Development of radiopharmaceuticals for complementary molecular imaging and systemic radiotherapy

~(99m)Tc是一种发射伽马的放射性同位素，用于放射性药物/放射性示踪剂的诊断成像。这些99mTc标记的放射性药物是用试剂盒生产的，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疾病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，以将99mTc掺入靶向生物分子中。二硫代氨基甲酸酯(DTC)螯合剂具有很强的适应性和通用性，可与包括放射性金属在内的多种金属的氧化态结合。仲胺-肌氨酸含有羧酸功能，可以简单地与受体靶向多肽结合。本实验以肌氨酸为原料制备了DTC。然后通过两步法合成了[99mTcN]2+的肌氨酸-DTC络合物：首先将[99mTcO4]-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]。利用反相高效液相色谱(RHP)和紫外-高效液相色谱(UV-HPLC)，比较了产物[99mTcN(C4H7NO2S2)2]与非放射性等结构稀土配合物[REN(C4H7NO2S2)2]的层析行为(用高效液相色谱、核磁共振和LC MS对其进行了表征)。这一比较的高效液相分析表明，[99mTcN(C4H7NO2S2)2]和[REN(C4H7NO2S2)2]分别由两个紧密洗脱的异构体组成。根据肌氨酸-DTC对[99mTcN]2+和[NatReN]2+的螯合作用，目前正在开发新型的DTC偶联物PSMAt。在合成后，将用[99mTcN]2+对其进行放射性标记，并将使用非放射性Re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，将进行体外和体内研究。

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.