Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer

The imaging potential of a new 18F-labelled methionine derivative, S-(3-[18F]fluoropropyl)-d-homocysteine (18F-D-FPHCys), and its selectivity for amino acid transporter subtypes were investigated in vitro and by imaging of human tumour xenografts. Expression of members of the system L (LAT isoforms 1-4 and 4F2hc) and ASCT (ASCT isoforms 1 and 2) amino acid transporter subclasses were assessed by quantitative real-time PCR in four human tumour models, including A431 squamous cell carcinoma, PC3 prostate cancer, and Colo 205 and HT-29 colorectal cancer lines. The first investigations for the characterization of 18F-D-FPHCys were in vitro uptake studies by comparing it with [1-14C]-l-methionine (14C-MET) and in vivo by PET imaging. In addition, the specific involvement of LAT1 transporters in 18F-D-FPHCys accumulation was tested by silencing LAT1 mRNA transcription with siRNAs. To determine the proliferative activity in tumour xenografts ex vivo, Ki-67 staining was used as a biomarker. A431 cells showed the highest 18F-D-FPHCys uptake in vitro and in vivo followed by Colo 205, PC3 and HT-29. A similar pattern of retention was observed with 14C-MET. 18F-D-FPHCys retention was strongly correlated with LAT1 expression both in vitro (R 2 = 0.85) and in vivo (R2 = 0.99). Downregulation of LAT1 by siRNA inhibited 18F-D-FPHCys uptake, demonstrating a clear dependence on this transporter for tumour uptake. Furthermore, 18F-D-FPHCys accumulation mirrored cellular proliferation. The favourable properties of 18F-D-FPHCys make this tracer a promising imaging probe for detection of tumours as well as for the noninvasive evaluation and monitoring of tumour growth. (orig.)