Cook Brendon E, Pickel Thomas C, Nag Sangram, Bolduc Philippe N, Beshr Rouaa, Forsberg Morén Anton, Muste Cathy, Boscutti Giulia, Jiang Di, Yuan Long, Datta Prodip, Ochniewicz Piotr, Khani Meynaq Yasir, Tang Sac-Pham, Plisson Christophe, Amatruda Mario, Zhang Qize, DuBois Jonathan M, Delavari Armin, Klein Stephanie K, Polyak Ildiko, Shoroye Adebowale, Girmay Sara, Halldin Christer, Martarello Laurent, Peterson Emily A, Kaliszczak Maciej
Biogen, Cambridge, MA 02142, USA.
Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-171 76 Stockholm, Sweden.
Sci Transl Med. 2025 May 7;17(797):eadl1732. doi: 10.1126/scitranslmed.adl1732.
Determination of a drug's biodistribution is critical to ensure that it reaches the target tissue of interest. This is particularly challenging in the brain, where invasive sampling methods may not be possible. Here, we present a pretargeted positron emission tomography (PET) imaging methodology that uses bioorthogonal click chemistry to determine the distribution of an antisense oligonucleotide (ASO) in the brains of rats and nonhuman primates after intrathecal dosing of ASO. A PET tracer, [F]BIO-687, bearing a click-reactive -cyclooctene was developed and tested in conjunction with a test Malat1 ASO conjugated with a methyltetrazine group. PET imaging in rats demonstrated that the tracer had good kinetic properties for PET imaging in the rodent central nervous system and could react to form a covalent linkage with high specificity to the methyltetrazine-conjugated ASO in vivo. Furthermore, the amount of PET tracer reacted by cycloaddition with the methyltetrazine was determined to be dependent on the concentration of ASO-methyltetrazine in rat brain tissue, as determined by comparing the PET imaging signal with the liquid chromatography-mass spectrometry signal in the tissue homogenates. The approach was evaluated in cynomolgus macaques using both the Malat1 test ASO and a candidate therapeutic ASO, BIIB080, targeting the microtubule-associated protein tau () gene. PET imaging showed favorable tracer kinetics and specific binding to both ASOs in nonhuman primate (NHP) brain in vivo. These results suggest that the PET imaging tracer [F]BIO-687 could show the distribution of intrathecally delivered ASOs in the rat and NHP brains.
确定药物的生物分布对于确保其到达感兴趣的靶组织至关重要。这在大脑中尤其具有挑战性，因为侵入性采样方法可能不可行。在此，我们提出一种预靶向正电子发射断层扫描（PET）成像方法，该方法使用生物正交点击化学来确定鞘内注射反义寡核苷酸（ASO）后大鼠和非人类灵长类动物大脑中ASO的分布。开发了一种带有点击反应性环辛烯的PET示踪剂[F]BIO-687，并与与甲基四嗪基团偶联的测试Malat1 ASO一起进行了测试。大鼠的PET成像表明，该示踪剂在啮齿动物中枢神经系统中具有良好的PET成像动力学特性，并且可以在体内与甲基四嗪偶联的ASO发生反应形成共价连接，具有高特异性。此外，通过比较PET成像信号与组织匀浆中的液相色谱-质谱信号，确定与甲基四嗪通过环加成反应的PET示踪剂的量取决于大鼠脑组织中ASO-甲基四嗪的浓度。使用Malat1测试ASO和靶向微管相关蛋白tau（）基因的候选治疗性ASO BIIB080在食蟹猴中评估了该方法。PET成像显示在非人类灵长类动物（NHP）大脑中，示踪剂具有良好的动力学特性且与两种ASO均有特异性结合。这些结果表明，PET成像示踪剂[F]BIO-687可以显示鞘内递送的ASO在大鼠和NHP大脑中的分布。
