One-step ¹⁸F-labeling of carbohydrate-conjugated octreotate-derivatives containing a silicon-fluoride-acceptor (SiFA): in vitro and in vivo evaluation as tumor imaging agents for positron emission tomography (PET).

Abstract

The synthesis, radiolabeling, and initial evaluation of new silicon-fluoride acceptor (SiFA) derivatized octreotate derivatives is reported. So far, the main drawback of the SiFA technology for the synthesis of PET-radiotracers is the high lipophilicity of the resulting radiopharmaceutical. Consequently, we synthesized new SiFA-octreotate analogues derivatized with Fmoc-NH-PEG-COOH, Fmoc-Asn(Ac₃AcNH-β-Glc)-OH, and SiFA-aldehyde (SIFA-A). The substances could be labeled in high yields (38 ± 4%) and specific activities between 29 and 56 GBq/μmol in short synthesis times of less than 30 min (e.o.b.). The in vitro evaluation of the synthesized conjugates displayed a sst2 receptor affinity (IC₅₀ = 3.3 ± 0.3 nM) comparable to that of somatostatin-28. As a measure of lipophilicity of the conjugates, the log P(ow) was determined and found to be 0.96 for SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate and 1.23 for SiFA-Asn(AcNH-β-Glc)-Tyr³-octreotate, which is considerably lower than for SiFA-Tyr³-octreotate (log P(ow) = 1.59). The initial in vivo evaluation of [¹⁸F]SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate revealed a significant uptake of radiotracer in the tumor tissue of AR42J tumor-bearing nude mice of 7.7% ID/g tissue weight. These results show that the high lipophilicity of the SiFA moiety can be compensated by applying hydrophilic moieties. Using this approach, a tumor-affine SiFA-containing peptide could successfully be used for receptor imaging for the first time in this proof of concept study.

• Authors: Carmen Wängler, Beatrice Waser, Andrea Alke, Ljuba Iovkova, Hans-Georg Buchholz, Sabrina Niedermoser, Klaus Jurkschat, Christian Fottner, Peter Bartenstein, Ralf Schirrmacher, Jean-Claude Reubi, Hans-Jürgen Wester, Björn Wängler
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 21 Issue 12 Pg. 2289-96 (Dec 15 2010) ISSN: 1520-4812 [Electronic] United States
• PMID: 21082773 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbohydrates
• Fluorine Radioisotopes
• Radiopharmaceuticals
• Receptors, Somatostatin
• Polyethylene Glycols
• Somatostatin-28
• Fluorides
• Silicon

Topics

• Animals
• Carbohydrates (chemistry)
• Cell Line, Tumor
• Diagnostic Imaging (methods)
• Drug Stability
• Fluorides (chemistry)
• Fluorine Radioisotopes (chemistry, metabolism, pharmacokinetics)
• Humans
• Hydrophobic and Hydrophilic Interactions
• Isotope Labeling (methods)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Pancreatic Neoplasms (diagnosis, metabolism)
• Polyethylene Glycols (chemistry)
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (blood, chemical synthesis, pharmacokinetics)
• Receptors, Somatostatin (metabolism)
• Silicon (chemistry)
• Somatostatin-28 (metabolism)
• Tissue Distribution