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99Tc peptide-peptide nucleic acid probes for imaging oncogene mRNAs in tumours.

We read with interest the paper by Rao et al. on the radiopharmaceutical application of radiolabelled antisense peptide–PNA chimeras [1]. The simplified method of synthesis described by Dr Rao and his colleagues should certainly facilitate the study of antisense approaches in nuclear medicine. However, the paper also very nicely demonstrates some of the pitfalls associated with this novel technology which we described in detail in our publication [2]. Dr Rao shows that the uptake of the labelled antisense probe in the MCF7 tumour xenograft at 4 h is about twice that of a mismatch control probe. The implied (but unstated) conclusion is that this ‘encouraging’ increased uptake is due to specific hybridization of the probe to the c-myc mRNA expressed in the tumour. However, a close examination of the data shows that this is unlikely to be the case since the uptake of the specific probe exceeds that of the control probe, not only in the tumour but in all other tissues measured, apart from the spleen. In most cases this difference is statistically significant. The increased uptake in these normal tissues cannot be mediated by hybridization to cmyc. Rather, the differences in uptake between the two proves in all tissues are almost certainly due to pharmacokinetic differences between the two tracers. The mismatch probe clears much more rapidly from the blood than the specific and results in a lower non-specific retention in almost all tissues including the tumour. The fact that such small differences in sequence can cause major changes is well recognized in the field of neuropeptide targeting [3], but, to my knowledge, this is the first published demonstration of such a phenomenon with antisense targeting. The real test of antisense imaging is to show that a single specific probe can distinguish in vivo between different levels of mRNA expression in otherwise similar tissues. A convincing demonstration of this is yet to be published.