Oligonucleotides in PET imaging

Nucleotides are the build blocks of DNA and RNA, consisting of a nucleobase (adenine, cytosine, guanine, thymine, or uracil), a 5-carbon sugar, and a phosphate group. Oligonucleotide can hybridize to another chain if their sequences can form G☰C and A⚌T or A⚌U pairs. Thus, oligonucleotides can be used as ligands for DNA and RNA (antisense oligonucleotides). Oligonucleotides can also be designed to specifically bind to other molecular targets (aptamer oligonucleotides). Techniques for generic labelling and protection from nucleases are available, but directing oligonucleotides into the cell cytoplasm and nucleus while still maintaining their functionality is still challenging.

In blood plasma, oligonucleotides are bound to albumin (Srinivasan et al., 1995), which is common to negatively charged molecules. Oligonucleotides tend to bind to other proteins, too, and while this may not be a problem for medicinal use of oligonucleotide, it increases the nonspecific binding and decreases the image quality.

Antisense oligonucleotides

Antisense oligonucleotide binds to its target RNA, and inhibits its translation. The secondary structures of RNAs (hairpins, stem-loops) may prevent or slow down the hybrid formation with the antisense oligonucleotide. The number of mRNAs copies in a cell may be too low for detection in vivo. Antisense imaging may therefore be most successful in detecting viral or bacterial mRNAs that are abundant in infected tissue.

Aptamer oligonucleotides

DNA and RNA aptamers (usually 20-100 bases) are usually single-stranded, and can form 3D-structures, enabling them to bind to a specific target (aptatope); targets can be anything from small ions such as Zn2+ to viruses and bacteria. Libraries of oligonucleotides can be synthesized randomly and simultaneously screened for their binding affinity to a target molecule. This procedure is easier and faster than the methods for production of monoclonal antibodies, and it works with targets that are toxic or non-immunogenic. Aptamers are an order of magnitude smaller than antibodies (10-20 kDa versus 150 kDa), and therefore have faster endothelial passage and clearance. Aptamers, like antibodies, are usually targeted against molecules that are abundant enough for successful detection with the excellent sensitivity of modern PET devices.

Escort aptamers can be used for targeted delivery of drugs, and diagnostic or therapeutic radionuclides.

Riboswitches are naturally occurring aptamers, mainly found in the untranslated regions of mRNA molecules; when bound to their target molecule, the 3D structural change in mRNA affects its translational activity.


See also:



References:

Boisgard R, Kuhnast B, Vonhoff S, Younes C, Hinnen F, Verbavatz JM, Rousseau B, Fürste JP, Wlotzka B, Dollé F, Klussmann S, Tavitian B. In vivo biodistribution and pharmacokinetics of 18F-labelled Spiegelmers: a new class of oligonucleotidic radiopharmaceuticals. Eur J Nucl Med Mol Imaging 2005; 32(4): 470-477.

Dougherty CA, Cai W, Hong H. Applications of aptamers in targeted imaging: state of the art. Curr Top Med Chem. 2015; 15(12): 1138-1152.

Gambhir SS. Using radiolabeled DNA as an imaging agent to recognize protein targets. J Nucl Med. 2006; 47(4): 557-558.

Gijs M, Aerts A, Impens N, Baatout S, Luxen A. Aptamers as radiopharmaceuticals for nuclear imaging and therapy. Nucl Med Biol. 2016; 43: 253-271.

Hong H, Zhang Y, Cai W. In vivo imaging of RNA interference. J Nucl Med. 2010; 51(2): 169-172.

Iyer AK, He J. Radiolabeled oligonucleotides for antisense imaging. Curr Org Synth. 2011; 8(4): 604-614.

Kiviniemi A, Mäkelä J, Mäkilä J, Saanijoki T, Liljenbäck H, Poijärvi-Virta P, Lönnberg H, Laitala-Leinonen T, Roivainen A, Virta P. Solid-supported NOTA and DOTA chelators useful for the synthesis of 3’-radiometalated oligonucleotides. Bioconjugate Chem. 2012; 23: 1981-1988. doi: 10.1021/bc300253t.

Roivainen A, Tolvanen T, Salomäki S, Lendvai G, Velikyan I, Numminen P, Välilä M, Sipilä H, Bergström M, Härkönen P, Lönnberg H, Långström B. 68Ga-Labeled oligonucleotides for in vivo imaging with PET. J Nucl Med. 2004; 45: 347-355.

Srinivasan SK, Tewary HK, Iversen PL. Characterization of binding sites, extent of binding, and drug interactions of oligonucleotides with albumin. Antisense Res Dev. 1995; 5: 131-139.

Tavitian B, Terrazzino S, Kühnast B, Marzabal S, Stettler O, Dollé F, Deverre JR, Jobert A, Hinnen F, Bendriem B, Crouzel C, Di Giamberardino L. In vivo imaging of oligonucleotides with positron emission tomography. Nat Med. 1998; 4(4): 467-471.

Tavitian B. In vivo imaging with oligonucleotides for diagnosis and drug development. Gut 2003; 52(Suppl IV): iv40-iv47.

Tavitian B. Oligonucleotides as radiopharmaceuticals. In: Bogdanov AA Jr, Licha K (eds.): Molecular Imaging - An Essential Tool in Preclinical Research, Diagnostic Imaging and Therapy. Springer, 2005. pp 1-34.

Viel T, Boisgard R, Kuhnast B, Jego B, Siquier-Pernet K, Hinnen F, Dollé F, Tavitian B. Molecular imaging study on in vivo distribution and pharmacokinetics of modified small interfering RNAs (siRNAs). Oligonucleotides 2008; 18(3): 201-212.

Wang F, Niu G, Chen X, Cao F. Molecular imaging of microRNAs. Eur J Nucl Med Mol Imaging 2011; 38: 1572-1579.

Wang AZ, Farokhzad OC. Current progress of aptamer-based molecular imaging. J Nucl Med. 2014; 55: 353-356.



Tags: ,


Created at: 2017-10-28
Updated at: 2017-10-29
Written by: Vesa Oikonen