First 18F-labeled tracer suitable for routine clinical imaging of sst receptor-expressing tumors using positron emission tomography

Purpose: Despite excellent radionuclide characteristics, no F-18-labeled peptides are available for quantitative peptide receptor mapping using positron emission tomography (PET) so far, mainly due to time-consuming multistep radiosyntheses with limited overall yields. A newly developed two-step chemoselective conjugation method allows rapid and high-yield [F-18]fluorination of peptides via oxime formation and was applied for the synthesis of new 18F-labeled carbohydrated Tyr(3)-octreotate (TOCA) analogs with optimized pharmacokinetics suitable for clinical routine somatostatin-receptor (sst) imaging. Experimental Design: F-18-labeled glucose (Gluc-S-) and cellobiose (Cel-S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime formation with 4-[F-18]fluorobenzaldehyde ([F-18]FBOA-peptides). Both the in vitro internalization profile of Gluc-S-Dpr([F-18]FBOA)TOCA and Cel-S-Dpr([F-18]FBOA)TOCA in hsst(2)-expressing Chinese hamster ovary cells (dual tracer protocol) and their biodistribution in AR42J tumor-bearing mice were investigated and compared with two [F-18]fluoropropionylated ([F-18]FP) analogs, Gluc-Lys([F-18]FP)TOCA and Gluc-S-Dpr([F-18]FP)TOCA. Results: In contrast to [F-18]FP-labeling (3 h), chemoselective [F-18]FBOA-formation (50 min) afforded the respective radiopeptides in high yields (65-85%). In vitro, Gluc-S-Dpr([F-18]FBOA)TOCA and Cel-S-Dpr([F-18]FBOA)-TOCA showed high internalization (139 +/-0 2 and 163 +/- 8 of the reference [I-125]Tyr(3)-octreotide, respectively), which was reflected by high tumor accumulation in vivo [21.8 +/- 1.4 and 24.0 +/- 2.5% of injected dose/g (1 h), respectively]. However, only Cel-S-Dpr([F-18]FBOA)TOCA and Gluc-S-Dpr([F-18]FP)TOCA (tumor: 15.1 +/- 1.5% of injected dose/g) with its very low accumulation in all of the nontarget organs showed improved tumor:organ ratios compared with Gluc-Lys([F-18]FP)TOCA.ForCel-S-Dpr([F-18]FBOA)TOCA, tumor:organ ratios (1 h) were 42:1, 27:1, 15:1, 3:1, and 208:1 for blood, liver, intestine, kidney, and muscle, respectively. Conclusion: Due to the fast and high-yield chemoselective radiofluorination strategy and to its excellent pharmacokinetics, Cel-S-Dpr([F-18]FBOA)TOCA represents the first tracer suitable for routine clinical application in PET somatostatin receptor imaging.