Radiosynthesis and biodistribution of a prosthetic group (¹⁸F-FENMA) conjugated to cyclic RGD peptides.
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 α(v)β₃. 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.
Department of Pharmaceutics & Biopharmaceutics, University of Tromsø, Norway.
Dag Erlend
DE
Olberg
Alan
A
Cuthbertson
Magne
M
Solbakken
Joseph M
JM
Arukwe
Hong
H
Qu
Alexandr
A
Kristian
Skjalg
S
Bruheim
Ole Kristian
OK
Hjelstuen
D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D003952:Diagnostic Imaging / Q000379:methods*; D004355:Drug Stability; D005462:Fluorine Radioisotopes / Q000737:chemistry; D054879:Halogenation; D006898:Hydroxylamines / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000175:diagnosis / Q000378:metabolism; D010456:Peptides, Cyclic / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011422:Propionates / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013343:Styrenes / Q000737:chemistry; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D002264:Carboxylic Acids; D005462:Fluorine Radioisotopes; D006898:Hydroxylamines; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D011422:Propionates; D019275:Radiopharmaceuticals; D013343:Styrenes; C507169:cyclic arginine-glycine-aspartic acid peptide; C011955:beta-nitrostyrene; C018338:N-methylhydroxylamine