RESUMEN
The increased knowledge of molecular changes associated with different neurological disorders calls for the development of novel radioligands. Tiagabine (Gabitril) is an anticonvulsive drug that binds selectively to GABA transporter-1 and thereby inhibits GABA uptake. As radioligands for in-vivo imaging of the GABA transporter are not yet available, we radiolabelled tiagabine and assessed its efficacy for in-vivo imaging of these transporters. Tiagabine was first brominated at its vinylic part, which was then exchanged with I. Next, anaesthetized rats received a bolus injection of [I]iodotiagabine in their tail vein, which was immediately followed by acquisition of planar and high-resolution micro-single-photon emission computed tomography (SPECT) images of the total body with special focus on the brain. Uptake in anatomical regions was assessed by coregistration of micro-SPECT with micro-CT images. Tiagabine labelling with I resulted in 50% yield and 99.7% radiochemical purity. Within 3 h after injection, SPECT demonstrated an increased signal-to-background ratio in the nasal mucosa and/or the Harderian glands but not in the brain. In addition we observed an increased signal-to-background ratio in organs such as the thyroid, heart, liver, kidney and bladder. More than 99% pure I-labelled tiagabine can be obtained and applied in animal micro-SPECT studies. However, this new radioligand is not taken up sufficiently by the brain and therefore cannot be used to successfully detect cerebral GABA transporters.
Asunto(s)
Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Ácidos Nipecóticos/síntesis química , Tiofenos/síntesis química , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Técnicas de Química Sintética , Ratas , TiagabinaRESUMEN
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.
Asunto(s)
Radioisótopos de Carbono , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacocinética , Morfolinas/síntesis química , Morfolinas/farmacocinética , Piperidinas/síntesis química , Piperidinas/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Receptores Histamínicos H3/metabolismo , Animales , Autorradiografía , Encéfalo/metabolismo , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Radiofármacos/farmacocinética , Ratas , Distribución TisularRESUMEN
Z-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridinyl)-2-propen-1-amine or zimelidine (ZIM) and its first metabolite nor-zimelidine, were radioiodinated via a nonisotopic exchange, using the Cu(I)-assisted nucleophilic labeling method. To evaluate their potential as SPECT ligands for the serotonin transporter (SERT), the biodistribution of both ligands was determined and pretreatment "blocking" studies performed. Both radioligands demonstrated a good brain penetration of 0.8-1% ID/g, stable after 60 min., p.i., and a brain/blood ratio of up to 3. In vivo brain distribution did not reveal specific binding. Blocking studies by pretreatment with a known SERT ligand, had minor influence on the uptake of [(123)I]I-ZIM, between the several isolated brain regions. It may therefore be concluded that [(123)I]I-ZIM and [(123)I]I-nor-ZIM do not appear to be promising SPECT ligands for the SERT.