Pharmacokinetic considerations in the development of oligomers as radiopharmaceuticals

Single-stranded oligomers are attractive candidates for the next generation of radiopharmaceuticals because of their ability to bind specifically to their complementary single-stranded oligomers by hybridization. However, native, phosphodiester DNAs have been universally judged to be unsuitable because of excessive in vivo nuclease hydrolysis. Chemical modifications to phosphodiester DNAs are therefore required to improve pharmacokinetic properties before the potential of oligomers for radiopharmaceutical use can be realized. Fortunately, hundreds of modified oligomers have been prepared and tested, mostly in vitro, in connection with antisense chemotherapy. This chapter provides an overview of those results which are relevant to the use of the more important of these modified oligomers as radiopharmaceuticals. In brief, the phosphorothioate DNAs are stable in vivo but may be unsuitable in all forms because of high protein binding affinities which delay clearance and increase background radioactivity levels. The methylphosphonate DNAs are also stable but do not show high protein binding affinities. Like the vast majority of modified oligomers, they have not as yet been investigated as radiopharmaceuticals. However, it may be the synthetic oligomers which are the most attractive at present. In particular, PNA has been radiolabeled with 99mTc and shown in mouse studies to be stable, to clear rapidly without excessive protein binding and to hybridize to its complement in vivo. In conclusion, several oligomers display pharmacokinetic properties in preliminary studies which suggest that they deserve further consideration for use as radiopharmaceuticals.