A Systematic Comparative Evaluation of 68Ga-Labeled RGD Peptides Conjugated with Different Chelators
The present paper reports a systematic study on the effect of bifunctional chelators (BFC) namely, NOTA, DOTA, and DTPA, on the radiochemical formulation, in vitro stability, and in vivo biological properties of 68Ga-labeled RGD peptide derivatives.
The three RGD conjugates namely, NOTA-Bn-E-[c(RGDfk)]2, DOTA-Bn-E-[c(RGDfk)]2, and DTPA-Bn-E-[c(RGDfk)]2 were radiolabeled with 68Ga and the radiolabeling was optimized with respect to the ligand amount, radiolabeling time, and temperature. Further, the 68Ga complexes were assessed for their in vitro and in vivo stabilities. The biodistribution studies of the three radiolabeled conjugates were carried out in C57BL/6 mice bearing melanoma tumor at 30 min and 1 h post-adimistration.
NOTA-Bn-E-[c(RGDfk)]2 could be radiolabeled with 68Ga at room temperature while DOTA-Bn-E-[c(RGDfk)]2 and DTPA-Bn-E-[c(RGDfk)]2 were radiolabeled at high temperature. 68Ga-NOTA-Bn-E-[c(RGDfk)]2 was found to be the most kinetically rigid in in vitro stability assay. The uptake of the three radiolabeled peptide conjugates in melanoma tumor was comparable at 1 h post-administration (NOTA; DOTA; DTPA (% I.D./g):: 2.78 ± 0.38; 3.08 ± 1.1; 3.36 ± 0.49). However, the tumor/background ratio of 68Ga-NOTA-Bn-E-[c(RGDfk)]2 was the best amongst the three radiotracers. 68Ga-complexes of NOTA-Bn-E-[c(RGDfk)]2 and DOTA-Bn-E-[c(RGDfk)]2 showed excellent in vivo stability while 68Ga-DTPA-Bn-E-[c(RGDfk)]2 showed significant metabolic degradation.
These studies show that 68Ga-NOTA-Bn-E-[c(RGDfk)]2 would be the most appropriate 68Ga-labeled radiotracer and the most amenable for kit formulation.
KeywordsTumor angiogenesis PET imaging RGD peptides 68Ga Bifunctional chelators
The authors are thankful to Dr. Aruna Korde, Head, Radiopharmaceutical Evaluation Section, Radiopharmaceuticals Division, BARC for providing access to the 68Ge/68Ga generator. Thanks are also due to Dr. B.S. Tomar, Director, Radiochemistry & Isotope Group, BARC for his support and encouragement.
Compliance with Ethical Standards
Conflict of Interest
Akanksha Jain, Sudipta Chakraborty, Haladhar Dev Sarma and Ashutosh Dash, declare that they have no conflict of interest financial, scientific or otherwise in the publication of this article. Research at the Bhabha Atomic Research Centre (BARC) is part of the ongoing activities of the Department of Atomic Energy, India and is fully supported by government funding.
All procedures performed in studies involving animals were in strict compliance with the approved protocols of Institutional Animal Ethics Committee of BARC, India.
The institutional review board of our institute, BARC, approved this retrospective study, and the requirement to obtain informed consent was waived.
- 7.Haubner R, Maschauer S, Prante O. PET radiopharmaceuticals for imaging integrin expression: tracers in clinical studies and recent developments. Bio Med Res Int. 2014;871609:1–17.Google Scholar
- 12.Ziegler SI. Positron emission tomography: principles, technology, and recent developments. Nucl Phys A. 2005;752:679–87.Google Scholar
- 15.Röesch F, Riss PJ. The renaissance of the 68Ge/68Ga radionuclide generator initiates new developments in 68Ga radiopharmaceutical chemistry. Curr Top Med Chem. 2010;10:1633–68.Google Scholar
- 18.Velikyan I, Maeck H, Langstrom B. Convenient preparation of 68Ga based PET radiopharmaceuticals at room temperature. Bioconjug Chem 2008; 19:569–573.Google Scholar
- 19.Chakraborty S, Chakravarty R, Vatsa R, Bhusari P, Sarma HD, Shukla J, et al. Toward realization of ‘mix-and-use’ approach in 68Ga radiopharmacy: preparation, evaluation and preliminary clinical utilization of 68Ga-labeled NODAGA-coupled RGD peptide derivative. Nucl Med Biol. 2016;43:116–23.CrossRefPubMedGoogle Scholar
- 25.Oxboel J, Brandt-Larsen M, Schjoeth-Eskesen C, Myschetzky R, El-Ali HH, Madsen J, et al. Comparison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2; in vivo imaging studies in human xenograft tumors. Nucl Med Biol. 2014;41:259–67.CrossRefPubMedGoogle Scholar