The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a 68Ga-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin

Abstract

Abstract: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 (PEG 2 ) spacer (NOTA-PEG 2 -RM26) and labeled with 68 Ga 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 IC 50 values of nat Ga-NOTA-PEG n -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 68 Ga-NOTA-PEG 3 -RM26 showed lower liver uptake. Biodistribution of 68 Ga-NOTA-PEG 3 -RM26 was evaluated in OPEN ACCESSMolecules 2014, 19 10456 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 68 Ga-NOTA-PEG 3 -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.

18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging

“…16 Among BBN antagonists, the potent RM26 (D-Phe-Gln-Trp-Ala-ValGly-His-Sta-Leu-NH 2 ) has been widely derivatized for radiolabeling with 64 Cu/ 68 Ga and 111 In for imaging GRPR-expressing prostate cancer with positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively. [17][18][19] Recent successful detection of GRPR-expressing prostate cancer in clinical studies using RM26 derivatives ( 68 Ga-BAY86-7548 20 and 64 Cu-CB-TE2A-AR06 21 ) further demonstrated the potential usefulness of radiolabeled GRPR antagonists for prostate cancer imaging.…”

“…For biodistribution study, 0.37-0.74 MBq ($0.1 mL) of 18 F-AmBF 3 -MJ9 was injected via the caudal lateral tail vein while mice were under brief isoflurane sedation. The radioactivity in the syringe was measured before and after injection to determine the total amount of administrated 18 F-AmBF 3 -MJ9.…”

“…Previously we reported a facile one-step 18 F-labeling approach via 18 F- 19 F isotope exchange reaction on an ammoniomethyltrifluoroborate (AmBF 3 ) moiety 23 generality of this approach for the design of peptide-based 18 Flabeled tracers, we report the synthesis and biological evaluation of a novel GRPR antagonist 18 F-AmBF 3 -MJ9 (Scheme 1) for prostate cancer imaging.…”

“…Among commercially available imaging radioisotopes, 18 F is the most widely used for clinical PET imaging because of its ideal nuclear properties including high positron branching fraction (97%), low positron energy (0.64 MeV), and a suitable physical half-life of 109.7 min. 22 Due to the popularity of 18 F-labeled 2-fluorodeoxyglucose for cancer imaging, 18 F is available daily in multi-Curie quantities from most of medical cyclotron facilities.…”

“…22 Due to the popularity of 18 F-labeled 2-fluorodeoxyglucose for cancer imaging, 18 F is available daily in multi-Curie quantities from most of medical cyclotron facilities. This facile and on-demand production underscores the importance of developing 18 F-labeled BBN-based PET probes for a more efficient application in clinic for prostate cancer imaging.…”