Development of radiopharmaceuticals for complementary molecular imaging and systemic radiotherapy

开发用于补充分子成像和全身放射治疗的放射性药物

• 批准号: 2701608
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2701608
• 关键词: Development; radiopharmaceuticals; complementary; molecular; imaging

Technetium-99m (99mTc) is a gamma-emitting radioisotope used in radiopharmaceuticals/radiotracers for diagnostic imaging. These 99mTc-labelled radiopharmaceuticals are produced using kits, however, most routinely used 99mTc tracers are perfusion imaging agents. This project aims to develop disease-specific molecular radiotracers that target receptors expressed on the surface of diseased cells. Efficient 99mTc chelators are required for development of such molecular radiotracers, to incorporate 99mTc into a targeting biomolecule. Dithiocarbamate (DTC) chelators are attractive candidates for this purpose, as they are highly adaptable and versatile in their binding to a wide range of oxidations states of metals, including radioactive metals.The secondary amine, sarcosine, contains a carboxylic acid function that enables simple attachment to receptor targeting peptides. Here, A DTC was prepared from sarcosine. A [99mTcN]2+ complex of sarcosine-DTC was then prepared via a two-step protocol: [99mTcO4]- was firstly reduced to [99mTcN]2+, followed by the addition of sarcosine-DTC in carbonate buffer, to yield [99mTcN(C4H7NO2S2)2]. Using radio-HPLC and UV-HPLC, the chromatographic behaviour of the resulting product, [99mTcN(C4H7NO2S2)2], was compared with the non-radioactive isostructural rhenium [ReN(C4H7NO2S2)2] complex (which was characterised using HPLC, NMR and LCMS). This comparative HPLC analysis suggested that each of [99mTcN(C4H7NO2S2)2] and [ReN(C4H7NO2S2)2] consisted of two closely eluting isomers. Upon showing that sarcosine-DTC chelates to [99mTcN]2+ and [natReN]2+, novel DTC conjugate PSMAt is currently under development. Upon synthesis of the chelator, it will be radiolabelled with [99mTcN]2+ and characterisation studies will be conducted with a non-radioactive rhenium surrogate. Once reproducible radiolabelling protocols are established, in vitro and in vivo investigations will be conducted.

锝-99m （99mTc）是一种发射伽马射线的放射性同位素，用于诊断成像的放射性药物/放射性示踪剂。这些99mTc标记的放射性药物是使用试剂盒生产的，然而，大多数常规使用的99mTc示踪剂是灌注显像剂。该项目旨在开发针对病变细胞表面表达的受体的疾病特异性分子放射性示踪剂。开发这种分子放射性示踪剂需要高效的99mTc螯合剂，以便将99mTc纳入目标生物分子中。二硫代氨基甲酸酯（DTC）螯合剂是有吸引力的候选物，因为它们具有高度适应性和通能性，可以结合各种金属的氧化态，包括放射性金属。仲胺，肌氨酸，含有羧酸功能，使受体靶向肽的简单附着。本文以肌氨酸为原料制备DTC。然后通过两步方案制备了肌氨酸- dtc的[99mTcN]2+络合物：首先将[99mTcN] -还原为[99mTcN]2+，然后在碳酸盐缓冲液中加入肌氨酸- dtc，得到[99mTcN(C4H7NO2S2)2]。采用放射性高效液相色谱法和紫外高效液相色谱法，比较了产物[99mTcN(C4H7NO2S2)2]与非放射性同构铼[ReN(C4H7NO2S2)2]配合物的色谱行为（用HPLC、NMR和LCMS进行了表征）。对比HPLC分析表明[99mTcN(C4H7NO2S2)2]和[ReN(C4H7NO2S2)2]由两个紧密洗脱的异构体组成。基于肌氨酸-DTC与[99mTcN]2+和[natReN]2+的螯合，新型DTC偶联物PSMAt目前正在开发中。在合成螯合剂后，将用[99mTcN]2+进行放射性标记，并使用非放射性铼替代物进行表征研究。一旦建立了可重复的放射性标记方案，将进行体外和体内调查。