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Preclinical Evaluation of New and Highly Potent Analogues of Octreotide for Predictive Imaging and Targeted Radiotherapy

¹ Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, Basel, Switzerland and ² Institute of Pathology, University of Berne, Berne, Switzerland

Requests for reprints: Helmut R. Maecke, Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Phone: 41-61-265-46-99; Fax: 41-61-265-55-59; E-mail: hmaecke{at}uhbs.ch.

Purpose: Molecular imaging and targeted radiotherapy are emerging fields in nuclear oncology. Five human somatostatin receptors (hsstr1-hsstr5) are known to be overexpressed to some degree on various tumors, sstr2 being the most important one. Clinically used somatostatin based radiopeptides target exclusively sstr2. The aim of this study was to develop novel analogues with a broader sstr profile for diagnostic (positron emission tomography and single-photon emission computed tomography) and radiotherapeutic applications.

Experimental Design: The following promising structures emerged from a parallel synthetic approach: [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA⁰),1-Nal³,Thr⁸]-octreotide (1, DOTA-NOC-ATE) and [DOTA⁰,BzThi³,Thr⁸]-octreotide (2, DOTA-BOC-ATE). The conjugates were labeled with cold and radioactive ¹¹¹In. Pharmacologic properties were compared with [¹¹¹In-DOTA,Tyr³]-octreotide ([¹¹¹In-DOTA]-TOC).

Results: The receptor affinity profile showed high affinity of both peptides to hsstr2, hsstr3, and hsstr5 and some intermediate affinity to hsstr4, whereas [¹¹¹In-DOTA]-TOC shows affinity only to sstr2. The internalization is fast in sstr2 expressing AR4-2J and in transfected sstr3 expressing human embryonic kidney 293 cells. Both radiopeptides internalize much more efficiently than [¹¹¹In-DOTA]-TOC. Animal biodistribution studies showed very high and specific uptake of [¹¹¹In]-1 and [¹¹¹In]-2 in s.c. implanted AR4-2J tumors (Lewis rats) and in somatostatin receptor expressing normal tissues. The uptake was at least 2-fold higher in these tissues and in the tumor compared with [¹¹¹In-DOTA]-TOC. In addition, the kidney uptake was significantly lower for both radiopeptides.

Conclusions: These data suggest that the novel radiopeptides are superior to [¹¹¹In/⁹⁰Y-DOTA]-TOC and show great promise for the clinical application in the imaging of somatostatin receptor–positive tumors and their targeted radiotherapy.

Key Words: Somatostatin receptors • DOTA • radiopeptides • Indium-111 • Yttrium-90

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