A new amphiphilic GdIII chelate, which is capable of forming micelles in aqueous solution (see diagram), has been synthesized. Due to this self‐aggregation, the compound has a long rotational ...correlation time and, consequently, has high proton relaxivities that thus far have only been obtained with macromolecular complexes.
All commercially available somatostatin analogs for clinical use have a preference for some but not all somatostatin receptor subtypes. We describe here the synthesis and evaluation in binding and ...cAMP assays with cell lines stably transfected with sst
1–sst
5 of a new type of nonapeptide somatostatin analog with a reduced-sized and stabilized structure, Tyr
0–(cyclo-
d-Dab–Arg–Phe–Phe–
d-Trp–Lys–Thr–Phe) (KE108). All five somatostatin receptors subtypes have an extremely high affinity for KE108, equivalent to SS-28 at sst
1 and two to four times higher than SS-28 at sst
2, sst
3, sst
4 and sst
5. Moreover, the compound has agonistic properties at all five subtypes, since it is able to inhibit the forskolin-stimulated cAMP production in sst
1–sst
5 cells. It is stable for several hours in human serum. This analog may therefore represent a considerable improvement over commercially available somatostatin analogs as it will target all somatostatin receptor subtypes, a particular advantage for cancer-related applications, as human cancers can express concomitantly several somatostatin receptor subtypes.
New DOTA-based bifunctional prochelators, e.g., 1-(1-carboxy-3-carbo
tertbutoxypropyl)-4,7,10-(carbo
tertbutoxymethyl)-1,4,7,10-tetraazacyclodode-cane (DOTAGA(tBu)
4), (
6d) for a broad application ...in the modification of biomolecules with metal ions were prepared. The five-step synthesis of
6d has an overall yield of about 20%. The coupling of
6d to a bioactive peptide on solid-phase was exemplified with use of a CCK-B (cholecystokinin) analogue.
The aim of this study was to determine the inter- and intrapatient variability of absorbed dose to the whole body, kidneys, and tumor, as well as the question of whether the first therapy could serve ...as a guide for future therapies. Fifty (50) (90)Y-DOTATOC therapies were given to 30 patients diagnosed with refractory stage IV neuroendocrine tumors (20 patients received two therapies, 10 patients received one therapy). The first and second therapies were delivered at standard intervals. (90)Y-activity was prescribed by surface area (3.7 GBq/m(2)), and approximately 100 MBq (111)In-DOTATOC was administered concurrently for imaging purposes. Amino acid coadministration for renal protection was performed. Measurements of activity in whole-body and single-photon emission computed tomography images were acquired at various time points after the administration of the radiopharmaceutical. The dosimetry for whole body, kidneys, and tumor was based on these data. The interpatient variability (the ratio of the maximum absorbed dose per injected activity for all patients) was larger than the intrapatient variability (the ratio of absorbed dose per injected activity for subsequent therapies in the same patient for whole body, kidneys, and tumor. These results imply that the first therapy could serve as a guide for future therapies. This approach might allow for targeted radionuclide therapy to be delivered by prescribed absorbed dose, rather than by administered activity.
Somatostatin analogs labeled with radionuclides are of considerable interest in nuclear oncology as diagnostic or therapeutic tools for somatostatin receptor (SSTR)-expressing tumors. We investigated ...the suitability of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as a replacement for the widely used diethylenetriaminepentaacetic acid, to enable stable labeling of somatostatin analogs with both therapeutic (90Y) and diagnostic (111In) radionuclides. The three clinically relevant somatostatin agonists, octreotide, vapreotide, and lanreotide, together with the newly designed Tyr3-octreotide (TyrOc), were conjugated to DOTA and labeled with 90Y or 111In. For all DOTA-somatostatin analogs tested, irrespective of the incorporated radionuclide, we observed favorable biodistribution profiles in AR4-2J tumor-bearing mice: 1) a rapid clearance from all SSTR-negative tissues except kidney; 2) a specific uptake in SSTR-positive tissues, including tumor; and 3) an excellent tumor penetration. The main route of excretion was via the kidneys. Nevertheless, DOTATOC was clearly superior to the other DOTA-somatostatin analogs tested, as well as OctreoScan, as indicated by the highest tumor-to-nontarget-tissue ratio, including the tumor-to-SSTR-positive-tissue ratios. The presence of different SSTR subtypes in the SSTR-positive tissues possibly contributes to these differential uptakes. We assume that the very favorable behavior of DOTATOC in our mouse model makes this radioligand very promising for future applications in nuclear oncology.
Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue Tyr3octreotide (D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) was ...derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled DOTA0,Tyr3octreotide in somatostatin receptor subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111In-labelled DOTA0, Tyr3octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled DOTA0,Tyr3octreotide in sst2-positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0. 1 (pituitary and stomach) and 0.25 (pancreas) microg. Uptake in the tumour was highest at 0.5 microg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for 111In-DTPA0octreotide ((D-Phe-c(Cys-Phe-D-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound. Our observations of mass-dependent differences in uptake of radiolabelled DOTA0, Tyr3octreotide, being the resultant of a positive effect of increasing amounts of peptide on, for example, receptor clustering and a negative effect of receptor saturation, are of consequence for rat radionuclide therapy studies with radiolabelled peptides and may also be of consequence for human radionuclide therapy studies with this compound.
Octreotide is a somatostatin analogue that is widely used for cancer therapy and tumor imaging. Its efficacy in tumors depends mainly on the expression of the somatostatin receptor type 2 (sst 2). ...Desensitization and down-regulation of sst 2 after agonist exposure can have important consequences for patients under ongoing octreotide therapy because it may induce temporary tumor unresponsiveness and impair sst 2-based tumor scintigraphy. Therefore, we have investigated the effect of octreotide on sst 2 expression in vitro, as well as in a tumor mouse model. In vitro, short exposure to octreotide induced rapid dose-dependent down-regulation of sst 2 in the rat pancreatic AR4-2J cell line. Within 0.5 h, 80% of sst 2 had disappeared from the cell surface. A total recovery required 24 h and was shown to depend on protein synthesis, but not on new sst 2 mRNA transcription, indicating that sst 2 was probably degraded during the down-regulation process. Similar results were obtained in vivo. On the other hand, long-term continuous release of octreotide for 7 days, as achieved with octreotide-containing osmotic minipumps, caused sst 2 up-regulation in vivo, but not in vitro. Furthermore, this up-regulation of sst 2 in tumor-bearing scid mice was shown to depend on constant exposure of the animals to octreotide, as it was not observed when octreotide was given discontinuously in two s.c. daily injections. These results demonstrate that the continuous release of a small amount of octreotide, which in cancer therapy may be achieved with long-acting release formulations of the peptide, can induce sst 2 up-regulation on cancer cells. This may improve the efficacy of both tumor imaging and long-term octreotide therapy.
Dynamic PET studies with(68)Ga-DOTATOC were performed in patients with non-small cell lung cancer (NSCLC) to assess the somatostatin receptor 2 (SSTR2) expression. Furthermore, ...dynamic(18)F-fluorodeoxyglucose (FDG) studies were performed in the same patients to compare the SSTR2 expression with the tumour viability. The study population comprised nine patients, examined with both tracers on two different days within 1 week. Standardised uptake values (SUVs) were calculated and a two-tissue compartment model was applied to the data. Furthermore, a non-compartment model based on the fractal dimension (FD) was applied to the data. The DOTATOC uptake was generally lower than the FDG uptake. Moderately enhanced DOTATOC uptake was noted in seven of the nine tumours. All kinetic parameters except k (4) were lower for DOTATOC than for FDG. The mean SUV was 2.018 for DOTATOC, in comparison to 5.683 for FDG. In particular, k (3) was highly variable for DOTATOC and showed an overlap with the normal lung tissue. The fractional blood volume V (B) was relatively low for both tracers, not exceeding 0.3. The highest significant logarithmic correlation was found for the FD of the two tracers (r=0.764, p=0.017). The logarithmic correlation for SUVs was also significant (r=0.646, p=0.060), as was that forV (B) (r=0.629, p=0.069). In contrast, none of the eight metastases which were positive on FDG PET showed any DOTATOC uptake. The results demonstrated moderate (68)Ga-DOTATOC uptake in primary NSCLC but did not provide any evidence for SSTR2 expression in metastases. This may be caused by loss of the gene expression in metastases as compared with the primary tumours.
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