Effects of adding an albumin binder chain on [177Lu]Lu-DOTATATE

Introduction: [Lu-177]Lu-DOTATATE peptide receptor radionuclide therapy is used for treatment of neuroendocrine tumours. We investigated whether prolonging blood residence time of [Lu-177]Lu-DOTATATE with albumin binders could increase tumour accumulation and tumour-to-kidney ratios for improved therapeutic efficacy. Methods: DOTATATE and its derivatives with an albumin-binder motif (GluAB-DOTATATE and AspAB-DOTATATE) were prepared by solid-phase peptide synthesis. Binding affinities of the Lu-labeled peptides for human somatostatin receptor 2 (SSTR2) were measured with membrane competition binding assays. Compounds were radiolabeled with [Lu-177]LuCl3 and purified by HPLC SPECT imaging and biodistribution studies (1, 4, 24, 72, and 120 h) were performed in immunodeficient mice bearing AR42J pancreatic tumour xenografts. Results: GluAB-DOTATATE and AspAB-DOTATATE were synthesized in 18.8% and 14.3% yields. while Lu-GluAB-DOTATATE and Lu-AspAB-DOTATATE were obtained in 86.5% and 50.0% yields, respectively. The compounds exhibited nanomolar binding affinity (K-i: 8.72-8.95 nM) for SSTR2. The Lu-177-labeled peptides were obtained in non-decay-corrected isolated yields of >= 41%, with >96% radiochemical purity, and molar activities in the range of 314-497 GBq/mu mol. In vivo, [Lu-177]Lu-GluAB-DOTATATE and [Lu-177]Lu-AspAB-DOTATATE had significantly higher blood activity at 1, 4 and 24 h compared to [Lu-177]Lu-DOTATATE. Tumour uptake of [Lu-177]Lu-DOTATATE was 2135 +/- 5.90%ID/g at 1 h and decreased to 10.10 +/- 5.78%ID/g at 120 h. For [Lu-177]Lu-GluAB-DOTATATE tumour uptake increased from 21.89 +/- 6.86%ID/g at 1 h to 24.44 +/- 5.84%ID/g at 4 h, before decreasing to 12.02 +/- 1.84%ID/g at 120 h. For [Lu-177]Lu-AspAB-DOTATATE tumour uptake was 11.12 +/- 3.18%ID/g at 1 h, 18.41 +/- 436% ID/g at 24 h, and decreased to 16.90 +/- 8.97%ID/g at 120 h. Renal uptake was 7.49 +/- 1.62%ID/g for [Lu-177]Lu-DOTATATE, 31.14 +/- 7.06%ID/g for [Lu-177]Lu-GluAB-DOTATATE, and 28.82 +/- 13.82%ID/g for [Lu-177]Lu-AspAB-DOTATATE at 1 h and decreased thereafter. Conclusion: The addition of albumin binder motifs to [Lu-177]Lu-DOTATATE enhanced mean residence time in blood. Increased tumour uptake was observed for [Lu-177]Lu-AspAB-DOTATATE compared to [Lu-177]Lu-DOTATATE at later time points, but its higher kidney uptake diminished the therapeutic index. (C) 2018 Elsevier Inc. All rights reserved.