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

Purpose: Despite excellent radionuclide characteristics, no ¹⁸F-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 [¹⁸F]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: ¹⁸F-labeled glucose (Gluc-S-) and cellobiose (Cel-S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime formation with 4-[ ¹⁸F]fluorobenzaldehyde ([¹⁸F]FBOA-peptides). Both the in vitro internalization profile of Gluc-S-Dpr([¹⁸F]FBOA)TOCA and Cel-S-Dpr([¹⁸F]FBOA)TOCA in hsst₂-expressing Chinese hamster ovary cells (dual tracer protocol) and their biodistribution in AR42J tumor-bearing mice were investigated and compared with two [ ¹⁸F]fluoropropionylated ([¹⁸F]FP) analogs, Gluc-Lys([ ¹⁸F]FP)TOCA and Gluc-S-Dpr([¹⁸F]FP)TOCA. Results: In contrast to [¹⁸F]FP-labeling (3h), chemoselective [ ¹⁸F]FBOA-formation (50 min) afforded the respective radiopeptides in high yields (65-85%). In vitro, Gluc-S-Dpr([¹⁸F]FBOA)TOCA and Cel-S-Dpr([¹⁸F]FBOA)TOCA showed high internalization (139 ± 2 and 163 ± 8 of the reference [¹²⁵I]Tyr³-octreotide, respectively), which was reflected by high tumor accumulation in vivo [21.8 ± 1.4 and 24.0 ± 2.5% of injected dose/g (1h), respectively]. However, only Cel-S-Dpr([¹⁸F]FBOA)TOCA and Gluc-S-Dpr-([ ¹⁸F]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([¹⁸F]FP)TOCA.ForCel-S-Dpr([ ¹⁸F]FBOA)TOCA, tumor:organ ratios (1h) 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([ ¹⁸F]FBOA)TOCA represents the first tracer suitable for routine clinical application in PET somatostatin receptor imaging.