Development of radiopharmaceuticals for complementary molecular imaging and systemic radiotherapy

点击翻译按钮获取中文摘要

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.