Selivanova Svetlana V, Toscano Annamaria, Abate Carmen, Berardi Francesco, Müller Adrienne, Krämer Stefanie D, Schibli Roger, Ametamey Simon M
Center for Radiopharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari ALDO MORO, Bari, Italy.
Nucl Med Biol. 2015 Apr;42(4):399-405. doi: 10.1016/j.nucmedbio.2014.12.018. Epub 2015 Jan 6.
Both subtypes of sigma (σ) receptors, σ₁ and σ₂, are over-expressed in many cancers with σ₂ proposed as a biomarker of tumor proliferation. We are interested in developing a high affinity selective σ₂ radioligand for in vivo monitoring of proliferative status of solid tumors and response to anti-cancer therapies. 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) represents one of the lead candidates in the development of σ receptor ligands for therapeutic and diagnostic applications. However, the utility of PB28 is limited due to its relatively high lipophilicity.
A more hydrophilic analogue (-)-(S)-1 was radiolabeled with (11)C via standard O-alkylation. In vitro autoradiography with (11)C-(S)-1 was done using rat brain slices. PET imaging was performed in mice bearing EMT6, C6 or PC-3 tumors after i.v. injection of (11)C-(S)-1.
(11)C-(S)-1 was produced in 53%±7% isolated decay-corrected yield with radiochemical and chemical purity over 99% and specific activity greater than 100 GBq/μmol. In vitro autoradiography with [(11)C(-)-(S)-1 resulted in a heterogeneous binding of the tracer in the rat brain with the highest radioactivity signals in the cortex region followed by cerebellum. This binding was successfully blocked by 10 μM of either haloperidol, (+)-(R)-1 or PB28. For C6 xenografts low target-to-nontarget ratio and high non-specific binding did not allow clear tumor visualization. No accumulation was visible in EMT6 tumor or in PC-3 tumor. Rat and mouse brain uptake was low and homogeneous while stronger signal was detected in the spinal cord. High accumulation of radioactivity was observed in liver and intestine suggesting hepatobiliary clearance.
Despite excellent in vitro properties, (11)C-(S)-1 did not provide high enough specific binding in vivo and is, therefore, not a useful PET tracer for imaging σ₂ expression in tumors.
σ受体的两种亚型，即σ₁和σ₂，在许多癌症中均过度表达，其中σ₂被认为是肿瘤增殖的生物标志物。我们有兴趣开发一种高亲和力的选择性σ₂放射性配体，用于体内监测实体瘤的增殖状态以及对抗癌治疗的反应。1-环己基-4-[3-(5-甲氧基-1,2,3,4-四氢萘-1-基)丙基]哌嗪（PB28）是用于治疗和诊断应用的σ受体配体开发中的主要候选物之一。然而，PB28的实用性因其相对较高的亲脂性而受到限制。
一种亲水性更强的类似物(-)-(S)-1通过标准的O-烷基化反应进行¹¹C放射性标记。使用大鼠脑切片对(¹¹C-(S)-1进行体外放射自显影。在静脉注射(¹¹C-(S)-1后，对荷EMT6、C6或PC-3肿瘤的小鼠进行PET成像。
(¹¹C-(S)-1的制备产率为53%±7%（经衰变校正后的分离产率），放射化学纯度和化学纯度均超过99%，比活度大于100 GBq/μmol。用(¹¹C-(S)-1进行体外放射自显影时发现，示踪剂在大鼠脑中的结合具有异质性，皮质区域的放射性信号最高，其次是小脑。10 μM的氟哌啶醇、(+)-(R)-1或PB28均可成功阻断这种结合。对于C6异种移植瘤，低靶非靶比值和高非特异性结合使得肿瘤无法清晰显影。在EMT6肿瘤或PC-3肿瘤中未观察到放射性聚集。大鼠和小鼠脑摄取较低且均匀，而在脊髓中检测到较强信号。在肝脏和肠道中观察到放射性的高聚集，提示存在肝胆清除。
尽管(¹¹C-(S)-1在体外具有优异的性质，但在体内并未提供足够高的特异性结合，因此不是用于成像肿瘤中σ₂表达的有用PET示踪剂。
