68Ga-labeled oligonucleotides for in vivo imaging with PET.

UNLABELLED The biologic evaluation in living rats of (68)Ga-labeled oligonucleotides as imaging agents for PET is reported. METHODS (68)Ga, a positron-emitting radionuclide (half-life, 68 min), along with a macrocyclic chelating agent, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), was used for labeling of antisense oligonucleotides targeting activated human K-ras oncogene. The biologic properties of 3 different forms of the oligonucleotides-that is, 2'-deoxyphosphodiester (PO), 2'-deoxyphosphorothioate (PS), and 2'-O-methyl phosphodiester (OMe)-were studied first. The biodistribution and biokinetics were evaluated in vivo in athymic rats, each bearing a tumor of A549 cells, containing K-ras point mutation in codon 12, and a tumor of BxPC-3 cells, containing wild-type K-ras. Dynamic PET imaging lasting up to 2 h was performed immediately after intravenous injection of (68)Ga-oligonucleotide. Blank studies were performed using (68)GaCl(3) or (68)Ga-DOTA alone without oligonucleotide. The (68)Ga-antisense oligonucleotide uptake in tumors was also compared with the (18)F-FDG and (68)Ga-sense oligonucleotide uptakes. In addition, oligonucleotide binding to human plasma proteins and to human albumin was examined by means of ultrafiltration. RESULTS The oligonucleotides can be stably labeled with (68)Ga and DOTA chelate. Intravenously injected (68)Ga-oligonucleotides of 17-mer length revealed high-quality PET images, allowing quantification of the biokinetics in major organs and in tumors. The biodistribution and biokinetics of intravenously administered (68)Ga-oligonucleotide varied considerably with the nature of the oligonucleotide backbone. CONCLUSION We conclude that (68)Ga labeling of oligonucleotides is a convenient approach for in vivo imaging and quantification of oligonucleotide biokinetics in living animals with PET.