free radioiodide (< or = 1%) was left after passing the silver membrane, while rest activity due to retention of the radiopharmaceutical on the membrane was negligible (2%-5%). This simple and reliable method offers the possibility of application as a last purification step in routine productions, in research or in a nuclear medicine department's pharmacy.
