Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2:: an in vitro/in vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3 human prostate cancer cells

Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to identify a BBN analogue that can be radiolabeled with Lu-177 and maintains high specificity for GRPr positive prostate cancer tumors in vivo. A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a DOTA-BBN (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid) conjugate with the following general structure: DOTA-X-Q-W-A-V-G-H-L-M-(NH2), where the spacer group, X = omega-NH2(CH2)(7)COOH (8-Aoc). The BBN-construct was purified by reversed phase-HPLC (RP-HPLC). Electrospray Mass Spectrometry (ES-MS) was used to characterize both metallated and non-metallated BBN-conjugates. The new DOTA-conjugate was metallated with Lu-177(III)Cl-3 or non-radioactive Lu(III)Cl-3. The Lu-177(III)- and non-radiolabeled Lu(III)-conjugates exhibit the same retention times under identical RP-HPLC conditions. The Lu-177-DOTA-8-Aoc-BBN[7-14]NH2 conjugate was found to exhibit optimal pharmacokinetic properties in CF-1 normal mice. In vitro and in vivo models demonstrated the ability of the Lu-177-DOTA-8-Aoc-BBN[7-14]NH2 conjugate to specifically target GRP receptors expressed on PC-3 human prostate cancer cells. (C) 2003 Elsevier Science Inc. All rights reserved.