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

Abstract

PURPOSE:

Despite excellent radionuclide characteristics, no (18)F-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 [(18)F]fluorination of peptides via oxime formation and was applied for the synthesis of new (18)F-labeled carbohydrated Tyr(3)-octreotate (TOCA) analogs with optimized pharmacokinetics suitable for clinical routine somatostatin-receptor (sst) imaging.

EXPERIMENTAL DESIGN:

(18)F-labeled glucose (Gluc-S-) and cellobiose (Cel-S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime formation with 4-[(18)F]fluorobenzaldehyde ([(18)F]FBOA-peptides). Both the in vitro internalization profile of Gluc-S-Dpr([(18)F]FBOA)TOCA and Cel-S-Dpr([(18)F]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 [(18)F]fluoropropionylated ([(18)F]FP) analogs, Gluc-Lys([(18)F]FP)TOCA and Gluc-S-Dpr([(18)F]FP)TOCA.

RESULTS:

In contrast to [(18)F]FP-labeling (3 h), chemo-selective [(18)F]FBOA-formation (50 min) afforded the respective radiopeptides in high yields (65-85%). In vitro, Gluc-S-Dpr([(18)F]FBOA)TOCA and Cel-S-Dpr([(18)F]FBOA)-TOCA showed high internalization (139 +/- 2 and 163 +/- 8 of the reference [(125)I]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]. How-ever, only Cel-S-Dpr([(18)F]FBOA)TOCA and Gluc-S-Dpr([(18)F]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([(18)F]FP)TOCA. For Cel-S-Dpr([(18)F]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([(18)F]FBOA)TOCA represents the first tracer suitable for routine clinical application in PET somatostatin receptor imaging.

• Authors: Margret Schottelius, Thorsten Poethko, Michael Herz, Jean-Claude Reubi, Horst Kessler, Markus Schwaiger, Hans-Jürgen Wester
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 11 Pg. 3593-606 (Jun 01 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15173065 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorine Radioisotopes
• Oximes
• Peptides
• Radiopharmaceuticals
• Receptors, Somatostatin
• Fluorodeoxyglucose F18
• Glucose

Topics

• Animals
• CHO Cells
• Cell Line, Tumor
• Chromatography, High Pressure Liquid
• Cricetinae
• Dose-Response Relationship, Drug
• Fluorine Radioisotopes
• Fluorodeoxyglucose F18 (chemistry)
• Glucose (chemistry)
• Glycosylation
• Inhibitory Concentration 50
• Kinetics
• Magnetic Resonance Spectroscopy
• Models, Chemical
• Neoplasms (diagnosis, pathology)
• Oximes (chemistry)
• Peptides (chemistry)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals
• Rats
• Receptors, Somatostatin (biosynthesis)
• Time Factors
• Tissue Distribution
• Transfection