A new radiolabelled somatostatin analogue [111In-DTPA-D-Phe1]RC-160: preparation,biological activity,receptor scintigraphy in rats and comparison with [111In-DTPA-D-Phe1]octreotide

We have evaluated the potential usefulness of indium-111 labelled [DTPA-D-Phe¹]RC-160, derived from the octapeptide somatostatin analogue RC-160, as a radiopharmaceutical for the in vivo detection of somatostatin receptor-positive tumours. For this purpose ¹¹¹In-and ¹¹¹In-labelled [DTPA-D-Phe¹]RC-160 was tested for its biological activity, and applied for somatostatin receptor scintigraphy in vivo to rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. We previously described the development of the ¹¹¹In-labelled somatostatin analogue [DTPA-D-Phe¹]octreotide and its use in the in vivo visualization of somatostatin receptor-positive tumours in rats and in humans. Like [¹¹¹In-DTPA-D-Phe¹]octreotide, [¹¹¹In-DTPA-D-Phe¹]RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumours, and the tumours were clearly visualized by gamma camera scintigraphy. However, as compared to [¹¹¹In-DTPA-D-Phe¹]octreotide, blood radioactivity (background) was higher, resulting in a lower tumour to blood (background) ratio. Using this animal model we therefore conclude that [¹¹¹In-DTPA-DPhe¹]RC-160 has no advantage over [¹¹¹In-DTPA-DPhe¹]octreotide as a radiopharmaceutical in the visualization of somatostatin receptors which bind both analogues. However, recent reports suggest the existence of different somatostatin receptor subtypes on some human cancers, which differentially bind RC-160 and not octreotide. These tumours include cancers of the breast, ovary, exocrine pancreas, prostate and colon. [¹¹¹In-DTPA-D-Phe¹]RC-160 might be of interest for future use in such cancer patients as a radiopharmaceutical for imaging somatostatin receptor-positive tumours, which do not bind octreotide.     

Radioiodinated somatostatin analogue RC-160: preparation,biological activity,in vivo application in rats and comparison with [123I-Tyr3]octreotide

We have evaluated the potential usefulness of the radioiodinated octapeptide RC-160, a somatostatin analogue, which might serve as a radiopharmaceutical for the in vivo detection of somatostatin receptor-positive tumours. For this purpose, iodine-123 and iodine-125 labelled RC-160 was tested for biological activity and applied in vivo in rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. Our group has recently described the in vivo visualization of such tumours in rats and in humans with the radioiodinated somatostatin analogue [Tyr³]octreotide. Like [¹²³I-Tyr³]octreotide, ¹²³I-RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumours. However, blood radioactivity (background) was higher, resulting in a lower tumour to blood (background) ratio. We therefore conclude that in this animal model ¹²³I-RC-160 has no advantage over [¹²³I-Tyr³]octreotide as a radiopharmaceutical for the in vivo use as a somatostatin receptor imager, although, like [¹²³I-Tyr³]octreotide, ¹²³I-RC-160 shows specific binding to different somatostatin receptor-positive organs. Recently differences were reported in affinity between somatostatin and its analogues for somatostatin receptors expressed in different human cancers, like those of the breast, ovary, exocrine pancreas, prostate and colon. Therefore ¹²³I-RC-160 might be of interest for future use in humans as a radiopharmaceutical for imaging octreotide receptor-negative tumours. Correspondence to: W.A.P. Breeman, Department of Nuclear Medicine, University Hospital Dijkzigt, Dr. Molewaterplein 40, NL-3015 GD Rotterdam, The NetherlandsThe authors wish to thank Dr. Wil Kort, Ineke Hekking-Weyma, Reno Mekes, Marcello Harms and Ina Loeve for their expert assistance during the experiments.     

[123I]Mtr-TOCA, a radioiodinated and carbohydrated analogue of octreotide: scintigraphic comparison with [111In]octreotide

Purpose Scintigraphy with maltotriose-[¹²³I]Tyr³-octreotate ([¹²³I]Mtr-TOCA) is compared with [¹¹¹In]DTPA-Phe¹-octreotide ([¹¹¹In]OC) to assess the differences in pharmacokinetics and imaging properties as well as to estimate the therapeutic potential of the corresponding [¹³¹I]Mtr-TOCA.Methods Six patients with somatostatin receptor (sstr)-positive tumours were assessed using a dual-head gamma camera. After injection of 137±28 MBq [¹²³I]Mtr-TOCA, dynamic data acquisition of the upper abdomen (30 min) was performed followed by whole-body scans at 0.5 h, 1 h, 3 h and 20 h as well as by SPECT imaging (tumour) at 2 h. [¹¹¹In]OC scintigraphy was performed by acquiring whole-body scans (4 h, 24 h) and SPECT (24 h). Using a region of interest (ROI) method, tissue and tumour bound activity was assessed and dosimetry performed.Results [¹²³I]Mtr-TOCA shows rapid tumour uptake. Up to 4 h, tumour/organ (tu/org) ratios are stable and generally higher than with [¹¹¹In]OC. From 3 h to 20 h, tu/org ratios increase for spleen, remain stable for liver and decrease significantly for all other tissues. In contrast, with [¹¹¹In]OC, tu/org ratios decrease slightly between 4 h and 24 h for liver, spleen and kidney and increase for all other tissues. On [¹²³I]Mtr-TOCA scintigraphy, a total of 27 lesions are detected, whereas 33 lesions are detected on [¹¹¹In]OC scintigraphy (p=0.50). Effective patient absorbed dose is 1.9±0.9 mSv per 100 MBq [¹²³I]Mtr-TOCA.Conclusion Compared with [¹¹¹In]OC, [¹²³I]Mtr-TOCA enables faster imaging of sstr-positive tumours with a lower radiation burden to the patient. [¹²³I]Mtr-TOCA and [¹¹¹In]OC allow for tumour imaging with almost identical contrast and diagnostic yield. As regards peptide receptor radionuclide therapy, radioiodinated Mtr-TOCA is hampered by limited intratumoural activity retention.     

Somatostatin receptor scintigraphy using <Superscript>99m</Superscript>Tc-EDDA/HYNIC-TOC in patients with medullary thyroid carcinoma

Purpose Several new somatostatin analogues have been developed for the diagnosis and therapy of different tumours. Since somatostatin receptors are often over-expressed in medullary thyroid carcinoma (MTC), the aim of our study was to evaluate the utility of scintigraphy with the somatostatin analogue ^99mTc-EDDA/HYNIC-TOC in MTC in comparison with other diagnostic techniques. Methods Forty-five patients with MTC, aged 14–83 years, were investigated. Scintigraphy using ^99mTc-EDDA/HYNIC-TOC (Tektrotyd) was performed 2 and 4 h post injection of 740 MBq (20 mCi) of the tracer. Other imaging techniques were also applied and analysed in individual cases (ultrasonography, computed tomography, ^99mTc(V)-DMSA, ¹³¹I-MIBG, ^99mTc-MDP, ¹¹¹In-DTPA-octreotide and ¹⁸F-FDG-PET) and compared with ^99mTc-EDDA/HYNIC-TOC. Results In group 1 (eight patients before thyroidectomy), uptake of the tracer was found in the primary tumours. In group 2 (six patients with remission), a false positive result was found in one patient; in the remaining five patients, no pathological foci were visualised. In group 3 (31 patients with post-surgical hypercalcitoninaemia), scintigraphy was true positive in 23 patients (74.2%): uptake in the thyroid bed was found in five patients, in the lymph nodes in 18 and in bone metastases in four. Using ^99mTc-EDDA/HYNIC-TOC scintigraphy, the overall sensitivity was 79.5%, specificity 83.3%, accuracy 80.0%, positive predictive value 96.9% and negative predictive value 38.5%. Conclusion ^99mTc-EDDA/HYNIC-TOC is clinically useful for scintigraphy in the follow-up of patients with MTC. It can be used in clinical practice for preoperative evaluation, for localisation of local recurrence or distant metastases and particularly for therapy decision making.     

Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.     

Peptide receptor radionuclide therapy in vitro using [111In-DTPA0]octreotide.

Peptide receptor radionuclide therapy (PRRT) using [(111)In-DTPA(0)]octreotide (where DTPA is diethylenetriaminepentaacetic acid) is feasible because, besides gamma-radiation, (111)In emits both therapeutic Auger and internal conversion electrons having a tissue penetration of 0.02-10 and 200-500 micro m, respectively. The aim of this study was to investigate the therapeutic effects of [(111)In-DTPA(0)]octreotide in a single-cell model including the effects of incubation time, radiation dose, and specific activity of [(111)In-DTPA(0)]octreotide. Finally, we discriminated between the effects of the Auger electrons and internal conversion electrons in PRRT. METHODS: An in vitro, colony-forming assay to study cell survival after PRRT using the sst subtype 2-positive rat pancreatic tumor cell line CA20948 was developed. RESULTS: In this in vitro system [(111)In-DTPA(0)]octreotide can control tumor growth to 0% survival, and the effects were dependent on incubation time, radiation dose, and specific activity used. Similar concentrations of (111)In-DTPA, which is not internalized into sst-positive tumor cells like [(111)In-DTPA(0)]octreotide, did not influence tumor survival. Excess unlabeled octreotide (10(-6) mol/L) could decrease tumor cell survival to 60% of control; the addition of radiolabeled peptide ([(111)In-DTPA(0)]octreotide [10(-9) mol/L] + 10(-6) mol/L octreotide) did not further decrease survival. CONCLUSION: These in vitro studies show that the therapeutic effect of (111)In is dependent on internalization, enabling the Auger electrons with their very short particle range to reach the nucleus. Our results also indicate that the PRRT effects were receptor mediated.     

[177Lu-DOTA0,Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients

The somatostatin analogue [DOTA⁰,Tyr³]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA⁰,Tyr³]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate) with [¹¹¹In-DTPA⁰]octreotide (¹¹¹In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after ¹⁷⁷Lu-octreotate expressed as a percentage of the injected dose was comparable with that after ¹¹¹In-octreotide. Urinary excretion of radioactivity was significantly lower than after ¹¹¹In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of ¹⁷⁷Lu-octreotate, was comparable to that after ¹¹¹In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, ¹⁷⁷Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of ¹⁷⁷Lu as compared with ⁹⁰Y may be especially important for small tumours.     

Radiolabeled somatostatin analog scintigraphy in oncology and immune diseases: an overview

[¹¹¹In-DTPA-D-Phe¹]-octreotide is a new radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors, granulomas, and diseases in which activated leukocytes play a role. The overall sensitivity of [¹¹¹In-DTPA-D-Phe¹]-octreotide scintigraphy to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. In our opinion, this holds true for patients with carcinoids, gastrinomas, paragangliomas, small-cell lung carcinoma, and selected cases of patients with insulinomas. The value of [¹¹¹In-DTPA-D-Phe¹]-octreotide scintigraphy in patients with other tumors, such as breast cancer, malignant lymphomas, or in patients with granulomatous diseases, has to be established. Received 19 June 1996; Revision received 28 October 1996; Accepted 6 November 1996     

Somatostatin receptor imaging in intracranial tumours

The somatostatin analogue [¹¹¹In-DTPA-d-Phe¹]-octreotide (¹¹¹In-octreotide) allows scintigraphic visualization of somatostatin receptor-expressing tissue. While it is well known that a large variety of tissues express somatostatin receptors and ¹¹¹In-octreotide scintigraphy has a clearly defined role in various neuroendocrine diseases, the clinical value of ¹¹¹In-octreotide scintigraphy in brain tumours is still under clinical investigation. In 124 patients with 141 brain lesions (63 meningiomas, 24 pituitary adenomas, 10 gliomas WHO class I and II, 12 gliomas WHO class III and IV, 11 neurinomas and 2 neurofibromas, 7 metastases and 12 other varieties: three non-Hodgkin B-cell lymphomas, two epidermoids, one abscess, one angioleiomyoma, one chordoma, one haemangiopericytoma, one osteosarcoma, one plasmacytoma and one pseudocyst), ¹¹¹In-octreotide scintigraphy was performed 4–6 and 24 h after i.v. injection of 110–220 MBq ¹¹¹In-octreotide. Planar images of the head in four views with a 128×128 matrix and single-photon emission tomographic images (64×64 matrix) were acquired, and lesions were graded according to qualitative tracer uptake. Fifty-nine of the 63 meningiomas showed moderate to intense tracer uptake. Nine of 24 pituitary adenomas were visible; the remaining 15 did not show any tracer uptake. None of the class I and II gliomas with an intact blood-brain barrier were detected whereas 11/12 class III and IV gliomas showed ¹¹¹In-octreotide uptake. None of the neurinomas or neurofibromas were positive. Five of seven metastases were classified as positive, as were the osteosarcoma, two of three non-Hodgkin B-cell lymphomas, one abscess, one angioleiomyoma, one chordoma and one haemangiopericytoma. The other varieties (one non-Hodgkin B-cell lymphoma, two epidermoids, one plasmacytoma and one pseudocyst) did not show ¹¹¹In-octreotide uptake. The results demonstrate that a large variety of intracranial lesions express somatostatin receptors and therefore can be visualized by [¹¹¹In-DTPA-d-Phe¹]-octreotide scintigraphy. This technique can be valuable in the differentiation between meningiomas and pituitary adenomas, based on qualitative tracer uptake. [¹¹¹In-DTPA-d-Phe¹]-octreotide scintigraphy allows differentiation between meningiomas and neurinomas or neurofibromas and therefore provides complementary information to computed tomography or magnetic resonance imaging. Furthermore, this technique allows differentiation between scar tissue and recurrent meningiomas postoperatively and can help in non-invasive tumour differentiation of multiple intracranial lesions, which can be of value in defining the most adequate therapeutic strategy. Received 1 December 1997 and in revised form 17 March 1998     

Improved visualization of carcinoid liver metastases by indium-111 pentetreotide scintigraphy following treatment with cold somatostatin analogue

Five patients with hepatic metastases of midgut carcinoid underwent somatostatin receptor scintigraphy with indium-111 pentetreotide before and during treatment with octreotide. Octreotide treatment changed the biodistribution of ¹¹¹In-pentetreotide significantly. Whereas the radioactivity in liver, spleen and kidney decreased, hepatic metastases showed increased contrast. In one patient, liver metastases could only be detected during octreotide treatment. These data suggest that the diagnostic reliability of somatostatin receptor scintigraphy in carcinoid liver metastases is not necessarily compromised by octreotide therapy. Because of different biodistributions, the detection of liver metastases may even be improved during octreotide therapy. Correspondence to: U. Dörr     

Indium-111 octreotide scintigraphy in patients with bone tumours of the extremities

Radiolabelled somatostatin analogues are of potential value in the imaging of somatostatin receptor-positive tumours. Recently, somatostatin receptors have been demonstrated in the osteoblast precursor cells. In this preliminary study, we evaluated the uptake characteristics of indium-111 octreotide in two benign and two malignant bone tumours. Tracer accumulation was observed in all four cases, and overall lesion to background ratio (mean±SD) was 2.74±0.84 and 2.98±1.49 at 4 h and 24 h, respectively. There was no clear relationship between I¹¹¹In-octreotide accumulation and the benign or malignant nature of the tumour. In one patient, tracer uptake was inhibited by unlabelled octreotide administration. These results suggest that¹¹¹In-octreotide can be taken up by benign and malignant bone tumours. The inhibition of tumour uptake by treatment with cold octreotide supports the concept that specific uptake mechanisms are responsible for¹¹¹In-octreotide deposition by bone tumours.     

Somatostatin receptor imaging in non-functioning pituitary adenomas: value of an uptake index

Somatostatin receptor imaging (SRI) was performed in five patients with known non-functioning pituitary adenomas. To determine whether the pituitary uptake correlates with response to octreotide therapy, an uptake index (UI) was calculated. Pituitary adenomas were detected in all five patients. The UI was, respectively, 15.1, 3.7, 2.2, 2.2 and 2.2 (the UI calculated in 12 normal subjects was between 1 and 1.9). Only the patient with the highest Ul (15.1) had a dramatic improvement in tumour volume and visual function in response to octreotide therapy. The Ul might be a good predictive parameter of octreotide therapy efficacy in non-functioning adenomas. Correspondence to: I. Virgolini, Department of Nuclear Medicine, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria     

Somatostatin receptor imaging in patients with sarcoidosis

Granulomatous diseases can be visualized in vivo after the injection of indium-111-DTPA-octreotide (¹¹¹In-pentetreotide), a radiolabelled somatostatin analogue. We evaluated whether somatostatin receptor imaging reflects disease activity, whether certain scintigraphic characteristics can predict the disease prognosis and whether repeat scintigraphy correlates with the clinical course in patients with sarcoidosis. ¹¹¹In-pentetreotide was injected in 46 patients and images were obtained 24 h later. Known mediastinal, hilar and interstitial disease was recognized in 36 of 37 patients. Also, such pathology was found in seven other patients who had normal chest X-rays. In five of these, somatostatin receptor imaging pointed to interstitial disease. Frequently, accumulation of radioactivity in parotid glands and supraclavicular lymph nodes was found. Neither the degree of radioactive accumulation in the thorax nor a specific pattern of pathological uptake was correlated with disease severity or clinical course. The degree of uptake of radioactivity in the parotid glands was correlated with significantly higher serum angiotensin-converting enzyme (ACE) levels. Somatostatin receptor imaging was repeated in 13 patients. In five of six patients in whom chest X-ray monitored improvement of disease activity, the pentetreotide scintigram also showed a decrease in pathological uptake. In two of five patients in whom the chest X-ray was unchanged, but serum ACE concentrations had decreased and lung function improved, normalization on pentetreotide scintigrams was found. It is concluded that: (1) somatostatin receptor imaging can demonstrate active granulomatous disease in patients with sarcoidosis; (2) pathological uptake of radioactivity in the parotid glands during somatostatin receptor imaging is correlated with higher serum ACE concentrations; (3) the value of somatostatin receptor imaging in the follow-up of patients with sarcoidosis will have to be determined in a prospective longitudinal study. Received 17 March and in revised form 17 April 1998     

Somatostatin receptor scintigraphy during treatment with lanreotide in patients with neuroendocrine tumors

To investigate possible changes in somatostatin receptor expression during treatment with high dose lanreotide, eight patients with neuroendocrine tumors were investigated by [¹¹¹In-DTPA-D-Phe¹]-octreotide scintigraphy before and during treatment. The spleen-to-background ratio decreased in all patients, whereas tumor-to-background ratio revealed a heterogeneous pattern with an average increase of 50% (−79% to +1,087%). This finding indicates that lanreotide treatment may influence the binding of radioactively labeled somatostatin to the spleen, while changes in the binding to functioning somatostatin receptors in tumor cells are more complex and not clearly related to treatment.     

Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization?

Radiolabeled somatostatin analogs are important tools for the in vivo localization and targeted radionuclide therapy of somatostatin receptor-positive tumors. The aim of this study was to compare 3 somatostatin analogs designed for the labeling with (99m)Tc (where HYNIC is 6-hydrazinopyridine-3-carboxylic acid): 6-hydrazinopyridine-3-carboxylic acid(0)-octreotide (HYNIC-OC/(99m)Tc-(1)), [HYNIC(0),Tyr(3)]octreotide (HYNIC-TOC/(99m)Tc-(2)), and [HYNIC(0),Tyr(3),Thr(8)]octreotide (HYNIC-TATE/(99m)Tc-(3)), using ethylenediamine-N,N'-diacetic acid (EDDA) as a coligand. In addition, we compared the (99m)Tc-labeled peptides [(111)In-diethylenetriaminepentaacetic acid(0)]octreotide ([(111)In-DTPA]-OC) and [(111)In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(0),Tyr(3),Thr(8)]octreotide ([(111)In-DOTA]-TATE) with regard to the rate of internalization and the biodistribution in AR4-2J (expressing the somatostatin receptor subtype 2) tumor-bearing rats. The main attention was directed toward a potential correlation between the rate of internalization and the tumor or pancreas uptake. METHODS: Synthesis was performed on solid phase using a standard Fmoc strategy. Internalization was studied in cell culture (AR4-2J) and biodistribution was studied using a Lewis rat tumor model (AR4-2J). RESULTS: The 5 radiopeptides showed a specific internalization into AR4-2J cells in culture (as shown by blocking experiments). The rate of internalization of the 5 radiopeptides differed significantly according to the following order: (99m)Tc-(1) approximately = [(111)In-DTPA]-OC < (99m)Tc-(2) < (99m)Tc-(3) approximately = [(111)In-DOTA]-TATE. All radiopeptides displayed a rapid blood clearance and a fast clearance from all somatostatin receptor-negative tissues predominantly via the kidneys. A receptor-specific uptake of radioactivity was observed for all compounds in somatostatin receptor-positive organs such as the pancreas, the adrenals, and the stomach. After 4 h, the uptake in the AR4-2J tumor was comparable for (99m)Tc-(2) (3.85 +/- 1.0 injected dose per gram tissue (%ID/g)), (99m)Tc-(3) (3.99 +/- 0.58%ID/g), and [(111)In-DOTA]-TATE (4.12 +/- 0.74%ID/g) but much lower for [(111)In-DTPA]-OC (0.99 +/- 0.08%ID/g) and (99m)Tc-(1) (0.70 +/- 0.13%ID/g). The specificity was determined by blocking experiments using a large excess of [Tyr(3)]octreotide. (99m)Tc-(3) displayed the highest tumor-to-kidney ratio (2.5:1), followed by (99m)Tc(2) (1.9:1) and [(111)In-DOTA]-TATE (1.7:1). CONCLUSION: These data show that the 5 radiopeptides are specific radioligands for the somatostatin receptor subtype 2. The rate of internalization correlates with the uptake in the tumor (R(2) = 0.75; P = 0.026) and pancreas (R(2) = 0.98; P = 7.4.10(-5)). [Tyr(3),Thr(8)]octreotide derivatives show superiority over the corresponding octreotide and [Tyr(3)]octreotide derivatives, indicating that [(111)In-DOTA]-TATE and [(99m)Tc/EDDA/HYNIC]-TATE are suitable candidates for clinical studies.     

Tumour uptake of the radiolabelled somatostatin analogue [DOTA0,TYR3]octreotide is dependent on the peptide amount

Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr³]octreotide (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,Tyr³]octreotide 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,Tyr³]octreotide 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,Tyr³]octreotide 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) μg. Uptake in the tumour was highest at 0.5 μg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [¹¹¹In-DTPA⁰]octreotide ((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, Tyr³]octreotide, 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. Received 6 January and in revised form 16 February 1999     

Clinical usefulness of <Superscript>99m</Superscript>Tc-EDDA/HYNIC-TOC scintigraphy in oncological diagnostics: a preliminary communication

This study assessed the clinical usefulness of a new technetium-99m labelled somatostatin analogue from the standpoint of oncological diagnostics. The study group comprised 40 patients in whom malignant neoplasms (32 primary and 8 metastatic) had been diagnosed. Among the primary tumours there were 21 cases of lung cancer (2 small cell and 19 non-small cell), seven pituitary adenomas (five hormonally active and two inactive), one liposarcoma, two carcinoids and one breast carcinoma. The metastatic tumours consisted of three malignant melanomas, one phaeochromocytoma, one prostatic cancer, one leiomyosarcoma, one pancreatic carcinoma ectopically secreting ACTH and one carcinoid of the thymus. The radiopharmaceutical ^99mTc-EDDA/HYNIC-Tyr³-octreotide was administered i.v. at an activity of 740–925 MBq. The imaging comprised a whole-body scan and a single-photon emission tomography acquisition. Positive scintigrams were obtained in all cases of small cell and non-small cell lung cancer, four out of five hormonally active pituitary adenomas, one out of two cases of carcinoid, the liposarcoma and the breast cancer. Neoplastic metastases were visualised in two out of three patients with melanoma and in patients with phaeochromocytoma, ACTH-secreting pancreatic carcinoma and thymic carcinoid. Scintigrams were negative in both hormonally inactive pituitary adenomas, in one case of metastatic malignant melanoma, in the leiomyosarcoma and in the case of metastasis from prostatic carcinoma. The results of this pilot study indicate that ^99mTc-EDDA/HYNIC-TOC is a potentially useful radiopharmaceutical for imaging of a wide range of primary and metastatic tumours. Special attention should be paid to the successful imaging of all cases of non-small cell lung cancer .     

DOTA-NOC,a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [¹¹¹In,⁹⁰Y-DOTA]-1-Nal³-octreotide (¹¹¹In,⁹⁰Y-DOTA-NOC), was isolated which showed an improved profile. In^III-DOTA-NOC exhibited the following IC₅₀ values (nM) when studied in competition with [¹²⁵I][Leu⁸, d-Trp²², Tyr²⁵]somatostatin-28 (values for Y^III-DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.4±1.6). Affinity towards sstr1 and 4 was very low or absent. In^III-DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than In^III,Y^III-DOTA-Tyr³-octreotide (In^III,Y^III-DOTA-TOC). In addition, [¹¹¹In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [¹¹¹In]DOTA-TOC and three times higher than that of [¹¹¹In]DOTA-octreotide ([¹¹¹In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2–3 h of externalization a plateau is reached, indicating a steady-state situation explained by reactivation of the receptors followed by re-endocytosis. Biodistribution studies in CA 20948 tumour-bearing rats showed rapid clearance from all sstr-negative tissues except the kidneys. At 4 h the uptake of [¹¹¹In]DOTA-NOC in the tumour and sstr-positive tissues, such as adrenals, stomach and pancreas, was three to four times higher than that of [¹¹¹In]DOTA-TOC. Differential blocking studies indicate that this is at least partially due to the uptake mediated by sstr3 and sstr5. These very promising preclinical data justify the use of this new radiopeptide for imaging and potentially internal radiotherapy studies in patients.Abbreviations of the common amino acids are in accordance with the recommendations of IUPAC-IUB [IUPAC-IUB Commission of Biochemical Nomenclature (CBN), Symbols for amino-acid derivatives and peptides, recommendations 1971. Eur J Biochem 1972; 27:201–207].     

177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients

The somatostatin analogue [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0, Tyr3]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) with [111In-DTPA0]octreotide (111In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after 177Lu-octreotate expressed as a percentage of the injected dose was comparable with that after 111In-octreotide. Urinary excretion of radioactivity was significantly lower than after 111In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of 177Lu-octreotate, was comparable to that after 111In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177Lu as compared with 90Y may be especially important for small tumours.     

Peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y-DOTATOC in recurrent meningioma

Purpose  Meningiomas are generally benign and in most cases surgery is curative. However, for high-grade histotypes or partially resected tumours, recurrence is fairly common. External beam radiation therapy (EBRT) is usually given in such cases but is not always effective. We assessed peptide receptor radionuclide therapy (PRRT) using ⁹⁰Y-DOTATOC in a group of patients with meningioma recurring after standard treatments in all of whom somatostatin receptors were strongly expressed on meningioma cell surfaces. Methods  Twenty-nine patients with scintigraphically proven somatostatin subtype 2 receptor-positive meningiomas were enrolled: 14 had benign (grade I), 9 had atypical (grade II) and 6 had malignant (grade III) disease. Patients received intravenous ⁹⁰Y-DOTATOC for 2–6 cycles for a cumulative dose in the range of 5–15 GBq. Clinical and neuroradiological evaluations were performed at baseline, during and after PRRT. Results  The treatment was well tolerated in all patients. MRI 3 months after treatment completion showed disease stabilization in 19 of 29 patients (66%) and progressive disease in the remaining 10 (34%). Better results were obtained in patients with grade I meningioma than in those with grade II–III, with median time to progression (from beginning PRRT) of 61 months in the low-grade group and 13 months in the high-grade group. Conclusion  PRRT with ⁹⁰Y-DOTATOC can interfere with the growth of meningiomas. The adjuvant role of this treatment, soon after surgery, especially in atypical and malignant histotypes, deserves further investigation.