Cyclic RGD Peptides Incorporating Cycloalkanes: Synthesisand Evaluation as PET Radiotracers for Tumor Imaging

摘要

Two new bicyclic arginine-glycine-aspartic acid (RGD) peptides, c(RGD-ACP-K) (>1a) and c(RGD-ACH-K) (>1b), incorporating the aminocyclopentane (ACP) and aminocyclohexane (ACH) carboxylic acids, respectively, were synthesized by grafting the aminocycloalkane carboxylic acids onto the tetra-peptide RGDK sequence. These peptides and their conjugates with DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid) (>2a–>b) exhibit high affinity toward U87MG glioblastoma cells. Their affinity is greater than that exhibited by c(RGDyK). Labeling these conjugates with radiometal ⁶⁴Cu resulted in high radiochemical yields (>97%) of the corresponding complexes, abbreviated as c(RGD-ACP-K)-DOTA-⁶⁴Cu (>3a) and c(RGD-ACH-K)-DOTA-⁶⁴Cu (>3b). Both >3a and >3b are stable for 24 h in human and mouse serums and show high tumor uptake, as observed by positron emission tomography (PET). Blocking experiments with >3a and >3b by preinjection of c(RGDyK) confirmed their target specificity and demonstrated their promise as PET radiotracers for imaging ανβ3-positive tumors.