Improved labelling of no-carrier-added 123I-MIBG and preliminary clinical evaluation in patients with ventricular arrhythmias.

Meta-[123I]iodobenzylguanidine (123I-MIBG) is currently used to assess myocardial sympathetic innervation by single photon emission tomography (SPET). In recent studies, an enhanced cardiac uptake of 123I-MIBG with high specific activity has been reported, suggesting the clinical potential of no-carrier-added (n.c.a.) 123I-MIBG in the assessment of abnormalities in cardiac sympathetic function. This paper describes the preparation of n.c.a. 123I-MIBG by non-isotopic Cu(I)-assisted [123I]iododebromination and by [123I]iododestannylation, both resulting in n.c.a. 123I-MIBG with radiochemical yields of 88 +/- 6% and high specific activity (> or = 6.3 TBq.mumol-1) in a total synthesis time of less than 50 min. The diagnostic potential of n.c.a. 123I-MIBG (> 6.3 TBq.mumol-1) was studied in 13 patients (nine patients with malignant ventricular arrhythmias and four patients suspected of phaeochromocytoma) and compared to commercial 123I-MIBG (approximately 75 MBq.mumol-1) using a dual-headed SPET camera (MULTISPECT II). High specific activity results in higher 123I-MIBG uptake in the heart and in the liver in all patients. The calculated heart-to-lung and heart-to-liver count ratios 4.5 h post-injection increased by 22 +/- 6% and 10 +/- 5% with n.c.a. 123I-MIBG compared to commercial 123I-MIBG respectively. In contrast, no significant correlation between the specific activity of 123I-MIBG and lung uptake could be established in this study. Analysis of radioactivity in blood after the intravenous injection of n.c.a. and commercially available 123I-MIBG showed an initial rapid clearance of radioactivity from blood, followed by a plateau from 60 min onwards. Within the first 24 h, more than 85% of the plasma activity was unchanged 123I-MIBG. The free 123I-iodide concentration determined 24 h post-injection was 2 +/- 1% with commercial 123I-MIBG and 3 +/- 2% with n.c.a. 123I-MIBG. In conclusion, the results of this investigation indicate that n.c.a. 123I-MIBG is a promising clinical tool for imaging myocardial sympathetic dysfunction by SPET. High specific activity n.c.a. 123I-MIBG can now be prepared by simple one-step methods giving high radiochemical yields and high purity suitable for clinical application. This encourages the further clinical validation of n.c.a. 123I-MIBG on a large scale.     

A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131I-MIBG (110 MBq) and with 131I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131I-mAb chCE7 and of 24 days with 131I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131I-chCE7 compared with 131I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131I-MIBG and 131I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not accumulate 131I-MIBG, and the antibody may hold potential for radioimmunotherapy, either by itself or in combination with 131I-MIBG.     

Patient dosimetry for 131I-MIBG therapy for neuroendocrine tumours based on 123I-MIBG scans

Pre-therapeutic metaiodobenzylguanidine (MIBG) scans can be performed using labelling with either iodine-123 or iodine-131. (123)I-MIBG scans provide better image quality and count statistics, while (131)I-MIBG allows registration of tracer kinetics over a longer period. The aim of this study was to determine how much information about the (131)I-MIBG therapy total body dose according to the MIRD formalism can be gathered from (123)I-MIBG pre-therapy scans. Thirty-eight (131)I-MIBG therapies administered to a total of 15 patients suffering from neuroblastoma ( n=6), carcinoid tumours ( n=5), phaeochromocytoma ( n=3) and medullary thyroid carcinoma ( n=1) were included. The mean administered activity was 5.3 GBq (SD 2.4 GBq). Three biplanar (123)I-MIBG total body scans were taken only once before a series of therapies while three biplanar (131)I-MIBG scans were taken after each therapy. Attenuation correction was performed taking into account the difference in attenuation between (123)I and (131)I. Using the MIRD formalism, the total body dose to the patient was calculated on the basis of: (1) a single exponential fit drawn through the data from the (123)I-MIBG pre-therapy scans, (2) a bi-exponential fit through the combined data of (123)I-MIBG pre-therapy and (131)I-MIBG post-therapy scans. The mean total body dose calculated in our study was significantly higher for patients suffering from neuroblastoma (mean+/-SD 0.37+/-0.21 mGy/MBq) than for patients suffering from phaeochromocytoma (0.08+/-0.02 mGy/MBq), carcinoid tumours (0.07+/-0.01 mGy/MBq) and medullary thyroid carcinoma (0.09 mGy/MBq). The correlation coefficient between the dose calculated on the basis of the (123)I-MIBG pre-therapy scans and the subsequent (131)I-MIBG therapy was 0.93 when a correction factor of 1.26 was taken into account. When considering all following therapies, the correlation was 0.85 and the correction factor, 1.20. Our results show that it is feasible to use data from pre-therapy (123)I-MIBG scans to calculate the total body dose of the subsequent (131)I-MIBG therapy.     

Uptake of mIBG and catecholamines in noradrenaline- and organic cation transporter-expressing cells: potential use of corticosterone for a preferred uptake in neuroblastoma- and pheochromocytoma cells

For imaging of neuroblastoma and phaeochromocytoma, [¹²³I]meta-iodobenzylguanidine ([¹²³I]mIBG) is routinely used, whereas [¹⁸F]6-fluorodopamine ([¹⁸F]6-FDA) is sporadically applied for positron emission tomography in pheochromocytoma. Both substances are taken up by catecholamine transporters (CATs). In competition, some other cell types are able to take up catecholamines and related compounds probably by organic cation (OCT) [extraneuronal monoamine (EMT)] transporters (OCT1, OCT2, OCT3=EMT). In this study, we investigated the uptake of radioiodine-labeled meta-iodobenzylguanidine (mIBG) as well as [³H]dopamine (mimicring 6-fluorodopamine) and [³H]noradrenaline. SK-N-SH (neuroblastoma) and PC-12 (phaeochromocytoma) cells were used and compared with HEK-293 cells transfected with OCT1, OCT2 and OCT3, respectively. In order to gain a more selective uptake in CAT expressing tumor cells, different specific inhibitors were measured. Uptake of mIBG into OCT-expressing cells was similar or even better as into both CAT-expressing cell lines, whereas dopamine and noradrenaline uptake was much lower in OCT-expressing cells. In presence of corticosterone (f.c. 10^?4 M], catecholamine and mIBG uptake into SK-N-SH and PC-12 cells was only slightly reduced. In contrast, this process was significantly inhibited in OCT2 and OCT3 transfected HEK-293 as well as in Caki-1 cells, which naturally express OCT3. We conclude that the well-known corticosteroid corticosterone might be used in combination with [¹⁸F]6-FDA or [¹²³I]mIBG to improve specific imaging of neuroblastoma and pheochromocytoma and to reduce irradiation dose to nontarget organs in [¹³¹I]mIBG treatment.     

Local delivery of <Superscript>131</Superscript>I-MIBG to treat peritoneal neuroblastoma

Internal radiotherapy involving systemic administration of iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) in neural crest tumours such as neuroblastoma has shown considerable success. Although peritoneal seeding of neuroblastoma occurs less often than metastases to organs such as the liver, no effective treatments exist in this clinical setting. Previous reports have demonstrated the effectiveness of peritoneal application of chemotherapeutic drugs or radiolabelled monoclonal antibodies in several kinds of carcinomas. Local delivery of ¹³¹I-MIBG should produce more favourable dosimetry in comparison with its systemic administration in the treatment of peritoneal neuroblastoma. In the current investigation, a peritoneal model of neuroblastoma was established in Balb/c nu/nu mice by i.p. injection of SK-N-SH neuroblastoma cells. Two weeks after cell inoculation, comparative biodistribution studies were performed following i.v. or i.p. administration of ¹³¹I-MIBG. Mice were treated with 55.5 MBq of ¹³¹I-MIBG administered either i.v. or i.p. at 2 weeks. Intraperitoneal injection of ¹³¹I-MIBG produced significantly higher tumour accumulation than did i.v. injection (P<0.01). Therapeutic ratios of i.p. injection were 4- to 14-fold higher than those of i.v. injection. Radiotherapy with i.v. administered ¹³¹I-MIBG failed to improve the survival of mice; mean survival of untreated mice and mice treated with i.v. administration of ¹³¹I-MIBG was 59.3±3.9 days and 60.6±2.8 days, respectively. On the other hand, radiotherapy delivered via i.p. administration of ¹³¹I-MIBG prolonged survival of mice to 94.7±17.5 days (P<0.02 vs untreated controls and mice treated with i.v. ¹³¹I-MIBG therapy). Radiation doses absorbed by tumours at 55.5 MBq of ¹³¹I-MIBG were estimated to be 4,140 cGy with i.p. injection and 450 cGy with i.v. injection. These results indicate the benefits of locoregional delivery of ¹³¹I-MIBG in the treatment of peritoneal neuroblastoma.     

Catabolism of 4-fluoro-3-iodobenzylguanidine and meta-iodobenzylguanidine by SK-N-SH neuroblastoma cells

BACKGROUND: A fluorine substituted derivative of meta-iodobenzylguanidine (MIBG), 4-fluoro-3-iodobenzylguanidine (FIBG), is retained in SK-N-SH human neuroblastoma cells in vitro to a higher degree than the MIBG. METHOD: To investigate whether the higher retention of FIBG is due to differences in the catabolic degradation of the two tracers, in vitro paired-label studies were performed using SK-N-SH cells. RESULTS: No detectable amount of benzyl amines, benzoic acids or hippuran derivatives, potential catabolites of these tracers, were seen in either case. Even after 48 h, the cell culture supernatants contained exclusively intact I-MIBG and I-FIBG. In contrast, in some cases, HPLC analysis of cell lysates indicated the presence of a very polar compound(s) as the predominant species with smaller quantities of intact tracers. The per cent total radioactivity in the lysate at each time point that was associated with intact I-FIBG was (average [range]) 25.4% [20.3-30.5], 22.5% [19.3-25.6], and 18.8% [14.3-23.3], at 0 h, 24 h and 48 h, respectively. The corresponding values for I-MIBG were 24.3% [21.0-27.5], 19.1% [11.7-26.5] and 17.4% [14.6-20.1]. No significant amount of activity was associated with high molecular weight species for either halobenzylguanidine, indicating that protein binding was not a major factor.     

Nuclear localizing sequences promote nuclear translocation and enhance the radiotoxicity of the anti-CD33 monoclonal antibody HuM195 labeled with 111In in human myeloid leukemia cells.

Our objective was to evaluate the toxicity of the anti-CD33 monoclonal antibody HuM195 modified with peptides (CGYGPKKKRKVGG) harboring the nuclear localizing sequence (NLS; underlined) of simian virus 40 large T antigen and labeled with (111)In against acute myeloid leukemia (AML) cells. METHODS: HuM195 was derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (sulfo-SMCC) to introduce maleimide groups for reaction with NLS-peptides and then conjugated with diethylenetriaminepentaacetic acid for labeling with (111)In. The immunoreactivity of NLS-HuM195 was evaluated by its ability to displace the binding of (111)In-HuM195 to HL-60 leukemia cells. Nuclear localization was measured in HL-60 cells by subcellular fractionation. The antiproliferative effects of (111)In-NLS-HuM195 and (111)In-HuM195 on HL-60, U937, or K562 cells with high, intermediate, or minimal CD33 expression, respectively, were studied. The survival of HL-60 cells or patient AML specimens treated with (111)In-NLS-HuM195 or (111)In-HuM195 was studied. Normal tissue toxicity was evaluated in BALB/c mice injected intravenously with of 3.7 MBq (22 microg) of (111)In-NLS-HuM195 or (111)In-HuM195. RESULTS: NLS-HuM195 exhibited relatively preserved CD33 binding affinity (dissociation constant [K(d)] = 4.3 +/- 1.7 x 10(-9) mol/L to 6.9 +/- 1.3 x 10(-9) mol/L). Nuclear uptake increased from 10.5% +/- 0.5% for (111)In-HuM195 to 28.5% +/- 4.1% or 65.9% +/- 1.5% for (111)In-HuM195 substituted with 4 or 8 NLS-peptides, respectively. The inhibitory concentrations of 50% (IC(50)) and 90% (IC(90)) for HL-60 cells treated with (111)In-NLS-HuM195 were 37 kBq per 10(3) cells and 77-81 kBq per 10(3) cells, respectively. The IC(50) and IC(90) values for (111)In-HuM195 were 92 kBq per 10(3) cells and 203 kBq per 10(3) cells. Growth inhibition was correlated with the level of CD33 expression. The survival of HL-60 cells was reduced from 232 +/- 22 colonies (control) to 7 +/- 1 colonies with 1.48 mBq per cell of (111)In-NLS-HuM195; no colonies were found at 3.33 mBq per cell. The surviving fraction decreased >2-fold in 7 of 9 AML specimens treated with an excess of (111)In-NLS-HuM195 and >10-fold in 2 of these specimens. There were no decreases in body weight or hematologic parameters or increases in alanine aminotransferase or creatinine in mice administered 3.7 MBq (22 microg) of (111)In-NLS-HuM195 or (111)In-HuM195. There was no morphologic damage to the liver or kidneys. CONCLUSION: We conclude that NLS-peptides routed (111)In-HuM195 to the nucleus of AML cells, where the emitted Auger electrons were lethal. (111)In-NLS-HuM195 is a promising targeted radiotherapeutic agent for AML.     

Toxicity from treatment of neuroblastoma with 131I-meta-iodobenzylguanidine

Toxic effects from 131I-meta-iodobenzylguanidine (131I-MIBG) treatments of neuroblastoma in six patients were recorded. The toxicity was largely confined to the hematologic system where circulating leukocytes and platelets regularly declined after each dose of 131I-MIBG; the values reached nadirs between three and seven weeks and recovered slowly over subsequent weeks. Prior bone marrow transplantation and infiltration of bone marrow by neuroblastoma appeared to make the hematologic system more vulnerable to the radiation. Dosimetry revealed greater absorbed radiation by the whole body than by the blood and bone marrow. These observations are explained by a relatively rapid exit of 131I-MIBG from the blood to other tissues (but not to the bone marrow). Since treatment of an aggressive and lethal tumor such as neuroblastoma should be pushed to a degree of toxicity, careful dosimetry in each case will be necessary as a guide to reach the point of maximally tolerable toxicity.     

Clinical usefulness of iodine-123-MIBG scintigraphy for patients with neuroblastoma detected by a mass screening survey

The purpose of this study was to evaluate the usefulness in a clinical setting of iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, planar and single photon emission computed tomography (SPECT) images, in patients with neuroblastoma as detected by a mass screening survey. METHODS: 123I-MIBG planar whole body images, and regional SPECT images of patients with neuroblastoma in 51 studies were reviewed. They were all detected by a mass screening survey performed in the 6th month after birth using vanil mandelic acid (VMA), and homovanillic acid (HVA) and the neuroblastoma had been confirmed by surgery. Scintigraphy was performed 24 hours after injection of 111 MBq of 123I-MIBG. We assessed the accuracy of the planar whole body images in order to demonstrate the extent of the lesion and the correlation between the degree and extent of the lesions of 123I-MIBG accumulation and clinical staging with tumor markers, such as urinary VMA, urinary HVA, serum neuron specific enolase (NSE) and serum lactate dehydrogenase (LDH). Additionally, we evaluated SPECT how useful supplemental SPECT might be in a clinical setting as compared with planar whole body images. RESULTS: 123I-MIBG planar whole body images revealed all 33 (100%) primary lesions, 4 of the 5 cases (80%) with liver metastasis, 3 of the 13 (23%) with lymph nodes metastasis and 1 of 3 (33%) with bone marrow infiltration. The extent and degree of accumulation correlated with the values of urinary VMA, urinary HVA and serum NSE. SPECT images helped to understand the positional relation in all cases and provided useful additional information for clinical staging in 7 cases. CONCLUSION: 123I-MIBG scintigraphy with planar and SPECT images is useful for evaluating patients with neuroblastoma, following detection by a mass screening survey.     

Radioiodinated metaiodobenzylguanidine (MIBG): radiochemistry, biology, and pharmacology

As an analogue of adrenergic neurotransmitter norepinephrine (NE), metaiodobenzylguanidine (MIBG) demonstrates high uptake both in normal sympathetically innervated tissues, such as the heart and salivary glands, and in tumors that express the NE transporter (NET), specifically those of neural crest and neuroendocrine origin. In 1994, (131)I-MIBG, also known as iobenguane I-131 intravenous, received Food and Drug Administration (FDA) approval as an imaging agent. In 2008, (123)I-MIBG was also approved by FDA as a tumor imaging agent. Commercial formulations of radioiodinated MIBG are prepared on the basis of radioiodide exchange reaction with unlabeled MIBG as a precursor and contain large mass amounts of unlabeled MIBG, or "cold carrier," molecules. Because the cold MIBG molecules competitively inhibit the uptake of radiolabeled MIBG molecules by adrenergic and neuroendocrine cells expressing NET, no-carrier-added (n.c.a.), high specific activity (SA) radioiodinated MIBG preparations have been developed on the basis of electrophilic radioiodination reaction and solid-phase technology by using dibutylstanyl benzylguanidine precursor linked to polymers. On the basis of n.c.a. synthetic procedures, therapeutic doses of [(131)I]MIBG can be administered with very high SA (1600 mCi/μmol or 5734 mCi/mg). The very high SA of n.c.a. [(131)I]MIBG drug would increase the specific cellular uptake of adrenergic neurons and neuroendocrine tumor cells expressing NET.     

Characteristics and regulation of 123I-MIBG transport in cultured pulmonary endothelial cells.

123I-Metaiodobenzylguanidine (123I-MIBG) is used for lung scintigraphy to assess pulmonary endothelial cell integrity, but its processing at the cellular level has not been investigated to date. We thus characterized the mechanisms that mediate 123I-MIBG transport in pulmonary endothelial cells and investigated the effects of stimuli associated with pulmonary dysfunction. METHODS: Calf pulmonary artery endothelial (CPAE) cells were examined for 123I-MIBG uptake and efflux rates and evaluated for the presence of norepinephrine (NE) transporters by Western blotting. The specificity of 123I-MIBG uptake was investigated with inhibitors of the uptake 1 and uptake 2 transport systems. In addition, we tested the effects of hypoxia (1% O2), phorbol 12-myristate 13-acetate (PMA, a protein kinase C [PKC] activator), and NG-nitro-L-arginine methyl ester (L-NAME) (a nitric oxide synthase inhibitor) treatments on CPAE cell 123I-MIBG uptake. RESULTS: CPAE cells demonstrated a time-dependent increase in 123I-MIBG uptake that reached a relative plateau (mean +/- SD) at 4 h of 375.6% +/- 5.9% the 30-min level. When the culture medium was changed after 30 min of uptake, 123I-MIBG gradually was eluted from the cells at an efflux rate of 43.8% over 2 h. Western blotting confirmed the presence of NE transporters in CPAE cells. The uptake 1 inhibitors desipramine, imipramine, and phenoxybenzamine at 50 micromol/L reduced 123I-MIBG uptake to 55.3% +/- 2.7%, 62.4% +/- 3.5%, and 48.0% +/- 2.2% control levels, respectively, whereas none of the uptake 2 inhibitors had an effect. Exposure to hypoxia resulted in a reduction in 123I-MIBG uptake to 77.5% +/- 0.2% and 50.0% +/- 3.4% control levels at 0.5 and 4 h, respectively. PMA (10 ng/mL) and L-NAME (2 nmol/L) decreased 123I-MIBG uptake to 76.7% +/- 9.0% and 86.5% +/- 5.6% control levels, respectively. CONCLUSION: Pulmonary endothelial cells express NE transporters and actively take up 123I-MIBG through the specific uptake 1 system. Furthermore, 123I-MIBG transport can be reduced by hypoxia, PKC activation, and nitric oxide deficiency, which may contribute partly to the lower levels of lung uptake observed in diseases that compromise pulmonary endothelial cell integrity.     

High uptake of 123I-metaiodobenzylguanidine related to olfactory neuroblastoma revealed by single-photon emission CT

We studied a case of olfactory neuroblastoma by noting 123I-metaiodobenzylguanidine (MIBG) uptake revealed by single-photon emission CT (SPECT). MR imaging revealed an enhancing tumor extending from the left nasal cavity to the bilateral anterior frontal cranial fossae. SPECT revealed high 123I-MIBG uptake in the enhancing tumor. SPECT-revealed 123I-MIBG uptake appears to be clinically useful for distinguishing olfactory neuroblastomas from other tumors, especially suprasellar meningiomas.     

Evaluation of clinical utility of 123I-MIBG scintigraphy in localization of tumors of sympathetic and adrenomedullary origin--a report of multicenter phase III clinical trials

Phase III clinical study was performed to evaluate clinical utility of 123I-MIBG in the localization of tumors in 48 patients with tumors of sympathetic and adrenomedullary origin, diagnosed or strongly suspected. Sixteen patients had pheochromocytoma, 23 had neuroblastoma, 7 had medullary carcinoma of the thyroid, and 2 had Sipple syndrome. In 3 out of 48 patients, 123I-MIBG scintigraphy was performed twice. The clinical utility of 123I-MIBG was evaluated in 50 cases. Out of 140 lesions, 123I-MIBG scintigraphy demonstrated 51 true positive, 79 true negative, 1 false positive, and 2 false negative. Seven lesions were not evaluable. Sensitivity was 96.2%, Specificity was 98.8%, and Accuracy was 97.7%. An acquisition between 4 hrs and a day after injection was adequate for tumor detection. Neither adverse reactions nor abnormal laboratory findings were noted in relation to 123I-MIBG injections. Our study indicates that 123I-MIBG is a safe and useful radiotracer for visualization and localization of tumors of sympathetic and adrenomedullary origin.     

Nuclear medicine therapy of neuroblastoma.

Specific targeting of radionuclides to neuroblastoma, a neural crest tumour occurring predominantly in young children and associated with a relatively poor prognosis, may be achieved via the metabolic route (MIBG), receptor binding (peptides) or immunological approach (antibodies). The clinical role of 131I-MIBG therapy and radioimmunotherapy in neuroblastoma is discussed. In recurrent or progressive metastatic disease after conventional treatment modalities have failed, 131I-MIBG therapy, with an overall objective response rate of 35%, is probably the best palliative treatment, as the invasiveness and toxicity of this therapy compare favourably with that of chemotherapy, immunotherapy and external beam radiotherapy. In patients presenting with inoperable stage III and IV neuroblastoma, 131I-MIBG therapy at diagnosis is at least as effective as combination chemotherapy but is associated with much less toxicity. In patients with recurrent disease 131I-MIBG therapy in combination with hyperbaric oxygen therapy proved feasible and encouraging effects on survival have been observed. Attempts to intensify the treatment in relapsed patients by combination of 131I-MIBG therapy with high dose chemotherapy and/or total body irradiation have met with considerable toxicity. Developments in MIBG therapy aiming at improving the therapeutic index are mentioned. Early results of radioimmunotherapy using 131I-UJ13A or 131I-3F8 monoclonal antibodies have shown moderate objective response and considerable side effects in patients with stage IV neuroblastoma, who had relapsed or failed conventional therapy. New developments in radioimmunotherapy of neuroblastoma include the use of chimaeric antibodies, the enhancement of tumour uptake by modulation of antigen expression or by increasing the tumour perfusion/vascularity/permeability, the use of other labels and multistep targeting techniques, e.g. using bispecific monoclonal antibodies.     

Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr 3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine

Purpose

⁶⁸Ga-DOTA-Tyr³-octreotide positron emission tomography (⁶⁸Ga-DOTA-TOC PET) has proven to be superior to ¹¹¹In-DTPA-D-Phe¹-octreotide (¹¹¹In-octreotide) planar scintigraphy and SPECT imaging in neuroendocrine tumours (NETs). Because of these promising results, we compared the accuracy of ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) imaging with PET in the diagnosis and staging of metastatic phaeochromocytoma and neuroblastoma, referring to radiological imaging as reference standard.

Methods

Three male and eight female patients (age range 3 to 68?years) with biochemically and histologically proven disease were included in this study. Three male and three female patients were suffering from phaeochromocytoma, and five female patients from neuroblastoma. Comparative evaluation included morphological imaging with CT or MRI, functional imaging with ⁶⁸Ga-DOTA-TOC?PET and ¹²³I-MIBG imaging. Imaging results were analysed on a per-patient and on a per-lesion basis.

Results

On a per-patient basis, both ⁶⁸Ga-DOTA-TOC and ¹²³I-MIBG showed a sensitivity of 100%, when compared with anatomical imaging. In phaeochromocytoma patients, on a per-lesion basis, the sensitivity of ⁶⁸Ga-DOTA-TOC was 91.7% and that of ¹²³I-MIBG was 63.3%. In neuroblastoma patients, on a per-lesion basis, the sensitivity of ⁶⁸Ga-DOTA-TOC was 97.2% and that of ¹²³I-MIBG was 90.7%. Overall, in this patient cohort, ⁶⁸Ga-DOTA-TOC PET identified 257 lesions, anatomical imaging identified 216 lesions, and ¹²³I-MIBG identified only 184 lesions. In this patient group, the overall sensitivity of ⁶⁸Ga-DOTA-TOC PET on a lesion basis was 94.4% (McNemar p<0.0001) and that of ¹²³I-MIBG was 76.9% (McNemar p<0.0001).

Conclusion

Our analysis in this relatively small patient cohort indicates that ⁶⁸Ga-DOTA-TOC PET may be superior to ¹²³I-MIBG gamma-scintigraphy and even to the reference CT/MRI technique in providing particularly valuable information for pretherapeutic staging of phaeochromocytoma and neuroblastoma.     

Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4-(2-mercapto-2-methylpropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

In developing technetium-99m-based radioligands for in vivo studies of cardiac adrenergic neurons, we compared the uptake characteristics of the (99m)Tc-labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4-(2-mercapto-2-methylpropylamino)-piperidine ((99m)Tc-FBPBAT) with those of the clinically established meta-[(123)I]iodobenzylguanidine ((123)I-MIBG) in rat vascular smooth muscle cells and neonatal cardiac myocytes. Furthermore, the cardiac and extracardiac uptake of both radiopharmaceuticals was assessed in intact rats and in rats pretreated with various alpha- and beta-adrenoceptor drugs, and adrenergic reuptake blocking agents. The uptake of (99m)Tc-FBPBAT and (123)I-MIBG into vascular smooth muscle cells and neonatal cardiac myocytes was rapid; more than 85% of the radioactivity accumulation into the cells occurring within the first 3 minutes. Radioactivity uptake after a 60-minute incubation at 37 degrees C (pH 7.4) varied from 15% to 65% of the total loaded activity per million cells. In all cases, (99m)Tc-FBPBAT showed the higher uptake, relative to (123)I-MIBG, at any given cell concentration. The cellular uptake of (99m)Tc-FBPBAT was lower at 4 degrees C and 20 degrees C than at 37 degrees C. In contrast, the (123)I-MIBG uptake was only slightly temperature dependent. Inhibition experiments confirmed that the cellular uptake of (123)I-MIBG is mediated by the uptake-I carrier, whereas alpha(1)- and beta(1)-adrenoceptors were predominantly involved in the uptake of (99m)Tc-FBPBAT into the cardiovascular tissues. Biodistribution studies in rats showed that (99m)Tc-FBPBAT accumulated in myocardium after intravenous injection. Radioactivity in rat heart amounted to 2.32% and 1.91% of the injected dose per gram at 15 and 60 minutes postinjection, compared with 3.10% and 2.21% injected dose per gram of tissue (%ID/g) in the experiment with (123)I-MIBG, respectively. Prazosin, urapidil, and metoprolol were as effective as treatment with other adrenergic drugs in lowering cardiac uptake of (99m)Tc-FBPBAT. Uptake reduction was more pronounced in myocardium than in other adrenergic-rich organs, including the lung, spleen, kidney, and adrenals, suggesting that the (99m)Tc-FBPBAT uptake in myocardium specifically reflects a high degree of alpha(1)/beta(1)-receptor binding to cardiac adrenergic neurons. In comparison, reduction of cardiac and pulmonary uptake of (123)I-MIBG was effective after pretreatment of rats with desipramine and reserpine, confirming distinct neuronal binding sites for (99m)Tc-FBPBAT and (123)I-MIBG. (99m)Tc-FBPBAT was excreted via urine and to a lower degree via feces. Urine analysis 6 hours p.i. revealed that more than 40% of the total excreted radioactivity was unmetabolized (99m)Tc-FBPBAT. In conclusion, the uptake of (99m)Tc-FBPBAT in rat myocardium specifically reflects binding to cardiac adrenergic neurons. The (99m)Tc-FBPBAT uptake appears to be predominantly mediated via the alpha(1)/beta(1)-adrenoceptor pathway. These data indicate that (99m)Tc-FBPBAT, like (123)I-MIBG, may be suitable for mapping cardiac adrenergic innervation by SPET, especially for alpha(1)/beta(1)-adrenoceptors as target in numerous heart diseases.     

Iodine-123-MIBG scintigraphy in neuroblastoma; relationship between the intensity of uptake and tumor characteristics

Iodine-123-MIBG (123I-MIBG) scintigraphy were performed for 23 patients with neuroblastoma at diagnosis. The intensity of MIBG activity in the primary tumor was evaluated visually (grade 3; intense uptake-grade 0; no definite uptake), and its relationship to the size, degree of tumor spread, urinary catecholamine metabolites (VMA, HVA), and histological types were investigated. The results of 123I-MIBG uptake grade were as follows: grade 3; 44% (10/23), grade 2; 30% (7/23), grade 1; 17% (4/23), grade 0; 9% (2/23). The grade was not associated with the tumor size, or the degree of tumor extension to the distant lesion, either. The more catecholamine metabolites were excreted in the urine, the tumor tended to have more intense uptake. The tumors of neuroblastoma rosette fibrillary type, and ganglioneuroblastoma poorly differentiated type had more intense uptake than neuroblastoma round cell type and ganglioneuroblastoma well differentiated type. The case of ganglioneuroma did not have definite MIBG uptake. The intensity of MIBG uptake is not relevant to the pathological grade of neuroblastoma, but considering the electromicroscopical features of neuroblastoma reported previously, it is thought to reflect the histological type.     

High 123I-MIBG uptake in neuroblastic tumours indicates unfavourable histopathology

Purpose

Scintigraphy using ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) is widely used for the detection of neuroblastic tumours. The aim of this study was to identify a possible correlation between the uptake intensity on ¹²³I-MIBG SPECT and histopathology of neuroblastic tumours.

Methods

¹²³I-MIBG SPECT examinations were performed in 55 paediatric patients with neuroblastic tumour and compared to histopathology after surgical resection or biopsy at a mean of 2 weeks after SPECT. For each lesion International Neuroblastoma Pathology Classification System (INPC) stage, mitosis karyorrhexis index (MKI), location and a semiquantitative tumour-to-liver count-rate ratio (TLCRR) were determined. Also, the presence or absence of MYCN amplification, p1 deletion, urine catecholamine and neuron-specific enolase blood levels at the time of scanning were recorded.

Results

In the 55 patients, 61 lesions were evaluated with ¹²³I-MIBG SPECT and corresponding histopathological findings were reviewed (11 ganglioneuroma, 11 ganglioneuroblastoma and 39 neuroblastoma). TLCRR was significantly higher in the neuroblastoma group (mean TLCRR 2.7) than in the ganglioneuroblastoma group (mean TLCRR 1.0) and ganglioneuroma group (mean TLCRR 0.7) at the time of primary diagnosis (p?<?0.001) and at follow-up (p?=?0.039). Intense ¹²³I-MIBG uptake was found in tumour tissue with a high mitotic activity (MKI-high or MKI-intermediate) after treatment. Four ganglioneuromas (36 %), three ganglioneuroblastomas (27 %) and six neuroblastomas (15 %) were ¹²³I-MIBG-negative.

Conclusion

In paediatric patients with peripheral neuroblastic tumours, strong ¹²³I-MIBG uptake indicates unfavourable histopathology. High uptake was seen in neuroblastomas and in tumours with a high mitotic activity.     

Thallium-201 scintigraphy of neuroblastoma: Different results for primary tumors and skeletal lesions

Thallium-201 scintigraphy was performed in 8 children with neuroblastoma, and uptake by the tumors was evaluated in comparison with the results of 123I-MIBG scintigraphy. No primary tumors or metastatic lymph nodes showed 201Tl accumulation, but in 4 cases of bone marrow metastases accompanied by focal cortical invasion, the metastatic lesion was demonstrated more clearly on the early image than on the delayed image. In another case of bone metastases infiltrating cortical bone revealed by 123I-MIBG scintigraphy and biopsy before treatment, 201Tl scintigraphy performed after chemotherapy showed abnormal accumulation in the tibia, but the second 123I-MIBG scintigraphy performed 1 week after the 201Tl scintigraphy showed no abnormal uptake. 201Tl does not appear to have good affinity for neuroblastoma, but it accumulates in metastatic skeletal lesions. A reactive hypermetabolic bone marrow, and/or inflammatory process and periosteal reaction due to the presence of metastatic foci may have induced the 201Tl accumulation. It seems that 201Tl is not useful for the diagnosis. Nevertheless, the discordance between 201Tl uptake in primary tumors and skeletal lesions allows speculation on the mechanism of 201Tl accumulation in skeletons.     

Use of iodine-123 metaiodobenzylguanidine scintigraphy for the detection of amiodarone induced pulmonary toxicity in a rabbit model: A comparative study with technetium-99m diethyltriaminepenta acetic acid radioaerosol scintigraphy

The purpose of the study was; (i) to determine whether 123I-MIBG scintigraphy is sensitive for detection of amiodarone induced pulmonary toxicity (AIPT) and (ii) to compare it with 99mTc-DTPA radioaerosol. Twelve white New Zealand rabbit with initial mean body weight 4.24 +/- 0.47 g were divided into two groups. AIPT group (n = 7) was administered amiodarone (20 mg/kg BW). The control group (n = 5) received the same amount of 0.9% saline. All animals underwent 123I-MIBG and 99mTc-DTPA radioaerosol scintigraphy at the end of the treatment period. 123I-MIBG static thorax images were obtained during 10 minutes at 15 minutes and 3-hours after intravenous injection of the radiopharmaceutical. Lung to heart ratios (LHR) and lung to mediastinum ratios (LMR), and retention index (LRI) of 123I-MIBG were determined. Two days after 123I-MIBG scintigraphy, 99mTc-DTPA radioaerosol scintigraphy was performed, and clearance from the lungs was measured for 10 min (1 min/frame) following termination of inhalation. 123I-MIBG lung retention index (LRI) was significantly higher in the AIPT group than the control (61 +/- 4.6 vs. 40 +/- 4.5, p = 0.01). Early LHR and LMR were significantly lower in the AIPT group than in the control group (p = 0.04, p = 0.01, respectively), whereas those of late LHR and LMR were not significantly different. T1/2 values of DTPA clearance were significantly increased in AIPT group according to the control group (55 +/- 7.2 vs. 86.6 +/- 18.5, p = 0.02). 123I-MIBG scintigraphy is a valuable tool for detecting AIPT in a rabbit model. Additionally, 99mTc-DTPA radioaerosol scintigraphy is an excellent comprehensive investigational tool for detecting AIPT with the added advantage of lower cost.