title: New trends in peptide receptor radioligands.
abstract: 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 sub-type 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 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-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 111In-DOTA-DPhe1-Tyr3-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 99mTc-HYNIC-octreotide or 99mTc-depreotide (NEOSPECT; NEOTECT). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-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 "MAURITIUS" (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase IIa study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-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 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-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 188Re-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.
authors.affiliation: Department of Nuclear Medicine, University of Vienna, Austria. irene.virgolini@akh-wien.ac.at
authors.forename: I
authors.initials: I
authors.lastname: Virgolini
authors.forename: T
authors.initials: T
authors.lastname: Traub
authors.forename: C
authors.initials: C
authors.lastname: Novotny
authors.forename: M
authors.initials: M
authors.lastname: Leimer
authors.forename: B
authors.initials: B
authors.lastname: Füger
authors.forename: S R
authors.initials: SR
authors.lastname: Li
authors.forename: P
authors.initials: P
authors.lastname: Patri
authors.forename: T
authors.initials: T
authors.lastname: Pangerl
authors.forename: P
authors.initials: P
authors.lastname: Angelberger
authors.forename: M
authors.initials: M
authors.lastname: Raderer
authors.forename: F
authors.initials: F
authors.lastname: Andreae
authors.forename: A
authors.initials: A
authors.lastname: Kurtaran
authors.forename: R
authors.initials: R
authors.lastname: Dudczak
mesh_terms: D000818:Animals; D006801:Humans; D007205:Indium Radioisotopes; D015282:Octreotide / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000032:analysis*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D007205:Indium Radioisotopes; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C060347:lanreotide; D013004:Somatostatin; D015282:Octreotide