Novel [18F]Fluorine-Based PET Tracers with Polar But Nonbasic Linkers to Image the Fibroblast Activation Protein in the Microenvironment of Tumors.

Köchel R; Schwegmann K; Breyholz HJ; Schäfers M; Wagner S; Wünsch B

Abstract

The fibroblast activation protein (FAP) is highly expressed by cancer associated fibroblasts in the microenvironment of tumors. The PET tracer [68Ga]Ga-oncoFAP-DOTAGA (1) is clinically used to detect FAP-positive tumors. In order to improve the imaging properties, fluorinated FAP inhibitors 8, 9, 14, and 21 with polar but nonbasic linkers were designed, synthesized, and biologically evaluated. The PEG-based ligand 21 exhibited particularly high FAP inhibitory activity (IC50 = 13 pM), high selectivity toward related dipeptidyl peptidases, very low log D7.4 value, and high metabolic stability in vitro. Nucleophilic substitution of tosylate 20 led to the PET tracer [18F]21 in 10.8% radiochemical yield and 97.4% radiochemical purity within a total synthesis time of 119 min [18F]21 revealed high stability in human and murine serum. In biodistribution studies in CD-1 mice, [18F]21 showed renal and hepatobiliary elimination. In a mouse xenograft model, considerable accumulation of [18F]21 in FAP-positive HT1080 tumors was observed.