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. Other (nontumoral) potential indications for SSTR scintigraphy are based on an increased lymphocyte binding at sites of inflammatory or
immunologic diseases such as thyroid-associated ophthalmology. The vast majority of human
tumors seem to over-express the one or the other of five distinct hSSTR subtype receptors. Whereas
neuroendocrine tumors frequently overexpress hSSTR2, intestinal
adenocarcinomas seem to overexpress more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to In-DTPA-DPhe(1)-octreotide (
OctreoScan(R)) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (K(d) 10-100 nM) and does not bind to hSSTR1 and hSSTR4, (111)In / (90)Y-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, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for
tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated
radionuclide therapy. As opposed to (111)In-DTPA-DPhe(1)-octreotide and (111)In-DOTA-DPhe(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 "higherrdquuo; high-affinity binding of (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide to hSSTR2 (K(d) 0.1-1 nM). Other
somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, such as (99m)Tc-depreotide (NeoSpect(R);
NeoTect(R)). Most of the imaging results are reported for
neuroendocrine tumors (
octreotide analogs) or
nonsmall cell lung cancer ((99m)Tc-depreotide), indicating high diagnostic cabability 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. Beneficial results were reported for high-dose treatment with (111)In-DTPA-DPhe(1)-octreotide, based on the emission of Auger electrons. The Phase IIa study "MAURITIUS" (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study) showed in progressive
cancer patients (
therapy entry criteria) with a calculated
tumor dose > 10 Gy / GBq (90)Y-DOTA-lanreotide, the proof-of-principle for treating
tumor patients with
peptide receptor imaging agents. In the "MAURITIUS" study, cummulative treatment doses up to 200 mCi (90)Y-DOTA-lanreotide were given as short-term infusion. Overall treatment results in 70 patients indicated stable
tumor disease in 35% of patients and regressive
tumor disease in 10% of
tumor patients with different
tumor entities expressing hSSTR. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to (90)Y-DOTA-lanreotide treatment, were reported. (90)Y-DOTA-DPhe(1)-Tyr(3)-octreotide may show a higher
tumor uptake in
neuroendocrine tumor lesions and may therefore be superior for treatment in patients with
neuroendocrine tumors. However, there is only limited excess to long-term and survival data at present. Potential indications for (90Y-
DOTA-
lanreotide are radioiodine-negative
thyroid cancer,
hepatocellular cancer and
lung cancer. Besides newer approaches and recent developments of 188)Re-labeled radioligands, no clinical results on the treatment response are yet available. 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 their potential use in diagnosis as well as "proof-of-principle" for
therapy of
cancer patients. However, an optimal radiopeptide formulatioents. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted
radionuclide therapy. Ongoing developments may result in
peptides more suitable for this kind of receptor-targeted
radionuclide therapy.