Labelled oligonucleotides as radiopharmaceuticals: pitfalls, problems and perspectives.

The labelling of single-stranded oligonucleotides with a positron or single-photon emitter can result in valuable radiopharmaceuticals with promising applications for: (i) Imaging of specific mRNAs, i.e. visualisation of the expression of specific genes in vivo (ii) Monitoring of antisense chemotherapy, i.e. measuring the efficiency of efforts to block the expression of specific genes; (iii) Gene radiotherapy, i.e. the targeting of radiation damage to specific DNA sequences in order to destroy tumours; (iv) Imaging of protein targets by the use of aptamer oligonucleotides, i.e. oligonucleotide ligands obtained by in vitro evolution of selection-amplification steps, or selected for their interaction with nucleic acid-binding proteins; (v) Pre-targeting strategies based on the specificity of complementary sequence hybridisation. Nevertheless, oligonucleotides are intrinsically poor pharmaceuticals because of their large size, low stability, poor membrane passage and a number of undesirable and sometimes unpredictable side effects. As an alternative to the inherently unstable phosphodiester DNAs, chemically modified oligonucleotides such as phosphorothioate, methylphosphonate and peptide nucleic acid oligomers have been developed, and some are in clinical trials for the chemotherapy of several types of tumours. Imaging techniques could be useful in the development of such therapies. In addition, the potential of targeting virtually any disease or physiological process, by changing only the sequence of the oligomer, could provide a means to identify serious diseases in a very early stage, and be a highly specific modality to diagnose and differentiate various cancers. This has stimulated efforts to develop such radiopharmaceuticals in many laboratories, and encouraging results have been reported using technetium-99m, indium-111, carbon-11, fluorine-18, bromine-76 and iodine-125 labelled oligonucleotides.