Novel 99mTc-labeled somatostatin receptor antagonists (TECANT)

Neuroendocrine neoplasms (NEN) are a heterogeneous group of tumours biologically characterized by somatostatin receptors (SSTR) on the surface of cells. Nuclear medicine is a molecular imaging method able to visualize NEN by radioactively labelled substances that bind to SSTR, allowing prediction and evaluation of response to various therapies available. Recently, novel molecular probes, so called SSTR antagonists, were shown to provide superior SSTR visualization than currently used agonists. The development of a widely available imaging approach in combination with improved radiopharmaceuticals would therefore represent a significant improvement in NEN patient management. The aim of this project is (1) to select a 99mTc-labelled SSTR antagonist and establish a pharmaceutical formulation for NEN imaging; (2) to initiate a clinical study in NEN patients and (3) develop a robust, reproducible quantitative imaging method. From two promising radiopharmaceutical candidates a superior candidate will be selected for human application and a kit-formulation for radiolabelling developed. Twelve NEN patients with proven SSTR expression on agonist imaging will be imaged at predefined time points for assessment of biological behaviour and radiation dose using a concurrently developed quantitative imaging protocol. 99m Tc-labeled SSTR antagonists can prove to be an effective, widely available method for quantitative assesment of SSTR status in NEN. As such, it could decisively influence management of patients with NEN, allowing a personalized therapeutic approach.

The project aimed to develop a novel 99mTc-labelled somatostatin receptor (SSTR) antagonist as a sensitive tool for imaging neuroendocrine neoplasms (NEN) in Nuclear Medicine. The Medical University Innsbruck The rationale of the project was based on the limited availability and efficacy of the current standard for NEN imaging (Ga-68-labeled SST agonists) in tumours with low SSTR expression. SSTR antagonists thereby recognize more binding sites on NEN cells compared to agonists with the potential of improved diagnostic sensitivity. Subsequent steps of the study included (1) selection of an optimal SSTR antagonist and pharmaceutical kit formulation (radiopharmaceutical development); (2) initiation of a clinical feasibility study and (3) development of a robust, reproducible quantitative imaging method. Within the first phase stability, radiolabelling, SSTR targeting properties and in vivo behaviour of N4-LM-3 (TECANT1) and N4-p-Cl-BASS (TECANT2) were compared. [99mTc]Tc-TECANT1 showed better NEN targeting properties, low toxicity, and was finally selected for clinical studies. A pharmaceutical kit formulation for hopaital preparation of [99mTc]Tc-TECANT1 was developed and all data compiled for approval by ethical committee and pharmaceutical authorities. In total 10 patients with NEN were imaged using Single Photon Emmission Tomography (SPECT), 3 patient recruited by the Medical University Innsbruck. Rapid distribution with predominant renal excretion with the typical pattern of SST analogues was observed, NEN lesions were very well visible in all examined patients (mostly with higher contrast and detection rate in comparison to 68Ga-SSTR agonist imaging). Obtained biodistribution and dosimetry data showed that the novel biomarker [99mTc]Tc-TECANT1 is safe after intravenous injection, has a low radiation burden and allowed for visualization of NEN lesions with high sensitivity. The use of [99mTc]Tc-TECANT1 appears to be of great clinical value and holds potential as a key element in a personalized approach to the management of NEN patients. This project was funded as part of the EU's ERA-Permed program. The Medical University of Innsbruck was part of a consortium with partners in Poland (University of Krakow and the National Center for Nuclear Research) and Slovenia (University and Medical Center Ljubljana), led the pharmaceutical development and was a partner in the clinical study.