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.     

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     

Somatostatin receptor scintigraphy in forty-eight patients with the Zollinger-Ellison syndrome

In patients with the Zollinger-Ellison syndrome, which is either sporadic or integrated into multiple endocrine neoplasia type 1, accurate localization of all the tumours is difficult and may have therapeutic implications. In an attempt to improve this localization, somatostatin receptor scintigraphy using [¹¹¹In-DTPA-D-Phe¹]-octreotide was performed prospectively in 48 consecutive patients with the Zollinger-Ellison syndrome. Thirty of them had the sporadic type of this disease. Scintigraphic data were compared with data obtained by conventional imaging methods, and also, in 32 selected patients, with those obtained by endoscopic ultrasonography. Somatostatin receptor scintigraphy showed abnormal tracer uptake in 39 patients (81%), in whom it correctly identified 50 of the 60 tumoral sites (83%) previously localized by the other imaging methods. In 17 patients (35%) somatostatin receptor scintigraphy disclosed abnormal tracer uptake at 18 different tumoral sites: 14 were located in the abdomen, including four in the liver and eight in the duodenopancreatic area, and four outside the abdomen, including two in the mediastinum. Six of the ten tumoral sites which were not correctly identified by somatostatin receptor scintigraphy were located in the duodeno-pancreatic area. However, in the 20 patients for whom conventional techniques failed to visualize any tumour in the duodenopancreatic area, somatostatin receptor scintigraphy was positive in ten (50%) whereas endoscopic ultrasonography was only positive in five (25%). In our patients with the Zollinger-Ellison syndrome, somatostatin receptor scintigraphy appeared to be a useful new addition to the battery of tests used for tumour detection.     

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.     

Somatostatin analogue scintigraphy in granulomatous diseases

Normal as well as activated lymphocytes and macrophages have previously been shown by radioreceptor analysis to express somatostatin receptors (SS-R). The somatostatin (SS) analogue [¹¹¹In-DTPA-d-Phe¹]octreotide (¹¹¹In-octreotide) is already used successfully in the visualization of a variety of neuro-endocrine tumours and malignant lymphomas. In the present study 20 consecutive patients were investigated, 12 with sarcoidosis, one with both sarcoidosis and aspergillosis, four with tuberculosis and three with Wegener's granulomatosis. For in vivo SS-R imaging, total-body scintigraphy was performed 24 and 48 h after the administration of ¹¹¹In-octreotide. Granuloma localizations could be visualized in all patients studied; additional sites were found in nine patients with sarcoidosis and in two patients with tuberculosis. In vitro autoradiography of fresh tissue biopsies, using the SS analogue [¹²⁵I-Tyr³]octreotide, showed binding at sites that were microscopically identified as granulomatous inflammation. These observations demonstrate the expression of SS-R by human granulomas. This scintigraphy procedure may contribute to a more precise staging and evaluation of granulomatous diseases, but more importantly it may be a sensitive indicator of the efficacy of glucocorticoid and/or immunosuppressive therapy.     

Somatostatin receptor scintigraphy using [111In-DTPA0]RC-160 in humans: a comparison with [111In-DTPA0]octreotide

Somatostatin receptor-positive lesions can be visualized by scintigraphy using [¹¹¹In-DTPA⁰]octreotide. Recently, there have been reports of differences in receptor binding between somatostatin receptor subtypes and between somatostatin analogues, such as RC-160 and octreotide, as well as of differences in internalization between the somatostatin receptor subtypes. The possibility that certain somatostatin receptor-positive tissues and tumours which do not bind octreotide may bind and internalize RC-160 would open new scintigraphic or radiotherapeutic applications of radiolabelled RC-160. We investigated the metabolism and tissue distribution of [¹¹¹In-DTPA⁰]RC-160 in comparison with [¹¹¹In-DTPA⁰]octreotide in four patients after injection of 250 MBq (10 μg) of these radiopharmaceuticals. Patient 1 had a metastatic follicular thyroid carcinoma, patient 2 a metastatic medullary thyroid carcinoma, patient 3 tuberculosis and patient 4 an insulinoma. The plasma clearance of the [¹¹¹In-DTPA⁰]RC-160 was slower than that of [¹¹¹In-DTPA⁰]octreotide, with 5% and 2%, respectively, of the initial plasma radioactivity remaining at 10 h p.i. The urinary excretion of [¹¹¹In-DTPA⁰]RC-160 was initially also slower than that of [¹¹¹In-DTPA⁰]octreotide, but the cumulative excretion of radioactivity was not significantly different at 48 h p.i. Approximately 80% of injected radioactivity was cleared in the urine, while in one patient 20% of the injected dose was recovered in the faeces. The slower clearance of [¹¹¹In-DTPA⁰]RC-160 resulted in a higher background in all organs studied i.e. liver, spleen, kidneys and lungs, at 24 h p.i. Although the target to background ratio with [¹¹¹In-DTPA⁰]octreotide was higher, no differences were found between the two analogues with regard to their sensitivity in detecting lesions in these four patients. We conclude that although only four subjects were studied, [¹¹¹In-DTPA⁰]RC-160 does not appear to have additional value for scintigraphy and is associated with higher background activity. Received 20 October and in revised form 31 October 1997     

New radiopharmaceuticals for receptor scintigraphy and radionuclide therapy.

In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for members of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proven its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals 111In/90Y-DOTA-lanreotide developed at the University of Vienna as well as 111In/90Y-DOTA-DPhe1-Tyr3-octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using 111In-DTPA-DPhe1-octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. We have used 111In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. 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 patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with 90Y-DOTA-lanreotide as well as 90Y-DOTA-DPhe1-Tyr3-octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radiotherapies or prolonged chemotherapies. Overall, receptor-mediated radiotherapy with 90Y-DOTA-lanreotide/90Y-DOTA-DPhe1-Tyr3-octre otide might also be effective in patients refractory to conventional strategies.     

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

Objective  Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA⁰, Tyr³, Thr⁸]-octreotide (DOTA-TATE) and [DOTA⁰, 1-Nal³]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods. Methods  The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells. Results  The renal clearance of ¹¹¹In-DOTA-NOC in the perfused rat kidney was significantly lower than that of ¹¹¹In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. ¹¹¹In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than ¹¹¹In-DOTA-TATE (ratio 3: 1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin > maleate > lysine. The uptake of the radiopeptides in the renal cells was temperature dependent. Conclusions  Both in vitro methods showed a higher renal accumulation of ¹¹¹In-DOTA-NOC in comparison with ¹¹¹In-DOTA-TATE. The renal uptake was partly decreased by inhibitors of receptor-mediated endocytosis and by a block of energy-dependent processes. A significant participation of active transport processes in renal accumulation of the studied peptides was confirmed.     

Affinity profiles for human somatostatin receptor subtypes SST1–SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use

In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases. Recently, several new, alternative somatostatin radioligands have been synthesised for diagnostic and radiotherapeutic use in vivo. Since human tumours are known to express various somatostatin receptor subtypes, it is mandatory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA-[Tyr³]-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DTPA-[Tyr³]-octreotate and DOTA-[Tyr³]-octreotate. Small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-[Tyr³]-octreotide (IC₅₀ 2.5 nM) compared with the Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the same range was also found for In-DTPA-[Tyr³]-octreotate (IC₅₀ 1.3 nM) and for Y-DOTA-[Tyr³]-octreotate (IC₅₀ 1.6 nM). Remarkably, Ga-DOTA-[Tyr³]-octreotate bound at sst2 with a considerably higher affinity (IC₅₀ 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA-octreotide compared with their Tyr³-containing analogue, suggesting that replacement of Tyr³ by Phe is crucial for high sst3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC₅₀ 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-[Tyr³]-octreotide, DOTA-lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked changes in subtype affinity profiles are due not only to the different chemical structures but also to the different charges and hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex remote from the pharmacophoric amino acids has a significant influence on affinity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr³]-octreotide or [Tyr³]-octreotate. Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor scintigraphy in order to correctly interpret in vivo scintigraphic data. These observations may represent basic principles relevant to the development of other peptide radioligands. Received 8 August and in revised form 26 October 1999     

110mIn-DTPA-D-Phe1-octreotide for imaging of neuroendocrine tumors with PET.

The somatostatin analog diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide labeled with 111In has been applied extensively for diagnosis of neuroendocrine tumors using SPECT or planar scintigraphy. However, the spatial resolution of planar scintigraphy and SPECT prohibits imaging of small tumors, and the quantification accuracy of both methods is limited. METHODS: We developed a method to prepare the positron-emitting radiopharmaceutical 110mIn-DTPA-D-Phe1-octreotide based on a commercially available kit. Phantom studies were done to investigate and compare the performance of 110mIn PET and 111In SPECT. A clinical imaging study using 110mIn-DTPA-D-Phe1-octreotide and PET was done to investigate the application of this radiopharmaceutical. RESULTS: An almost 3-fold better resolution and much better quantitative capabilities were found for 110mIn PET than for 111In SPECT. The clinical imaging study demonstrated the potential use of 110mIn-octreotide in PET to image tumors and quantify radioactivity uptake in humans using (110m)In-DTPA-D-Phe1-octreotide. CONCLUSION: PET with 110mIn-DTPA-D-Phe1-octreotide greatly improved detection of small tumors and offers a possibility of more accurate quantification of tumor uptake than can be obtained with 111In-DTPA-D-Phe1-octreotide and SPECT.     

Nuclear localization of 111In after intravenous injection of [111In-DTPA-D-Phe1]-octreotide in patients with neuroendocrine tumors.

Treatment with tumor-targeting substances is currently being evaluated in clinical trials. For patients with neuroendocrine tumors expressing somatostatin receptors, the 111In-labeled somatostatin analog [diethylenetriaminepentaacetic acid (DTPA)-DPhe1]-octreotide has been used with promising results. To further investigate the clinical effect of the injected conjugate, we analyzed the cellular distribution of 111In by ultrastructural autoradiography. METHODS: Seven patients with somatostatin receptor-expressing midgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, fixed, and processed for electron microscopy. A thin layer of film emulsion was applied on sections and after the exposure film was developed. The cellular distribution of silver precipitations indicating the presence of isotope was evaluated. RESULTS: Cell surface receptor binding and internalization of [111In-DTPA-D-Phe1]-octreotide in the tumor cells was easily revealed by silver precipitations in the film. Multiple silver grains were seen at the plasma membrane, in the cytoplasmic area among secretory granules and vesicular compartments, and in the perinuclear area. Silver grains were also regularly located in the nucleus. For all patients, the silver precipitation patterns from 111In decay were identical in all examined cells from removed tumors, and in most cells 111In could be seen in the nucleus. The specificity of the silver reaction products is supported by the observation that enterocytes in intestinal tissue specimens from near the tumor did not show any silver grains and no background labeling was seen in the plastic. CONCLUSION: After internalization through the somatostatin receptor system, 111In is translocated to the perinuclear area and into the nucleus. Whether the nuclide is still conjugated to the intact somatostatin analog or to part of it cannot be evaluated in this study. Despite the short irradiation range of 111In, the nuclear localization can explain its clinical effectiveness. The results from this study suggest that [111In-DTPA-D-Phe1]-octreotide may act as a powerful tumor cell-targeting substance.     

[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.     

The role of octreotide scintigraphy in rheumatoid arthritis and sarcoidosis.

Somatostatin receptors are widely expressed on cells and tissues throughout the human body. Apart from their expression in the physiological target organs of the peptide, somatostatin receptors are also expressed in various tumours. The expression of somatostatin receptors on neuroendocrine tumours led to the development of somatostatin receptor scintigraphy using [(111)In-DTPA-D-Phe(1)]-octreotide ((111)In-pentetreotide) in order to visualize somatostatin receptor positive tumours and their metastases in vivo. Previous studies reported the expression of somatostatin receptors in both normal and pathological cells and tissues of the human immune system as well. Somatostatin receptors have been demonstrated in Hodgkin's and non-Hodgkin's lymphomas and sst scintigraphy has shown to be a useful tool in diagnosis and staging of these diseases. Moreover, sst expression has also been detected in granulomateus diseases, like sarcoidosis and auto-immune diseases, like rheumatoid arthritis. In this paper we discuss the (possible) role of somatostatin receptor scintigraphy in diagnosis, staging or follow-up of patients suffering from sarcoidosis and rheumatoid arthritis.     

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     

A comparison of <Superscript>111</Superscript>In-DOTATOC and <Superscript>111</Superscript>In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours

[Yttrium-90-DOTA-Tyr³]-octreotide (DOTATOC) and [¹⁷⁷Lu-DOTA-Tyr³-Thr⁸]-octreotide (DOTATATE) are used for peptide receptor-mediated radionuclide therapy (PRMRT) in neuroendocrine tumours. No human data comparing these two compounds are available so far. We used ¹¹¹In as a surrogate for ⁹⁰Y and ¹⁷⁷Lu and examined whether one of the ¹¹¹In-labelled peptides had a more favourable biodistribution in patients with neuroendocrine tumours. Special emphasis was given to kidney uptake and tumour-to-kidney ratio since kidney toxicity is usually the dose-limiting factor. Five patients with metastatic neuroendocrine tumours were injected with 222 MBq ¹¹¹In-DOTATOC and ¹¹¹In-DOTATATE within 2 weeks. Up to 48 h after injection, whole-body scans were performed and blood and urine samples were collected. The mean absorbed dose was calculated for tumours, kidney, liver, spleen and bone marrow. In all cases ¹¹¹In-DOTATATE showed a higher uptake (%IA) in kidney and liver. The amount of ¹¹¹In-DOTATOC excreted into the urine was significantly higher than for ¹¹¹In-DOTATATE. The mean absorbed dose to the red marrow was nearly identical. ¹¹¹In-DOTATOC showed a higher tumour-to-kidney absorbed dose ratio in seven of nine evaluated tumours. The variability of the tumour-to-kidney ratio was high and the significance level in favour of ¹¹¹In-DOTATOC was P=0.065. In five patients the pharmacokinetics of ¹¹¹In-DOTATOC and ¹¹¹In-DOTATATE was found to be comparable. The two peptides appear to be nearly equivalent for PRMRT in neuroendocrine tumours, with minor advantages for ¹¹¹In/⁹⁰Y-DOTATOC; on this basis, we shall continue to use ⁹⁰Y-DOTATOC for PRMRT in patients with metastatic neuroendocrine tumours.     

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].     

In situ radiotherapy with 111In-pentetreotide. State of the art and perspectives.

111In-pentetreotide (Octreoscan) and other radiolabeled somatostatin analogs are useful in the management of well differentiated neuroendocrine malignancies such as carcinoid or islet cell neoplasms. These radiopeptides bind to membrane bound somatostatin receptors (sst 1-5) which are over-expressed in a wide variety of neoplasms, especially those arising from the neuroectoderm. Imaging advances allow for the noninvasive determination of the presence of sst receptors by combining radioactivity [111Indium with a somatostatin analog, DTPA-D-phe1-octreotide (pentetreotide)]. Radiolabeled somatostatin analogs bind to membrane receptors and internalization of the complex occurs. Auger emitting somatostatin analogs offer a novel and significantly less toxic approach to controlling neoplastic diseases by delivering targeted radiation specifically to receptor bearing cells while sparing receptor negative cells. Responses of 62-69% in 85 patients with metastatic neuroendocrine tumors treated with high dose (6-19.6 GBq) 111In-pentetreotide, specifically targeting tumor somatostatin receptors, have been reported. Objective responses observed included biochemical and radiographic responses with prolonged survival. This article will discuss and review the multi-center data available to date, the mechanisms of action of radiolabeled somatostatin analogs, dosimetry, clinical response parameters, and toxicity.     

Indium-111 octreotide scintigraphy in neurofibromatosis

Scintigraphy with the radiolabelled somatostatin analogue indium-111-DTPA-D-Phe-l-octreotide has recently been proposed for the imaging of CNS neoplasms expressing somatostatin receptors. While meningiomas are imaged with high sensitivity, neurinomas do not take up octreotide owing to the lack of somatostatin receptors. Neurofibromatosis is a relatively uncommon disorder in which meningiomas and neurinomas often occur in the same patient. Differential diagnosis between these two tumours by computed tomography and magnetic resonance imaging can be difficult. This study reports on^{1 11}In-octreotide scintigraphy in four patients with neurofibromatosis.¹¹In-octreotide scintigraphy was shown to be very helpful in the in vivo differential diagnosis: all four meningiomas showed intense tracer uptake, while all 15 neurinomas were negative (P<0.001 by Fisher's exact test). It may be concluded that scintigraphy with¹¹¹In-octreotide is a useful diagnostic procedure in neurofibromatosis, complementing standard neuroradiological imaging procedures.     

Radioiodinated somatostatin analog scintigraphy in small-cell lung cancer.

Somatostatin receptors have been characterized on biopsy specimens from small-cell lung carcinoma (SCLC) and on cultured human SCLC cells. We recently described the in vivo visualization of various somatostatin receptor-positive tumors, such as carcinoids and endocrine pancreatic tumors, after injection of 123I-Tyr-3-octreotide, a radiolabeled somatostatin analog. In the present study, this imaging procedure using 123I-Tyr-3-octreotide is reported in 11 patients with lung tumors. In five of eight patients with SCLC (63%), we were able to demonstrate tumor deposits using 123I-Tyr-3-octreotide scintigraphy. Unexpected metastases were found in two patients. In one of three patients with SCLC in whom tumor was not visualized, nonvisualization may have been caused by tumor necrosis and recent radiotherapy. In one of two patients with malignant small-cell tumors as described by Askin, the neoplasm was visualized. Like SCLC, these tumors are thought to derive from neuroendocrine cells. In one patient, a squamous-cell carcinoma and a bronchial adenoma were not visualized. We conclude that in the majority of patients with SCLC, the tumor and its metastases can be visualized using 123I-Tyr-3-octreotide scintigraphy. However, the value of this new technique in terms of specificity and sensitivity requires further studies in a larger group of patients.     

Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours

Somatostatin receptors are over-expressed in many tumours, mainly of neuroendocrine origin, thus enabling treatment with somatostatin analogues. Almost a decade of clinical experience of receptor radionuclide therapy with the analogue ⁹⁰Y-[DOTA]⁰-Tyr³-octreotide [⁹⁰Y-DOTATOC] has now been obtained at a few centres of excellence. This review reports on the present state of the art of receptor radionuclide therapy and discusses new perspectives.