Targeting GRPR-expressing tumors with an ¹⁸F-labeled bombesin analog

Objectives Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate and breast cancers. In this study, the GRPR-targeting characteristics of an ¹⁸F-labeled NOTA-conjugated bombesin derivative (IMP468) were determined in vitro and in vivo, and compared with those of the ⁶⁸Ga-labeled compound.

Methods For ¹⁸F-labeling of IMP468, we used our new 1-pot, 2-step method for labeling peptides with ¹⁸F. A solution of AlCl₃ was mixed with an aqueous solution of ¹⁸F to form the Al¹⁸F²⁺ complex. This was added to a solution of IMP468 and heated to 100 °C for 15 min. The labeled product was purified by RP-HPLC. The Log P values of the radiotracers were determined. Tumor targeting characteristics of the compounds were assessed in mice with sc PC3 xenografts. GRPR-binding specificity was studied by coinjection of an excess of unlabeled IMP468. MicroPET images were acquired using an Inveon PET/CT system.

Results IMP468 was labeled with ¹⁸F in a single step with 50-90% yield. Radiolabeling, including purification, was performed in 45 min and resulted in a spec. act. >10 MBq/nmol. Log P values of ⁶⁸Ga- and ¹⁸F-labeled IMP468 were -1.98 ± 0.03 and -1.47 ± 0.05, respectively. Radiolabeled IMP468 cleared rapidly from the blood (0.05 ± 0.02 %ID/g at 1 h p.i.), mainly via the kidneys. At 1 h p.i., tumor uptake of ¹⁸F-IMP468 was higher (2.15 ± 0.55 %ID/g) than all other nontarget tissues (muscle: 0.15 ± 0.28; liver: 1.30 ± 0.66; kidney: 0.94 ± 0.46 %ID/g). GRPR-binding specificity was demonstrated by reduced tumor uptake of radiolabeled IMP468 after coinjection of a 100-fold excess of unlabeled IMP468 (0.88 ± 0.12 %ID/g at 1 h p.i.). The accumulation of ¹⁸F-IMP468 in the sc PC3 tumors was clearly visualized with microPET.

Conclusions IMP468 could be labeled rapidly and efficiently with ¹⁸F using a 2-step, 1-pot method. ¹⁸F-IMP468 accumulated efficiently and specifically in the sc PC3 tumors in mice