Reid Alicia E, Ding Yu-Shin, Eckelman William C, Logan Jean, Alexoff David, Shea Colleen, Xu Youwen, Fowler Joanna S
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Nucl Med Biol. 2008 Apr;35(3):287-98. doi: 10.1016/j.nucmedbio.2008.01.001.
The only radiotracer available for the selective imaging of muscarinic M2 receptors in vivo is 3-(3-(3-[18F]fluoropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine) ([18F]FP-TZTP). We have prepared and labeled 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridne (FP-TZTP, 3) and two other TZTP derivatives with 11C at the methylpyridine moiety to explore the potential of using 11C-labeled FP-TZTP for positron emission tomography imaging of M2 receptors and to compare the effect of small structural changes on tracer pharmacokinetics (PK) in brain and peripheral organs.
11C-radiolabeled FP-TZTP, 3-(3-propylthio)-TZTP (6) and 3,3,3-(3-(3-trifluoropropyl)-TZTP (10) were prepared, and log D, plasma protein binding (PPB), affinity constants, time-activity curves (TACs), area under the curve (AUC) for arterial plasma, distribution volumes (DV) and pharmacological blockade in baboons were compared.
Values for log D, PPB and affinity constants were similar for 3, 6 and 10. The fraction of parent radiotracer in the plasma was higher and the AUC lower for 10 than for 3 and 6. TACs for brain regions were similar for 3 and 6, which showed PK similar to the 18F tracer, while 10 showed slower uptake and little clearance over 90 min. DVs for 3 and 6 were similar to the 18F tracer but higher for 10. Uptake of the three tracers was significantly reduced by coinjection of unlabeled 3 and 6.
Small structural variations on the TZTP structure greatly altered the PK in brain and behavior in blood with little change in the log D, PPB or affinity. The study suggests that 11C-radiolabeled 3 will be a suitable alternative to [18F]FP-TZTP for translational studies in humans.
用于体内毒蕈碱M2受体选择性成像的唯一放射性示踪剂是3-(3-(3-[18F]氟丙基)硫代)-1,2,5-噻二唑-4-基)-1,2,5,6-四氢-1-甲基吡啶（[18F]FP-TZTP）。我们制备并标记了3-(3-(3-氟丙基硫代)-1,2,5-噻二唑-4-基)-1,2,5,6-四氢-1-甲基吡啶（FP-TZTP，3）以及另外两种在甲基吡啶部分用11C标记的TZTP衍生物，以探索使用11C标记的FP-TZTP进行M2受体正电子发射断层扫描成像的潜力，并比较小的结构变化对示踪剂在脑和外周器官中药代动力学（PK）的影响。
制备了11C放射性标记的FP-TZTP、3-(3-丙基硫代)-TZTP（6）和3,3,3-(3-(3-三氟丙基)-TZTP（10），并比较了它们的log D、血浆蛋白结合率（PPB）、亲和常数、时间-活度曲线（TAC）、动脉血浆曲线下面积（AUC）、分布容积（DV）以及在狒狒中的药理阻断作用。
3、6和10的log D、PPB和亲和常数的值相似。与3和6相比，10的血浆中母体放射性示踪剂的比例更高，AUC更低。3和6在脑区的TAC相似，其PK与18F示踪剂相似，而10在90分钟内摄取较慢且清除很少。3和6的DV与18F示踪剂相似，但10的DV更高。同时注射未标记的3和6可显著降低三种示踪剂的摄取。
TZTP结构上的小结构变化极大地改变了脑内的PK和血液中的行为，而log D、PPB或亲和力变化很小。该研究表明，11C放射性标记的3将是[18F]FP-TZTP在人体转化研究中的合适替代品。
