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)

Bioconjug Chem. 2010 Dec 15;21(12):2289-96. doi: 10.1021/bc100316c. Epub 2010 Nov 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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