Bioimaging Research Laboratories, Astellas Pharma Inc., Tsukuba, Japan.
Nucl Med Biol. 2012 Nov;39(8):1232-5. doi: 10.1016/j.nucmedbio.2012.06.012. Epub 2012 Aug 11.
Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT(1)) receptor (AT(1)R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using (11)C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques.
Three male rhesus macaques were bolus intravenously administered [(11)C]telmisartan either alone or as a mixture with unlabeled telmisartan (1mg/kg). Dynamic PET images were acquired for 95min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain.
Telmisartan penetrated into the brain little but enough to block AT(1)R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT(1)R distribution was noted over the entire brain, even on tracer alone dosing.
Telmisartan penetrated into the brain enough to block AT(1)R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.
替米沙坦是一种广泛使用的长效降压药。已知替米沙坦是一种选择性血管紧张素 II 型 1 型受体（AT(1)R）阻滞剂（ARB），作为过氧化物酶体增殖物激活受体-γ（PPAR-γ）的部分激动剂，替米沙坦在大鼠外周给予后抑制血管紧张素 II 的中枢介导作用，尽管替米沙坦在大脑中的穿透性仍不清楚。我们使用（11）C 标记的替米沙坦和正电子发射断层扫描（PET）在清醒的恒河猴中研究了替米沙坦的脑浓度和定位。
三只雄性恒河猴静脉内单次给予（11）C 替米沙坦或与未标记的替米沙坦（1mg/kg）混合物。给药后 95 分钟内采集动态 PET 图像。采集血样以分析血浆浓度和代谢物，并使用给予药物制剂的比活度从检测到的放射性中计算脑和血浆浓度，其中全血放射性用于校正脑内血管内血液放射性。
替米沙坦很少穿透到大脑中，但足以阻断 AT(1)R，并在 PET 扫描期间显示出一致增加的脑/血浆比，表明与血浆清除相比，化合物从大脑中的清除速度较慢。30、60 和 90 分钟时的脑/血浆比分别为 0.06、0.13 和 0.18。即使单独给予示踪剂，整个大脑也没有注意到根据 AT(1)R 分布的明显定位。
替米沙坦足以穿透大脑以阻断 AT(1)R，并在清醒的恒河猴中显示出从大脑缓慢清除的特点，支持替米沙坦作为 ARB 中一种独特特性的长效和中枢反应。
