Tsukada Hideo, Ohba Hiroyuki, Kanazawa Masakatsu, Kakiuchi Takeharu, Harada Norihiro
Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan,
Eur J Nucl Med Mol Imaging. 2014 Apr;41(4):755-63. doi: 10.1007/s00259-013-2628-z. Epub 2013 Nov 21.
We have reported on the development of a novel PET probe, (18)F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ((18)F-BCPP-EF), for quantitative imaging of mitochondrial complex 1 (MC-1) activity in the brain of the living rat. For clinical application in humans, translational research in the monkey was conducted.
PET measurements with (18)F-BCPP-EF were performed in young and old monkeys (Macaca mulatta) in a conscious state with arterial blood sampling. The binding specificity of (18)F-BCPP-EF was evaluated with rotenone, a specific MC-1 inhibitor, in young animals. The binding (total distribution volume, V T) of (18)F-BCPP-EF was calculated using Logan graphical analysis, and one-tissue compartment model (1-TC) and two-tissue compartment model (2-TC) analyses using a metabolite-corrected plasma input function.
F-BCPP-EF was rapidly taken up into the brain just after intravenous injection, peaked between 10 and 20 min after injection, and was then gradually eliminated. The 2-TC analysis provided a better fit than the 1-TC analysis, and the V T values from the 2-TC analysis correlated well with those from the Logan plot. With predosing with rotenone, (18)F-BCPP-EF showed a higher uptake peak in the brain, followed by more rapid elimination thereafter than in the vehicle condition, resulting in significant reductions in 2-TC V T values in all regions. In old animals, the kinetics of (18)F-BCPP-EF were slightly slower with lower peak levels than in young animals, resulting age-related reductions in (18)F-BCPP-EF binding in all brain regions.
The present study demonstrated that (18)F-BCPP-EF may be a potential PET probe for quantitative imaging MC-1 activity in the living brain using PET.
我们已报道了一种新型正电子发射断层扫描（PET）探针，即（18）F - 2 - 叔丁基 - 4 - 氯 - 5 - {6 - [2 - （2 - 氟乙氧基） - 乙氧基] - 吡啶 - 3 - 基甲氧基} - 2H - 哒嗪 - 3 - 酮（（18）F - BCPP - EF）的研发情况，该探针用于对活体大鼠大脑中的线粒体复合物1（MC - 1）活性进行定量成像。为了在人体中的临床应用，我们在猴子身上开展了转化研究。
对年轻和老年猕猴（恒河猴）进行了（18）F - BCPP - EF的PET测量，测量时动物处于清醒状态并采集动脉血样。在年轻动物中，使用鱼藤酮（一种特异性MC - 1抑制剂）评估了（18）F - BCPP - EF的结合特异性。（18）F - BCPP - EF的结合（总分布容积，VT）通过Logan图形分析以及使用代谢物校正的血浆输入函数的单组织隔室模型（1 - TC）和双组织隔室模型（2 - TC）分析来计算。
静脉注射后，（18）F - BCPP - EF迅速被摄取到大脑中，在注射后10至20分钟达到峰值，然后逐渐消除。2 - TC分析比1 - TC分析拟合效果更好，并且2 - TC分析得到的VT值与Logan图得到的值相关性良好。预先给予鱼藤酮后，（18）F - BCPP - EF在大脑中显示出更高的摄取峰值，随后消除速度比给予赋形剂时更快，导致所有区域的2 - TC VT值显著降低。在老年动物中，（18）F - BCPP - EF的动力学略慢，峰值水平低于年轻动物，导致所有脑区中（18）F - BCPP - EF的结合出现与年龄相关的降低。
本研究表明，（18）F - BCPP - EF可能是一种潜在的PET探针，用于使用PET对活体大脑中的MC - 1活性进行定量成像。
