The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a 68Ga-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin
Zohreh Varasteh,
Ulrika Rosenström,
Irina Velikyan,
Bogdan Mitran,
Mohamed Altai,
Hadis Honarvar,
Maria Rosestedt,
Gunnar Lindeberg,
Jens Sörensen,
Mats Larhed,
Vladimir Tolmachev,
Anna Orlova
Affiliations
Zohreh Varasteh
Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
Ulrika Rosenström
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
Irina Velikyan
Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
Bogdan Mitran
Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
Mohamed Altai
Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Sciences, Faculty of Medicine, Uppsala University, Uppsala SE-751 85, Sweden
Hadis Honarvar
Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Sciences, Faculty of Medicine, Uppsala University, Uppsala SE-751 85, Sweden
Maria Rosestedt
Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
Gunnar Lindeberg
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
Jens Sörensen
Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Sciences, Faculty of Medicine, Uppsala University, Uppsala SE-751 85, Sweden
Mats Larhed
Department of Medicinal Chemistry, Science for Life Laboratory, BMC, Uppsala University, Uppsala SE-751 23, Sweden
Vladimir Tolmachev
Biomedical Radiation Sciences, Department of Radiology, Oncology and Radiation Sciences, Faculty of Medicine, Uppsala University, Uppsala SE-751 85, Sweden
Anna Orlova
Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala SE-751 23, Sweden
The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethyleneglycol (PEG2) spacer (NOTA-PEG2-RM26) and labeled with 68Ga can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of natGa-NOTA-PEGn-RM26 (n = 2, 3, 4, 6) were 3.1 ± 0.2, 3.9 ± 0.3, 5.4 ± 0.4 and 5.8 ± 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however 68Ga-NOTA-PEG3-RM26 showed lower liver uptake. Biodistribution of 68Ga-NOTA-PEG3-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 ± 0.6%ID/g and 2.8 ± 0.4%ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/blood of 44 ± 12 and 42 ± 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of 68Ga-NOTA-PEG3-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.
