Dynamic PET studies with a 68Ga-bombesin analog, DOTA-PEG2-d-Tyr6, beta-Ala11,Thi13,Nle14 BN(6-14) amide (68Ga-BZH3; DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid, and PEG is ...ethylene glycol 2-aminoethyl-carboxymethyl ether), were performed on patients with gastrointestinal stromal tumors (GIST) to investigate the impact of complementary receptor scintigraphy on diagnosis and the potential of a radionuclide treatment. Furthermore, dynamic 18F-FDG studies were performed on the same patients.
This study comprised 17 patients with GIST. All patients were scheduled for therapy with imatinib because of unresectable primary or recurrent GIST or because of metastatic disease. Dynamic PET scans using 68Ga-BZH3 and 18F-FDG were obtained on 2 consecutive days. Multivariate analysis was used to evaluate the kinetic data. Standardized uptake values (SUVs) were calculated, and a compartmental model (2-tissue) and noncompartmental model were used for data evaluation of both tracers.
Fourteen of 17 patients (25/30 lesions) were positive for uptake on 18F-FDG imaging, whereas 68Ga-BZH3 demonstrated an enhanced accumulation in 7 of 17 patients (8/30 lesions). Thirteen lesions were confirmed by histologic examination, and the remaining 17 were confirmed by follow-up. One recurrent tumor in the stomach could not be delineated on 18F-FDG imaging but showed enhanced 68Ga-BZH3 uptake. The median SUV for 68Ga-BZH3 was 3.3, in comparison with 7.9 for 18F-FDG. Best-subset analysis demonstrated that the global SUV (55-60 min after injection) for 18F-FDG was primarily dependent on k3, followed by k1. Multivariate analysis did not show a significant correlation between the kinetic parameters (k1-k4, fractional blood volume, and SUV) for 18F-FDG and bombesin.
68Ga-BZH3 may be helpful for diagnostic reasons in a subgroup of patients with GIST, as in the case of negative 18F-FDG findings and suspicion of viable tumor tissue. The meaning of the enhanced 68Ga-BZH3 uptake is open at the moment.
Bombesin (BN), a 14-amino-acid peptide, shows high affinity for the human gastrin-releasing peptide receptor (GRP-r), which is overexpressed on several types of cancer, including prostate, breast, ...gastrointestinal, and small cell lung cancer. Thus, radiolabeled BN or BN analogs may prove to be specific tracers for diagnostic and therapeutic targeting of GRP-r-positive tumors in nuclear medicine. This study evaluated a novel BN analog labeled with the positron emitter 68Ga for receptor imaging with PET.
DOTA-PEG2-D-Tyr6,beta-Ala11,Thi13,Nle14 BN(6-14) amide (BZH3) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid; PEG is ethyleneglycol (2-aminoethyl)carboxymethyl ether) was synthetized using the Fmoc strategy and radiolabeled with either 67Ga or 177Lu for in vitro and biodistribution experiments. 68Ga for PET was obtained from a 68Ge/68Ga generator. In vitro binding, internalization, and efflux were determined using the pancreatic tumor cell line AR42J. Biodistribution of the peptide as a function of time and dose was studied in AR42J tumor-bearing mice.
In vitro assays demonstrated a high affinity of 67Ga-BZH3 (dissociation constant = 0.46 nmol/L), a rapid internalization (70% of total cell-associated activity was endocytosed after a 15-min incubation), and an intracellular retention half-life (t1/2) of the 67Ga activity of 16.5 +/- 2.4 h. Biodistribution indicated a dose-dependent uptake in the tumor and a prolonged tumor residence time (t1/2 approximately 16 h). Clearance from GRP-r-negative tissues was fast, resulting in high tumor-to-tissue ratios as early as 1 h after injection. Replacing 67Ga by 177Lu, a therapeutic radionuclide, for peptide labeling resulted in a slightly reduced (approximately 20%) tumor uptake and tumor residence time of 177Lu-BZH3. In contrast, 177Lu decline in the pancreas was significantly accelerated by a factor of 3 compared with that of 67Ga. PET of mice with 68Ga-BZH3 clearly delineated tumors in the mediastinal area.
The promising in vivo data of 68Ga-BZH3 indicate its potential for an improved localization of GRP-r-positive tumors and also suggest its application in patients. PET may also be favorably used for GRP-r density determination, a prerequisite for therapeutic applications.
We evaluated the following (111)In-labeled somatostatin (SS) analogues (diethylenetriaminepentaacetic acid, DTPA; tetraazacyclododecanetetraacetic acid, DOTA): DTPA0octreotide, DTPA0,Tyr3octreotide, ...DTPA0,D-Tyr1octreotide, DTPA0,Tyr3octreotate Thr(ol) in octreotide replaced with Thr, and DOTA0,Tyr3octreotide, in vitro and in vivo. In vitro, all compounds showed high and specific binding to SS receptors in mouse pituitary AtT20 tumor cell membranes, and IC50s were in the nanomolar range. Furthermore, all compounds showed specific internalization in rat pancreatic tumor cells; uptake of (111)In-DTPA0,Tyr3octreotate was the highest of the compounds tested, and that of (111)In-DTPA0,D-Tyr1octreotide was the lowest. Biodistribution experiments in rats showed that, 4, 24, and 48 h after injection of (111)In-DTPA0,Tyr3octreotide, (111)In-DTPA0,Tyr3octreotate, and (111)In-DOTA0,Tyr3octreotide, radioactivity in the octreotide-binding, receptor-expressing tissues and tumor-to-blood ratios were significantly higher than those after injection of (111)In-DTPA0octreotide. Uptake of (111)In-DTPA0,Tyr3octreotate in the target organs was also, in vivo, the highest of the radiolabeled peptides tested, whereas that of (111)In-DTPA0,D-Tyr1octreotide was the lowest. Uptake of (111)In-DTPA0,Tyr3octreotide, (111)In-DTPA0,Tyr3octreotate, and (111)In-DOTA0,Tyr3octreotide in target tissues was blocked by >90% by 0.5 mg of unlabeled octreotide, indicating specific binding to the octreotide receptors. Blockade of (111)In-DTPA0,D-Tyr1octreotide was >70%. In conclusion, radiolabeled DTPA0,Tyr3octreotide and, especially, DTPA0,Tyr3octreotate and their DOTA-coupled counterparts are most promising for scintigraphy and radionuclide therapy of SS receptor-positive tumors in humans.
The highest known binding constant for the silver(I) complex with a cyclen‐derived ligand was recently measured (lg K = 19.63; crystal structure shown on the right). This ligand is preorganized in ...the metal‐free form. It contains four nitrogen and four sulfur atoms, but the soft silver(I) ion prefers coordination through the nitrogen atoms and binds to only two sulfur atoms in the solid state. The chelating ligand was designed for in vivo therapeutic application of the β‐emitting radio‐nuclide IIIAg.
An investigation into the
in vitro behaviour of two yttrium-90-labelled somatostatin analogues was performed. Further
in vivo characterisation was performed with the most promising agent. A new ...DTPA-octreotide analogue (Bz-DTPA-oct) was synthesised by coupling a bifunctional DTPA chelator to the
N-terminal amine of the D-Phe
1 of Tyr
3-octreotide. This new SRIF analogue and DTPA-octreotide (OctreoScan) were radiolabelled with
90Y prior to serum stability being evaluated. Receptor binding assays were also performed on the two radioligands using rat cortex membranes. The
90Y-Bz-DTPA-oct was further evaluated
in vivo using tumour-bearing rats. The first conjugate (DTPA-octreotide) bound with a high affinity to SRIF receptors and the
90Y complex was relatively stable in human serum (
t
1/2 3.8 d for
90Y lost to serum proteins). The second conjugate (Bz-DTPA-oct) also exhibited a high binding affinity to SRIF receptors, but it demonstrated an even slower loss of
90Y to serum proteins (
t
1/2 12.1 d). The
in vivo evaluation of the more stable
90Y-Bz-DTPA-oct showed a very rapid and high accumulation in somatostatin receptor-positive tumours, which after 1 h resulted in tumour/nontumour ratios of 3.8, 21, and 4.9 (for blood, muscle, and liver, respectively). These tumour/nontumour ratios increased, and were by 24 h postinjection 138, 285, and 6.1 (for blood, muscle, and liver). Yttrium-90-labelled Bz-DTPa-oct is rapidly and selectively accumulated in somatostatin receptor-positive tissue. Octadentate Bz-DTPA-oct could be ligand for
90Y radiotherapy of somatostatin receptor-positive tumours and their metastases.
In vitro octreotide receptor binding of 111In-DOTA0,d-Phe1, Tyr3octreotide (111In-DOTATOC) and the in vivo metabolism of 90Y- or 111In-labelled DOTATOC were investigated in rats in comparison with ...111In-DTPA0octreotide 111In-DTPAOC). 111In-DOTATOC was found to have an affinity similar to octreotide itself for the octreotide receptor in rat cerebral cortex microsomes. Twenty-four hours after injection of 90Y- or 111In-labelled DOTATOC, uptake of radioactivity in the octreotide receptor-expressing tissues pancreas, pituitary, adrenals and tumour was a factor of 2-6 that after injection of 111In-DTPAOC. Uptake of labelled DOTATOC in pituitary, pancreas, adrenals and tumour was almost completely blocked by pretreatment with 0.5 mg unlabelled octreotide, indicating specific binding to the octreotide receptors. These findings strongly indicate that 90Y-DOTATOC is a promising radiopharmaceutical for radiotherapy and that 111In-DOTATOC is of potential value for diagnosis of patients with octreotide receptor-positive lesions, such as most neuroendocrine tumours.
The aim of this study was to compare renal handling and distribution of (99m)Tc-octreotide and (99m)Tc-EDDA/HYNIC-Tyr(3)-octreotide (HYNIC-TOC) in rats. In kidney perfusion experiments, the renal ...clearance value of (99m)Tc-octreotide was three times lower than that of (99m)Tc-EDDA/HYNIC-TOC. The predominant renal excretion of (99m)Tc-EDDA/HYNIC-TOC was associated with a high and long-term renal accumulation up to 48 hrs. Microautoradiographic results indicated that (99m)Tc-EDDA/HYNIC-TOC was retained mainly in the renal medulla within the cells of the collecting ducts and in the surrounding tissue. Lower positivity was found in the proximal and distal tubular cells. We conclude that the mechanism of renal accumulation of somatostatin analogues renal accumulation is complex and that proximal tubular reabsorption is probably not the main mechanism for uptake of (99m)Tc-EDDA/HYNIC-TOC in the kidneys. The presence of the somatostatin receptors, differences in the tonicity level within kidneys and other possible mechanisms could participate in their renal accumulation.
Because biopsy has a high risk of hemorrhage and the findings of CT and MRI are often ambiguous, especially at the base of the skull, additional methods for the characterization of intracranial ...tumors are needed. Meningiomas show high expression of the somatostatin receptor subtype 2 and thus offer the possibility of receptor-targeted imaging. We used the somatostatin analog (68)Ga-DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTA-TOC) labeled with the positron emitter (68)Ga (half-life, 68 min), obtained from a (68)Ge/(68)Ga generator, for PET of these tumors. In contrast to (18)F-FDG, this ligand shows high meningioma-to-background ratios. The aim was to evaluate kinetic parameters in meningiomas before radiotherapy.
Dynamic PET scans (3-dimensional mode; 28 frames; ordered-subsets expectation maximization reconstruction) were acquired for 21 patients (mean age +/- SD, 51 +/- 13 y) before radiotherapy during the 60 min after intravenous injection of 156 +/- 29 MBq of (68)Ga-DOTA-TOC. We analyzed 28 meningiomas (median grade I according to the system of the World Health Organization) with volumes of at least 0.5 mL (mean volume, 13.1 mL) and nasal mucosa as reference tissue, showing a slight to moderate physiologic uptake. For evaluation of the (68)Ga-DOTA-TOC kinetics, the vascular fraction (vB) and the rate constants (k1, k2, k3, and k4 1/min) were computed using a 2-tissue-compartment model. Furthermore, receptor binding (RB) (k1 - k1 x k2) and the ratios k1/k2 and k3/k4 were calculated.
Significant differences (P < 0.05; t test) between meningiomas and the reference tissue were found for the mean standardized uptake value (10.5 vs.1.3), vB (0.42 vs. 0.11), k2 (0.12 vs. 0.56), k3 (0.024 vs. 0.060), k4 (0.004 vs. 0.080), and RB (0.49 vs. 0.13). Although there was no significant difference for k1 (0.54 vs. 0.40), the ratios k1/k2 (4.50 vs. 0.71) and k3/k4 (6.00 vs. 0.75) were markedly greater in meningiomas than in reference tissue.
The high uptake of (68)Ga-DOTA-TOC in meningiomas can be explained by the high values for vB and by the remarkably low values for k2 and k4, leading to significantly greater k1/k2 and k3/k4 ratios and RB in meningiomas than in reference tissue. Thus, pharmacokinetic modeling offers a more detailed analysis of biologic properties of meningiomas. In further studies, these data might serve as a basis for monitoring the somatostatin receptors of meningiomas after radiotherapy.
The aim of this study was to determine the maximum tolerated dose of (90)Y-DOTATOC per cycle administered in association with amino acid solution as kidney protection in patients with somatostatin ...receptor-positive tumours. Forty patients in eight groups received two cycles of (90)Y-DOTATOC, with activity increased by 0.37 GBq per group, starting at 2.96 and terminating at 5.55 GBq. All patients received lysine +/- arginine infusion immediately before and after therapy. Forty-eight percent developed acute grade I-II gastrointestinal toxicity (nausea and vomiting) after amino acid infusion whereas no acute adverse reactions occurred after (90)Y-DOTATOC injection up to 5.55 GBq/cycle. Grade III haematological toxicity occurred in three of seven (43%) patients receiving 5.18 GBq, which was defined as the maximum tolerable activity per cycle. Objective therapeutic responses occurred. Five GBq per cycle is the recommended dosage of (90)Y-DOTATOC when amino acids are given to protect the kidneys. Although no patients developed acute kidney toxicity, delayed kidney toxicity remains a major concern, limiting the cumulative dose to ~25 Gy. The way forward with this treatment would seem to be to identify more effective renal protective agents, in order to be able to increase the cumulative injectable activity and hence tumour dose.
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