title: 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.affiliation: Department of Nuclear Medicine, Hospital of the Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wängler
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Andrea
authors.initials: A
authors.lastname: Alke
authors.forename: Ljuba
authors.initials: L
authors.lastname: Iovkova
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Buchholz
authors.forename: Sabrina
authors.initials: S
authors.lastname: Niedermoser
authors.forename: Klaus
authors.initials: K
authors.lastname: Jurkschat
authors.forename: Christian
authors.initials: C
authors.lastname: Fottner
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.forename: Björn
authors.initials: B
authors.lastname: Wängler
mesh_terms: D000818:Animals; D002241:Carbohydrates / Q000737:chemistry; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging / Q000379:methods*; D004355:Drug Stability; D005459:Fluorides / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012825:Silicon / Q000737:chemistry; D053561:Somatostatin-28 / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002241:Carbohydrates; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D011092:Polyethylene Glycols; D053561:Somatostatin-28; D005459:Fluorides; D012825:Silicon