Radiolabelled 177Lu‐Bispidine‐Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers

Abstract Radioimmunotherapy (RIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanoid‐selective nonadentate bispidine ligand suitable for 177 Lu 3+ ion complexation. The ligand (bisp, 1 ) was derivatised with a photoactivatable aryl azide (ArN 3 ) group as a bioconjugation handle for light‐induced labelling of proteins. Quantitative radiosynthesis of [ 177 Lu]Lu‐ 1 + was accomplished in 10 minutes at 40 °C. Subsequent incubation of [ 177 Lu]Lu‐ 1 + with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH 8.0–8.3, gave the radiolabelled mAb, [ 177 Lu]Lu‐ 1 ‐azepin‐trastuzumab ([ 177 Lu]Lu‐ 1 ‐mAb) in a decay‐corrected radiochemical yield of 14 %, and radiochemical purity (RCP)>90 %. Stability studies and cellular binding assays in vitro using the SK‐OV‐3 human ovarian cancer cells confirmed that [ 177 Lu]Lu‐ 1 ‐mAb remained biological active and displayed specific binding to HER2/ neu . Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK‐OV‐3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4 %ID g −1 vs. 14.8±6.1 %ID g −1 , respectively; P ‐value=0.037). The data indicate that bispidine‐based ligand systems are suitable starting points for constructing novel, high‐denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides.