Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
PET Preclinical Imaging Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
Mol Imaging Biol. 2019 Oct;21(5):879-887. doi: 10.1007/s11307-019-01317-6.
The α-adrenoceptors mediate many effects of norepinephrine and epinephrine, and participate in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. Of the three receptor subtypes, only α and α are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α-adrenoceptors has been limited to the α subtype. Here, we report the synthesis of 6-[F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α-adrenoceptors, and its preclinical evaluation in rats and mice.
6-[F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α-knockout (KO) and wild-type (WT) mice for subtype selectivity. In vivo PET imaging and ex vivo brain autoradiography were performed to determine the tracer distribution in the brain. The specificity of the tracer for the target was determined by pretreatment with the subtype-non-selective α-agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[F]fluoro-marsanidine were also analyzed.
6-[F]Fluoro-marsanidine was synthesized with [F]Selectfluor bis(triflate) in a radiochemical yield of 6.4 ± 1.7 %. The molar activity was 3.1 to 26.6 GBq/μmol, and the radiochemical purity was > 99 %. In vivo studies in mice revealed lower uptake in the brains of α-KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α-adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice.
6-[F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α-adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[F]fluoro-marsanidine unsuitable for α-adrenoceptor targeting in rodents in vivo.
α-肾上腺素受体介导去甲肾上腺素和肾上腺素的许多作用，并参与神经元、内分泌、心血管、植物性和代谢功能的调节。在这三种受体亚型中，只有 α 和 α 在大脑中大量存在。α-肾上腺素受体的亚型选择性正电子发射断层扫描（PET）成像仅限于 α 亚型。在这里，我们报告了 6-[F]氟马嗪的合成，这是一种用于 α-肾上腺素受体的亚型选择性 PET 示踪剂候选物，并在大鼠和小鼠中进行了其临床前评估。
使用亲电 F-18 氟代[F]Selectfluor 双三氟甲磺酸酯对 6-[F]氟马嗪进行合成。在 Sprague Dawley 大鼠和 α 敲除（KO）和野生型（WT）小鼠中评估示踪剂的亚型选择性。进行体内 PET 成像和脑外放射性自显影，以确定示踪剂在大脑中的分布。通过用非选择性 α 激动剂右美托咪定预处理来确定示踪剂对靶标的特异性。还分析了 6-[F]氟马嗪的外周生物分布和代谢程度。
使用[F]Selectfluor 双三氟甲磺酸酯以 6.4±1.7%的放射化学产率合成了 6-[F]氟马嗪。摩尔活性为 3.1 至 26.6GBq/μmol，放射化学纯度>99%。在小鼠体内研究中，与 WT 小鼠相比，α-KO 小鼠大脑中的摄取量较低。离体脑放射性自显影证实了选择性结果。阻断研究表明，在预处理动物中，α-肾上腺素受体丰富的脑区摄取减少，证明了示踪剂的特异性。代谢产物分析表明，6-[F]氟马嗪在大鼠和小鼠中具有快速代谢，血脑屏障通透性代谢产物。
合成了 6-[F]氟马嗪并将其评估为脑 α-肾上腺素受体的 PET 示踪剂候选物。然而，在小鼠和大鼠脑中，快速代谢、大量存在标记代谢物以及非特异性摄取量高，使得 6-[F]氟马嗪不适合在体内对啮齿动物进行 α-肾上腺素受体靶向。
