Fani Melpomeni, Weingaertner Viktoria, Kolenc Peitl Petra, Mansi Rosalba, Gaonkar Raghuvir H, Garnuszek Piotr, Mikolajczak Renata, Novak Doroteja, Simoncic Urban, Hubalewska-Dydejczyk Alicja, Rangger Christine, Kaeopookum Piriya, Decristoforo Clemens
Division of Radiopharmaceutical Chemistry, University Hospital Basel, Universitätsspital Basel, CH-4031 Basel, Switzerland.
Department of Nuclear Medicine, Medical University Innsbruck, 6020 Innsbruck, Austria.
Pharmaceuticals (Basel). 2020 Dec 28;14(1):19. doi: 10.3390/ph14010019.
Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project "TECANT" two Tc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log , protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [Tc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [Tc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [Tc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [Tc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [Tc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [Tc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [Tc]Tc-TECANT-1 for clinical translation of the first Tc-based SST2 antagonist.
最近，针对神经内分泌肿瘤中生长抑素受体2型（SST2）的放射性标记拮抗剂表现出比激动剂某些更优越的特性。在ERA-PerMED项目“TECANT”中，研究了两种锝-四胺（N4）衍生的SST2拮抗剂（TECANT-1和TECANT-2），以选择临床转化的最佳候选药物。在转染了人SST2的人胚肾-293（HEK293）细胞（HEK-SST2）中进行了受体亲和力、内化和解离研究。评估了人血清中的对数、蛋白质结合和稳定性。在携带HEK-SST2异种移植瘤的裸鼠中进行了生物分布和SPECT/CT研究，并进行了从小鼠到人的剂量估算。[锝]锝-TECANT-1比[锝]-TECANT-2表现出更高的亲水性和更低的蛋白质结合，而稳定性相当。两种放射性示踪剂显示出相似的结合亲和力，而[锝]锝-TECANT-1具有更高的细胞摄取（在2小时/37℃时>50%）和更低的解离率（在2小时/37℃时<30%）。在体内，[锝]锝-TECANT-1显示出更低血液值、肾脏和肌肉摄取，而肿瘤摄取与[锝]锝-TECANT-2相当。SPECT/CT成像证实了生物分布结果，在注射后4小时（p.i.）为[锝]锝-TECANT-1提供了最佳的肿瘤与背景图像对比度。两种放射性示踪剂的估计辐射剂量约为6μSv/MBq。这项临床前研究为选择[锝]锝-TECANT-1进行首个基于锝的SST2拮抗剂的临床转化提供了依据。
