Development of radiopharmaceuticals for complementary molecular imaging and systemic radiotherapy

锝-99m（99 mTc）是一种γ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99 mTc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99 mTc示踪剂是灌注成像剂。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有效的99 mTc螯合剂，以将99 mTc掺入靶向生物分子中。二硫代氨基甲酸盐（DTC）螯合剂是这一目的的有吸引力的候选者，因为它们具有高度的适应性和多功能性，能够结合各种氧化态的金属，包括放射性金属。仲胺肌氨酸含有羧酸官能团，能够简单地连接到受体靶向肽。在这里，DTC由肌氨酸制备。以肌氨酸-DTC为配体，经还原成[99 mTcN] 2+，再与肌氨酸-DTC在碳酸盐缓冲液中反应，得到[99 mTcN（C4 H7 NO2 S2）2]。使用放射性HPLC和UV-HPLC，将所得产物[99 mTcN（C4 H7 NO2 S2）2]的色谱行为与非放射性同构双[ReN（C4 H7 NO2 S2）2]络合物（使用HPLC、NMR和LCMS表征）进行比较。该比较HPLC分析表明，[99 mTcN（C4 H7 NO2 S2）2]和[ReN（C4 H7 NO2 S2）2]中的每一个均由两个紧密洗脱的异构体组成。在显示肌氨酸-DTC与[99 mTcN]2+和[natReN]2+螯合后，目前正在开发新型DTC缀合物PSMat。螯合剂合成后，将用[99 mTcN]2+进行放射性标记，并使用非放射性同位素替代物进行表征研究。一旦建立了可重现的放射性标记方案，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.