van Waarde Aren, Doorduin Janine, de Jong Johan R, Dierckx Rudi A, Elsinga Philip H
Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Neurochem Int. 2008 Mar-Apr;52(4-5):729-33. doi: 10.1016/j.neuint.2007.09.009. Epub 2007 Sep 19.
Positron-emitting beta-adrenoceptor ligands for the CNS could allow determination of changes in beta-adrenoceptor availability after treatment of patients with norepinephrine reuptake inhibitors or tricyclic antidepressants, and differential diagnosis between multiple sclerosis and other brain disorders in an early stage of the disease. No ligands suitable for this purpose are available for human use. In order to prepare a tracer for human studies, we labeled the biologically active enantiomer of the beta-blocker exaprolol with (11)C. Exaprolol has the appropriate lipophilicity (log P + 1.6) for entry of the CNS and is claimed to be a very potent beta-adrenoceptor antagonist. (S)-Desisopropyl-exaprolol was synthesized by reaction of 2-hexylphenol with (S)-glycidyl-nosylate followed by ring opening using ammonia gas. The desisopropyl precursor was reacted with (11)C-acetone in methanol to produce (S)-[(11)C]-exaprolol. Radiochemical purification was performed with RP-HPLC and was followed by Sep-Pak formulation. The labeled product was i.v. injected into male Wistar rats. Brain images were acquired using a microPET Focus 220 and the biodistribution of (11)C was assessed. The radiochemical yield of (S)-[(11)C]-exaprolol was 7% with a total synthesis time of 30 min. Specific activities were >10 GBq/micromol. Brain uptake of the tracer reached a maximum after 15 min. Standardized uptake values were moderate (0.5-0.9) but sufficient for imaging. However, beta-blockade (propranolol, 2.5mg/kg body weight) did not lower tracer uptake in any CNS region and washout from the brain was not accelerated when propranolol was administered 40 min after injection of (S)-[(11)C]-exaprolol. Tracer binding in lung, spleen and erythrocytes was lowered after beta-blockade, but the myocardial uptake of radioactivity was not affected. These data indicate that (S)-[(11)C]-exaprolol is not a suitable beta-adrenoceptor ligand for PET, probably because the in vivo affinity of exaprolol to beta-adrenoceptors is in the nM rather than the sub-nM range. The observed inhibition of tracer uptake in lung, spleen and erythrocytes seems due to an interaction of propranolol with amine transporters rather than beta-adrenoceptors.
用于中枢神经系统的正电子发射型β-肾上腺素能受体配体，可用于确定用去甲肾上腺素再摄取抑制剂或三环类抗抑郁药治疗患者后β-肾上腺素能受体可用性的变化，以及在疾病早期对多发性硬化症和其他脑部疾病进行鉴别诊断。目前尚无适用于此目的的人类可用配体。为了制备用于人体研究的示踪剂，我们用（11）C标记了β受体阻滞剂依沙洛尔的生物活性对映体。依沙洛尔具有适合进入中枢神经系统的亲脂性（log P + 1.6），据称是一种非常有效的β-肾上腺素能受体拮抗剂。（S）-去异丙基依沙洛尔是通过2-己基苯酚与（S）-缩水甘油基对甲苯磺酸酯反应，然后用氨气开环合成的。去异丙基前体与甲醇中的（11）C-丙酮反应生成（S）-[（11）C]-依沙洛尔。用反相高效液相色谱法进行放射化学纯化，随后进行Sep-Pak制剂处理。将标记产物静脉注射到雄性Wistar大鼠体内。使用微型PET Focus 220采集脑图像，并评估（11）C的生物分布。（S）-[（11）C]-依沙洛尔的放射化学产率为7%，总合成时间为30分钟。比活度>10 GBq/μmol。示踪剂的脑摄取在15分钟后达到最大值。标准化摄取值适中（0.5 - 0.9），但足以用于成像。然而，β受体阻断（普萘洛尔，2.5mg/kg体重）并未降低任何中枢神经系统区域的示踪剂摄取，并且在注射（S）-[（11）C]-依沙洛尔40分钟后给予普萘洛尔时，示踪剂从脑中的清除并未加速。β受体阻断后，肺、脾和红细胞中的示踪剂结合降低，但心肌对放射性的摄取未受影响。这些数据表明，（S）-[（11）C]-依沙洛尔不是一种适用于PET的β-肾上腺素能受体配体，可能是因为依沙洛尔在体内对β-肾上腺素能受体的亲和力处于纳摩尔而非亚纳摩尔范围。观察到的普萘洛尔对肺、脾和红细胞中示踪剂摄取的抑制作用似乎是由于普萘洛尔与胺转运体的相互作用，而非与β-肾上腺素能受体的相互作用。
