To chelate thallium(i) - synthesis and evaluation of Kryptofix-based chelators for Tl-201

While best known for its toxic properties, thallium has also been explored for applications in nuclear diagnostics and medicine. Indeed, [Tl-201]TlCl has been used extensively for nuclear imaging in the past before it was superceded by other radionuclides such as Tc-99m. One reason for this loss of interest is the severe lack of suitable organic chelators able to effectively coordinate ionic forms of Tl and deliver it to specific diseased tissue by means of attached biological vectors. Herein, we describe the synthesis and characterisation of a series of Kryptofix 222-based chelators that can be radiolabelled with Tl-201(i) in high radiochemical yields at ambient temperature. We demonstrate that from these simple chelators, targeted derivatives are readily accessible and describe the synthesis and preliminary biological evaluation of a PSMA-targeted Tl-201-labelled Kryptofix 222-peptide conjugate. While the Kryptofix system is demonstrably capable of binding the thallium cation, no PSMA-mediated cell-uptake could be detected with the PSMA conjugate, suggesting that this targeting moiety may not be ideal for use in conjunction with Tl-201.