New trends in peptide receptor radioligands

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to In-111-DTPA-(D)Phe(1)-octreotide (OCTREOSCAN (R)) which binds to hSSTR2 and 5 with high affinity (K-d 0.1-5 nM), to hSSTR3 with moderate affinity (K-d 10-100 nM) and does not bind to hSSTR1 and hSSTR4, In-111/Y-90-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K-d 200 nM). Based on its unique hSSTR binding profile, In-111-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and Y-90-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to In-111-DTPA-(D)Phe(1)-octreotide and In-111-DOTA-(D)Phe(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higher" high-affinity binding of In-111-DOTA-(D)Phe(1)-Tyr(3)-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including (99)mTc-HYNIC-octreotide or Tc-99m-depreotide (NEOSPECT (R) ;NEOTECT (R)). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non small cell lung cancer (Tc-99m-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study "MAURTTTUS" (Multicenter Analysis of a Universal Receptor imaging and Treatment Initiative, a eUropean Study), a Phase Pa study, showed in patients with a calculated tumor dose > 10 Gy/GBq Y-90-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in > 60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to Y-99-DOTA-lanreotide, was reported. In-90-DOTA-(D)Phe(1)-Tyr(3)-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of Re-188-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm "proof-of-principle'' for their use in diagnosis as well as therapy of cancer patients, However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy.