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.