Medullary thyroid cancer (MTC) arises from the Calcitonin (Ctn) producing C-cell of the thyroid and accounts for 1- 2% of all thyroid cancer. Due to the unspecific signs and symptoms the patients present at a metastasized stage in 40-50% of the cases. Ctn is a reliable tumormarker and is associated with tumor mass. The diagnostic work up in order to establish the extent of disease includes conventional imaging (neck ultrasound, MRI, CT) and as molecular imaging 18F-DOPA-PET (gold standard). However, by combining these modalities there are still ca. 20% of patients with elevated Ctn levels without morphological evidence of disease (small tumor remnants). There is, therefore, an unmet need for a more sensitive diagnostic tool. The only curative approach is surgery. Conventional chemotherapy is not efficacious and targeted therapy using tyrosine kinase inhibitors stabilize, but do not cure the disease and are associated with significant toxicity. There is, therefore, and unmet need for a more effective therapeutical tool.A promising tool is targeting of peptide hormone receptors, over-expressed on the surface of MTC cells. The over-expression on MTC cells allows specific targeting of MTC with radiolabeled analogues. Both, imaging and therapy are possible with this approach (theranostic). Potential receptors are cholecystokinin-2 receptors (CCK2-R) targeted by a minigastrin analogue (177Lu-PP-F11N) and somatostatin subtype 2 receptors (sst2-R) targeted by an sst2-R antagonist (177Lu-OPS201). Both compounds are exclusively available for research in our institution.Working HypothesisBoth, 177Lu-PP-F11N and 177Lu-OPS201 are promising radiotracers for imaging and therapy of patients with MTC. Both compounds perform better than 18F-DOPA-PET and 177Lu-DOTATOC (sst2-R agonist) and will improve therapy of patients with MTC. It is currently unclear which compound performs better. Specific AimsThe performance of the two novel radiotracers 177Lu-PP-F11N and 177Lu-OPS201 will be compared with each other, with 18F-DOPA and 177Lu-DOTATOC in the same patient. The primary endpoint is the tumor-to-organ ratio (in relation to the dose limiting organ) as it is the most relevant parameter to predict the efficacy of the radiotracers.Experimental DesignPatients with a diagnosis of MTC (initial work-up or during follow-up) and elevated Ctn levels are included. They undergo 18F-DOPA-PET imaging (gold standard). 177Lu-PP-F11N and 177Lu-OPS201 imaging will be performed in a randomized cross-over order. Whole body dosimetry is done and tumor-to-organ dose ratios will be calculated (including ratios of dose limiting organs). In case of a better tumor-to-organ dose ratio with 177Lu-PP-F11N and absence of a surgical option the patients are included in a phase II trial of peptide receptor radionuclide therapy (PRRT) using 177Lu-PP-F11N (supported by Oncosuisse). In case of a mainly positive result with 177Lu- OPS201 and absence of a surgical option the patients will be offered peptide receptor radionuclide therapy using 177Lu-DOATOC. In the case of surgery, tissue specimens are investigated in vitro for the expression of sst2- and CCK2-R using autoradiography and compared with the obtained tumor doses of the respective radiotracers. Expected ValueThe results of this study will be crucial for the planning of a phase II study by answering the following question: (1) Which radiotracer/targeting system performs best in patients with MTC, (2) are tumor doses high enough for an efficient therapy of residual, recurrent or metastatic MTC disease and (3) are efficient tumor doses safe in relation to the dose limiting organs (i.e. stomach, bone marrow, kidney).