Radiosynthesis and Biodistribution of a Prosthetic Group (18F-FENMA) Conjugated to Cyclic RGD Peptides

• Published in: Bioconjugate chemistry Vol. 21; no. 12; pp. 2297 - 2304
• Main Authors: Olberg, Dag Erlend, Cuthbertson, Alan, Solbakken, Magne, Arukwe, Joseph M., Qu, Hong, Kristian, Alexandr, Bruheim, Skjalg, Hjelstuen, Ole Kristian
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.12.2010
• Subjects: Animals; Biochemistry; Carboxylic Acids - chemistry; Diagnostic Imaging - methods; Drug Stability; Fluorine Radioisotopes - chemistry; Halogenation; Hydroxylamines - chemistry; Integrin alphaVbeta3 - metabolism; Isotope Labeling; Kidneys; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Osteosarcoma - diagnosis; Osteosarcoma - metabolism; Peptides; Peptides, Cyclic - blood; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - pharmacokinetics; Positron-Emission Tomography - methods; Propionates - chemistry; Proteins; Radiopharmaceuticals - blood; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Rodents; Styrenes - chemistry; Tissue Distribution; Transplantation, Heterologous; Tumors
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc1003229

We have recently reported a new N-methylaminooxy-based prosthetic group for the site-selective introduction of 18F-fluorine under mild acidic aqueous conditions into model peptides functionalized with a Michael acceptor moiety. To further investigate the utility of this methodology, the radiosynthesis of two cyclic RGD peptides was carried out, and in vivo biodistribution and microPET studies were performed in tumor-bearing mice. A cyclic RGD peptide was functionalized with the Michael acceptors trans-β-nitrostyrene carboxylic acid and 3-vinylsulfonylpropionic acid. Radiolabeling was then performed with the prosthetic group O-(2-(2-[18F]fluoroethoxy)ethyl)-N-methylhydroxylamine (18F-FENMA) yielding the 18F-conjugates in moderate yields (8.5−12%). Biodistribution, blocking, and microPET imaging studies were performed in a mouse xenograft model. The vinylsulfonyl-modified conjugate demonstrated good in vitro plasma stability. Biodistribution and microPET studies revealed excellent tumor uptake with low background in key organs and renal elimination as the predominant route of excretion. Blocking studies with coinjected nonlabeled RGD peptide confirmed the in vivo specificity for the integrin αvβ3. On the other hand, 18F-FENMA-nitrostyrene-RGD, although stable at conjugation pH 5, was found to rapidly degrade at physiological pH through loss of the 18F-prosthetic group.