Synthesis and 177Lu Labeling of the First Retro Analog of the HER2-Targeting A9 Peptide: A Superior Variant

The retro analog of the HER2-targeting A9 peptide wassynthesizedby coupling amino acids in a reverse fashion and switching the N-terminalin the original sequence of the L-A9 peptide (QDVNTAVAW) to the C-terminalin rL-A9 (WAVATNVDQ). Modification in the backbone resulted in higherconformational stability of the retro peptide as evident from CD spectra.Molecular docking analysis revealed a higher HER2 binding affinityof [Lu-177]Lu-DOTA-rL-A9 than the original radiopeptide[Lu-177]Lu-DOTA-L-A9. Enormously enhanced metabolic stabilityof the retro analog led to significant elevation in tumor uptake andretention. SPECT imaging studies corroborated biodistribution resultsdemonstrating a remarkably higher tumor signal for [Lu-177]Lu-DOTA-rL-A9. The presently studied retro probe has promisingefficiency for clinical screening.