Albutate-1, a Novel Long-Circulating Radiotracer Targeting the Somatostatin Receptor Subtype 2

Abstract

Currently, radiolabeled DOTA-[Tyr3]-octreotate (DOTA-TATE) is most commonly used in the clinic to image and treat neuroendocrine tumors. To further improve tumor uptake, and thus treatment, the amount of radiotracer that can accumulate in the tumor might be increased by prolonging the blood circulation time of the radiotracer. To achieve this, we designed Albutate-1, with both DOTA and an albumin-binding domain coupled to TATE via a suitable linker. The aim of this study was to determine the characteristics of the novel radiotracer Albutate-1. A competition binding assay was performed using [111In]In-DOTA-TATE on fresh-frozen SSTR2+ tumor sections. In vitro cell-uptake and internalization of [111In]In-Albutate-1 and [111In]In-DOTA-TATE were determined. The stability of [177Lu]Lu-Albutate-1 was tested. A biodistribution study was performed to provide tumor and organ uptake of [177Lu]Lu-Albutate-1. The biodistribution data was used to determine time-activity curves and the radiation dose for each organ and the tumor. The in vitro IC50 value of Albutate-1 was 1.2 nM. A higher amount of the tracer was found in the intracellular fraction than in the membrane fraction ([111In]In-Albutate-1 14.0 vs 1.9% of the added amount; [111In]In-DOTA-TATE 11.0 vs 1.5% of the added amount). After radiolabeling [111In] In-Albutate-1 was stable up to 3 days (93.1-88.9%) in labeling solution and very stable in mouse serum (90-94%) for at least 24 h. In vivo, [177Lu]Lu-Albutate-1 was cleared slowly from the circulation (1 h p.i. 58%ID/g, 168h p.i. 2%ID/g). The addition of an albumin-binding domain to DOTA-TATE extended the blood circulation to T1/2= 27.5h. The tumor absorbed dose was raised to 1455 mGy/MBq. Bone marrow, the dose-limiting organ in the mouse spine, unfortunately, received 765 mGy/MBq. All other organs also received a high radiation dose, reducing the therapeutic index.