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⁶⁸Ga-Labeled Oligonucleotides for In Vivo Imaging with PET

¹ Turku PET Centre, Turku University Hospital, Turku, Finland
² Uppsala Imanet, Uppsala, Sweden
³ Department of Chemistry, University of Turku, Turku, Finland
⁴ Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Uppsala, Sweden
⁵ Institute of Biomedicine and Medicity Research Laboratory, University of Turku, Turku, Finland

The biologic evaluation in living rats of ⁶⁸Ga-labeled oligonucleotides as imaging agents for PET is reported. Methods: ⁶⁸Ga, 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 ⁶⁸Ga-oligonucleotide. Blank studies were performed using ⁶⁸GaCl₃ or ⁶⁸Ga-DOTA alone without oligonucleotide. The ⁶⁸Ga-antisense oligonucleotide uptake in tumors was also compared with the ¹⁸F-FDG and ⁶⁸Ga-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 ⁶⁸Ga and DOTA chelate. Intravenously injected ⁶⁸Ga-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 ⁶⁸Ga-oligonucleotide varied considerably with the nature of the oligonucleotide backbone. Conclusion: We conclude that ⁶⁸Ga labeling of oligonucleotides is a convenient approach for in vivo imaging and quantification of oligonucleotide biokinetics in living animals with PET.

Key Words: ⁶⁸Ga • oligonucleotides • in vivo imaging • PET • biokinetics

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