44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations

Katharina A Domnanich; Cristina Müller; Renata Farkas; Raffaella M Schmid; Bernard Ponsard; Roger Schibli; Andreas Türler; Nicholas P van der Meulen

doi:10.1186/s41181-016-0013-5

⁴⁴Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations

EJNMMI Radiopharm Chem. 2017;1(1):8. doi: 10.1186/s41181-016-0013-5. Epub 2016 May 5.

Authors

Katharina A Domnanich^{1

2}, Cristina Müller^{3

4}, Renata Farkas³, Raffaella M Schmid³, Bernard Ponsard⁵, Roger Schibli^{3

4}, Andreas Türler^{1

2}, Nicholas P van der Meulen^{1

3}

Affiliations

¹ Laboratory of Radiochemistry, Paul Scherrer Institute, CH-5232 Villigen-PSI, Switzerland.
² Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland.
³ Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI, Switzerland.
⁴ Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
⁵ SCK.CEN, BR2 Reactor, 2400 Mol, Belgium.

Abstract

Background: Recently, ⁴⁴Sc (T_1/2 = 3.97 h, Eβ⁺_av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of ⁴⁴Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with ⁴⁴Sc compared with its ⁶⁸Ga-labeled counterparts.DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with ⁴⁴Sc and ⁶⁸Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe³⁺ and Cu²⁺. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice.

Results: Both RGD- and NOC-based peptides with a DOTA chelator were readily labeled with ⁴⁴Sc and ⁶⁸Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with ⁴⁴Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. ⁴⁴Sc-NODAGA peptides were clearly more susceptible to metal challenge than ⁴⁴Sc-DOTA peptides under the same conditions. Instability of ⁶⁸Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu²⁺. Biodistribution data of the ⁴⁴Sc-labeled peptides were largely comparable with the data obtained with the ⁶⁸Ga-labeled counterparts. It was only in the liver tissue that the uptake of ⁶⁸Ga-labeled DOTA compounds was markedly higher than for the ⁴⁴Sc-labeled version and this was also visible on PET/CT images. The ⁴⁴Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability.

Conclusions: Although DOTA revealed to be the preferred chelator for stable coordination of ⁴⁴Sc, the data presented in this work indicate the possibility of using NODAGA in combination with ⁴⁴Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of ⁴⁴Sc-labeled NODAGA compounds.

Keywords: 44Sc; 68Ga; AR42J; DOTA-NOC; DOTA-RGD; Imaging; NODAGA-NOC; NODAGA-RGD; PET; Stability; U87MG.