Wyffels Leonie, Thomae David, Waldron Ann-Marie, Fissers Jens, Dedeurwaerdere Stefanie, Van der Veken Pieter, Joossens Jurgen, Stroobants Sigrid, Augustyns Koen, Staelens Steven
Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium; University Hospital Antwerp, Department of Nuclear Medicine, Edegem, Belgium.
Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium; Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
Nucl Med Biol. 2014 Jul;41(6):513-23. doi: 10.1016/j.nucmedbio.2014.03.023. Epub 2014 Apr 2.
The tetrazine-trans-cylooctene cycloaddition using radiolabeled tetrazine or radiolabeled trans-cyclooctene (TCO) has been reported to be a very fast, selective and bioorthogonal reaction that could be useful for in vivo radiolabeling of molecules. We wanted to evaluate the in vivo biodistribution profile and brain uptake of (18)F-labeled TCO ([(18)F]TCO) to assess its potential for pre-targeted imaging in the brain.
We evaluated the in vivo behavior of [(18)F]TCO via an ex vivo biodistribution study complemented by in vivo μPET imaging at 5, 30, 60, 90, 120 and 240 min post tracer injection. An in vivo metabolite study was performed at 5 min, 30 min and 120 min post [(18)F]TCO injection by RP-HPLC analysis of plasma and brain extracts. Incubation with human liver microsomes was performed to further evaluate the metabolite profile of the tracer.
μPET imaging and ex-vivo biodistribution revealed an high initial brain uptake of [(18)F]TCO (3.8%ID/g at 5 min pi) followed by a washout to 3.0%ID/g at 30 min pi. Subsequently the brain uptake increased again to 3.7%ID/g at 120 min pi followed by a slow washout until 240 min pi (2.9%ID/g). Autoradiography confirmed homogenous brain uptake. On the μPET images bone uptake became gradually visible after 120 min pi and was clearly visible at 240 min pi. The metabolite study revealed a fast metabolization of [(18)F]TCO in plasma and brain into three main polar radiometabolites.
Although [(18)F]TCO has previously been described to be a useful tracer for radiolabeling of tetrazine modified targeting molecules, our study indicates that its utility for in vivo chemistry and pre-targeted imaging will be limited. Although [(18)F]TCO clearly enters the brain, it is quickly metabolized with a non-specific accumulation of radioactivity in the brain and bone.
据报道，使用放射性标记的四嗪或放射性标记的反式环辛烯（TCO）进行的四嗪-反式环辛烯环加成反应是一种非常快速、选择性且生物正交的反应，可用于分子的体内放射性标记。我们希望评估（18）F标记的TCO（[（18）F]TCO）的体内生物分布情况和脑摄取，以评估其在脑内预靶向成像的潜力。
我们通过体外生物分布研究评估了[（18）F]TCO的体内行为，并在注射示踪剂后5、30、60、90、120和240分钟进行了体内μPET成像。在注射[（18）F]TCO后5分钟、30分钟和120分钟，通过RP-HPLC分析血浆和脑提取物进行了体内代谢物研究。与人肝微粒体孵育以进一步评估示踪剂的代谢物谱。
μPET成像和体外生物分布显示，[（18）F]TCO在脑内有较高的初始摄取（注射后5分钟时为3.8%ID/g），随后在注射后30分钟时降至3.0%ID/g。随后，脑摄取在注射后120分钟时再次增加至3.7%ID/g，随后缓慢洗脱直至注射后240分钟（2.9%ID/g）。放射自显影证实脑摄取均匀。在μPET图像上，骨摄取在注射后120分钟后逐渐可见，在注射后240分钟时清晰可见。代谢物研究显示，[（18）F]TCO在血浆和脑内迅速代谢为三种主要的极性放射性代谢物。
尽管[（18）F]TCO先前被描述为用于四嗪修饰靶向分子放射性标记的有用示踪剂，但我们的研究表明，其在体内化学和预靶向成像中的应用将受到限制。尽管[（18）F]TCO明显进入脑内，但它会迅速代谢，放射性在脑和骨内非特异性蓄积。
