Cyclic RGD peptides are potent antagonists for the alpha(v)beta(3) integrin receptor. In this Letter, microwave-assisted solid-phase synthesis of cyclic RGD peptides is described. In a coupling reaction between Fmoc-Arg(Pbf)-OH and high-loading H-Gly-Trt(2-Cl) resin, multiple coupling reactions were required for completion under the conventional HBTU activation. We found that the use of COMU, a new coupling reagent, under microwave heating to 50 degrees C accelerated the reaction even inside the resin. This method was applicable to the synthesis of linear pentapeptides, H-Asp(OtBu)-Xxx-Yyy-Arg(Pbf)-Gly-OH (Xxx = D-Phe(p-Br) or D-Tyr, Yyy = Lys(Boc) or MeVal). Cyclization of these peptides followed by deprotection gave the desired cyclic RGD peptides with high purity. (C) 2011 Elsevier Ltd. All rights reserved.