Preparation and preliminary biological evaluation of ¹⁸F-metal complex labeled glycosylated somatostatin analogues

Objectives: The aims of this study were doing the synthesis of Al/Fe¹⁸F labeled glycosylated somatostatin analogues, the investigation of the SSTR positive tumor-targeting, the PET imaging in tumor bearing nude mice.

Methods: The glycosylated somatostatin analogue Glu-Lys(NOTA)-Octreotate was synthesized, and labelled using the chelation reaction with Al/Fe¹⁸F complex. The octanol-water partition coefficient and the stability in saline and calf serum were investigated as well. The studies were focused on the biodistribution and the Micro-PET imaging in nude mice bearing AR42J tumor.

Results: The chemical purity of Glu-Lys(NOTA)-Octreotate was more than 95%, and synthetic yield was 11%. Glu-Lys([Al¹⁸F]NOTA)-Octreotate (1) and Glu-Lys([Fe¹⁸F]NOTA)-Octreotate (2) were prepared in 72% and 40% labeling rates, >95% radiochemical purity after purification, and 25~30 min preparation time. (1) and (2) showed excellent water-solubility with logP value of -4.23 ± 0.19 and -4.18 ± 0.15, respectively. (1) was stable, but radiochemical purity of (2) decreased significantly after incubation in the saline and the fetal bovine serum at 37℃ for 120min, this indicated that (2) was unstable in vitro. The biodistribution experiments in normal mice showed: both (1) and (2) were fast clear from blood, liver uptake was very low, all excluded by kidney. The uptake in pancreas which showed SSTR express was high. The high bone uptake of (2) was showed gradually with in 120min post injection. The biodistribution experiments and Micro-PET scans of (1) in nude mice bearing AR42J tumor showed: The high uptake was found in tumor, and tumor delineation of Micro-PET was clear. Receptor blocking experiments showed that the uptake of (1) in tumor was receptor-mediated.

Conclusions: A glycosylated somatostatin analogues was radio-synthesized fast and efficiently with Al¹⁸F. Fe¹⁸F labelled conjugate of (2) was unstable in vitro and in vivo, and not suitable for PET imaging. The targeting of the probe (1) to the SSTR positive tumors was excellent. (1) is expected for PET imaging of SSTR positive tumors, and this study provides experimental basis for further research and development PET probes which could be used for the SSTR positive tumors diagnosis clinically.