A rapid and efficient preparation of [123I]radiopharmaceuticals using a small HPLC (Rocket) column.

A simplified method for the rapid and efficient preparation of [(123)I]radiopharmaceuticals is described. Three radiopharmaceuticals, [(123)I]beta-CIT, [(123)I]MIBG and [(123)I]clioquinol, were synthesised and purified as model compounds. The radiotracers were labelled with iodine-123 using electrophilic oxidative conditions and purified by a compact semi-preparative reverse phase column (C-18, 3 microm, 7 x 53 mm, Alltima Rocket, Alltech) using aqueous-ethanol as HPLC solvents that were directly used for radiopharmaceutical formulation. The radiochemical purity of the radioiodinated tracers as assessed by analytical HPLC was higher than 99% with specific activity higher than 3 GBq/nmol. The total preparation time of a radiotracer ranged from 40 to 60 min and, starting from 3.7 GBq of iodine-123, more than 2.5 GBq of formulated radiopharmaceuticals were available for clinical investigations.     

A scintigraphic comparison of iodine-123-metaiodobenzylguanidine and an iodine-labeled somatostatin analog (Tyr-3-octreotide) in metastatic carcinoid tumors.

A number of neoplasms are known to express somatostatin receptors, and the use of somatostatin receptor imaging in their localization has recently been described. We compared an 123I-labeled somatostatin analog Tyr-3-octreotide (TOCT) and 123I-labeled metaiodobenzylguanidine (MIBG) scintigraphy in seven patients with histologically proven metastatic carcinoid tumors. The optimum time for identifying tumor uptake on scanning after [123I]MIBG was 24-48 hr, and after 123I-TOCT 10-30 min postinjection. Both radiopharmaceuticals showed a varying spectrum of tracer uptake ([123I]MIBG showed no uptake in one patient; minimal in two; moderate in two; and intense in two; 123I-TOCT showed no uptake in two patients; minimal uptake in one; moderate uptake in two; and intense uptake in two). In two patients, 123I-TOCT identified metastatic lesions not seen by [123I]MIBG scintigraphy. These preliminary results suggest that [123I]MIBG and 123I-TOCT are useful and complementary imaging techniques for detecting metastatic carcinoid tumors.     

Experimental and clinical experience with iodine 123-labeled iodophenylpentadecanoic acid in cardiology

Iodine 123-labeled iodophenylpentadecanoic acid (IPPA) has been synthesized for investigating myocardial free fatty acid (FFA) metabolism. The diagnostic application of labeled FFA in heart disease may be important, because FFA is the preferred substrate of cardiac energy metabolism at rest in the fasting state. In addition, regional myocardial FFA uptake and regional myocardial blood flow are tightly coupled in normal myocardium with β-oxidation, which is extremely sensitive to oxygen deprivation. This article outlines basic physiologic pathways of cardiac IPPA metabolism in normal, acutely ischemic, and reperfused viable myocardium and summarizes the results of experimental studies in animals, validating the application of IPPA as an¹²³I-labeled fatty acid analog. In addition, the most important clinical studies indicating the clinical use of IPPA for diagnosis of coronary heart disease and myocardial viability are presented.     

Iodine 123-labeled metaiodobenzylguanidine imaging in heart disease

Scintigraphic images of myocardial iodine 123-labeled metaiodobenzylguanidine (MIBG) reflect the relative distribution of adrenergic neurodensity and function in the myocardium. In patients with hypertrophic cardiomyopathy or after infarction, MIBG uptake in hypertrophied myocardium and the infarct-related myocardium was found to be decreased in comparison to blood flow distribution, delineated with thallium 201. Most intriguingly, semiquantitative measurements in patients with congestive heart failure demonstrated reduced myocardial MIBG uptake. This reduction correlated directly with indexes of left ventricular function. Decreases in neuronal density, dysfunction of adrenergic neurons, or chronically elevated circulating norepinephrine levels may account for this diminished myocardial uptake, which, as demonstrated in a pilot study of 90 patients with congestive heart failure, was found to be of predictive value for survival.     

Iodine 123-labeled metaiodobenzylguanidine imaging in heart disease

Scintigraphic images of myocardial iodine 123-labeled metaiodobenzylguanidine (MIBG) reflect the relative distribution of adrenergic neurodensity and function in the myocardium. In patients with hypertrophic cardiomyopathy or after infarction, MIBG uptake in hypertrophied myocardium and the infarct-related myocardium was found to be decreased in comparison to blood flow distribution, delineated with thallium 201. Most intriguingly, semiquantitative measurements in patients with congestive heart failure demonstrated reduced myocardial MIBG uptake. This reduction correlated directly with indexes of left ventricular function. Decreases in neuronal density, dysfunction of adrenergic neurons, or chronically elevated circulating norepinephrine levels may account for this diminished myocardial uptake, which, as demonstrated in a pilot study of 90 patients with congestive heart failure, was found to be of predictive value for survival.     

Radiopharmaceuticals for single-photon emission computed tomography brain imaging

In the past 10 years, significant progress on the development of new brain-imaging agents for single-photon emission computed tomography has been made. Most of the new radiopharmaceuticals are designed to bind specific neurotransmitter receptor or transporter sites in the central nervous system. Most of the site-specific brain radiopharmaceuticals are labeled with (123)I. Results from imaging of benzodiazepine (gamma-aminobutyric acid) receptors by [(123)I]iomazenil are useful in identifying epileptic seizure foci and changes of this receptor in psychiatric disorders. Imaging of dopamine D2/D3 receptors ([(123)I]iodobenzamide and [(123)I]epidepride) and transporters [(123)I]CIT (2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane) and [(123)I]FP-beta-CIT (N-propyl-2-beta-carboxymethoxy-3-beta(4-iodophenyl)-nortropane has proven to be a simple but powerful tool for differential diagnosis of Parkinson's and other neurodegenerative diseases. A (99m)Tc-labeled agent, [(99m)Tc]TRODAT (technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino] ethanethiolato(3-)]oxo-[1R-(exo-exo)]-), for imaging dopamine transporters in the brain has been successfully applied in the diagnosis of Parkinson's disease. Despite the fact that (123)I radiopharmaceuticals have been widely used in Japan and in Europe, clinical application of (123)I-labeled brain radiopharmaceuticals in the United States is limited because of the difficulties in supplying such agents. Development of (99m)Tc agents will likely extend the application of site-specific brain radiopharmaceuticals for routine applications in aiding the diagnosis and monitoring treatments of various neurologic and psychiatric disorders.     

Matched pairs dosimetry: 124I/131I metaiodobenzylguanidine and 124I/131I and 86Y/90Y antibodies

The technological advances in imaging and production of radiopharmaceuticals are driving an innovative way of evaluating the targets for antineoplastic therapies. Besides the use of imaging to better delineate the volume of external beam radiation therapy in oncology, modern imaging techniques are able to identify targets for highly specific medical therapies, using chemotherapeutic drugs and antiangiogenesis molecules. Moreover, radionuclide imaging is able to select targets for radionuclide therapy and to give the way to in vivo dose calculation to target tissues and to critical organs. This contribution reports the main studies published on matched pairs dosimetry with (124)I/(131)I- and (86)Y/(90)Y-labelled radiopharmaceuticals, with an emphasis on metaiodobenzylguanidine (MIBG) and monoclonal antibodies.     

Scintigraphic assessment of patients with electrocardiographic left ventricular hypertrophy with ST-T changes without apparent cause

PURPOSE: Some patients who show electrocardiographic left ventricular hypertrophy with ST-T changes (ECG-LVH) are difficult to evaluate using routine examinations. To clarify the pathologic process in these patients, the authors performed several scintigraphic examinations. MATERIALS AND METHODS: Twenty-nine patients with ECG-LVH, without apparent cause, such as left ventricular (LV) systolic overloading or increased LV mass, were examined by myocardial I-123 MIBG imaging, I-123 BMIPP imaging, and exercise-induced stress perfusion imaging. In addition to the visual assessment of each image, we calculated global and regional myocardial washout of I-123 MIBG (%washout). The LV was assessed using conventional echocardiography. RESULTS: Visually observed abnormalities were located exclusively at the LV apex with all imaging methods and were detected in 76%, 52%, and 17% of patients by I-123 MIBG, I-123 BMIPP, and perfusion imaging, respectively. A follow-up study revealed that the apical defects of I-123 MIBG were subsequently followed by defects of I-123 BMIPP and then perfusion abnormalities. In patients with an apical defect revealed by I-123 MIBG imaging, apical %washout was high. In nine patients who underwent myocardial biopsy, myocardial disarray was observed at the apical regions. CONCLUSIONS: In many patients with ECG-LVH without apparent cause, sympathetic abnormalities are observed at the apex, similar to pathologic changes in hypertrophic cardiomyopathy. These abnormalities may lead to changes in fatty acid metabolism and perfusion.     

Single photon emission computed tomography (SPECT). Part II: Clinical applications

The clinical applications of SPECT are just beginning to be defined since complete systems have only recently become available. SPECT studies are more difficult to perform than planar imaging studies, and close attention to quality control is important to obtain optimal studies. SPECT has higher lesion contrast and is able to detect smaller lesions than planar imaging in Tc-99m sulfur colloid liver studies. Preliminary results of SPECT T1-201 studies are encouraging, but further work comparing SPECT and planar imaging of T1-201 is needed. SPECT does give more information than planar imaging in certain bone imaging cases such as suspected avascular necrosis of the hip. Although interesting results have been published using SPECT in brain and lung perfusion studies, the clinical utility of this work has not been determined. The development of certain radiopharmaceuticals would enhance the future of SPECT. Technetium-99m labeled brain and myocardial perfusion agents would be ideally suited for SPECT studies. The ability to quantitate lesion volume (eg, in liver metastases) has not been studied and could be useful in following patents on chemotherapy. SPECT could give additional information if monoclonal antibodies labeled with I-123 or Tc-99m can be demonstrated to have appropriate sensitivity. The advantages of SPECT over planar imaging will be greater as new agents are developed.     

New horizons in cardiac innervation imaging: introduction of novel <Superscript>18</Superscript>F-labeled PET tracers

Cardiac sympathetic nervous activity can be uniquely visualized by non-invasive radionuclide imaging techniques due to the fast growing and widespread application of nuclear cardiology in the last few years. The norepinephrine analogue ¹²³I–meta-iodobenzylguanidine (¹²³I–MIBG) is a single photon emission computed tomography (SPECT) tracer for the clinical implementation of sympathetic nervous imaging for both diagnosis and prognosis of heart failure. Meanwhile, positron emission tomography (PET) imaging has become increasingly attractive because of its higher spatial and temporal resolution compared to SPECT, which allows regional functional and dynamic kinetic analysis. Nevertheless, wider use of cardiac sympathetic nervous PET imaging is still limited mainly due to the demand of costly on-site cyclotrons, which are required for the production of conventional ¹¹C-labeled (radiological half-life, 20 min) PET tracers. Most recently, more promising ¹⁸F-labeled (half-life, 110 min) PET radiopharmaceuticals targeting sympathetic nervous system have been introduced. These tracers optimize PET imaging and, by using delivery networks, cost less to produce. In this article, the latest advances of sympathetic nervous imaging using ¹⁸F-labeled radiotracers along with their possible applications are reviewed.     

In vitro and in vivo properties of human/mouse chimeric monoclonal antibody specific for common acute lymphocytic leukemia antigen

A human/mouse chimeric monoclonal antibody specific for a common acute lymphocytic leukemia antigen was efficiently obtained by ligating human heavy-chain enhancer element to the chimeric heavy- and light-chain genes. Cell binding and competitive inhibition assays of both radioiodine and indium-111- (111In) labeled chimeric antibodies demonstrated in vitro immunoreactivity identical with that of the parental murine monoclonal antibodies. The biodistribution of the radiolabeled chimeric antibody in tumor-bearing nude mice was similar to that of the parental murine antibody. Tumor accumulation of radioiodinated parental and chimeric antibodies was lower than that of 111In-labeled antibodies, probably because of dehalogenation of the radioiodinated antibodies. Indium-111-labeled chimeric antibody clearly visualized xenografted tumor. These results suggest that a human/mouse chimeric antibody can be labeled with 111In and radioiodine without the loss of its immunoreactivity, and that chimeric antibody localizes in vivo in the same way as the parental murine antibody.     

Myocardial iodine-labeled metaiodobenzylguanidine 123 uptake relates to age

Background  

¹²³I-labeled metaiodobenzylguanidine (¹²³I-MIBG) is used increasingly to assess cardiac adrenergic neuron function. Few studies have reported data on myocardial MIBG uptake in relation to age, with contradictory results. This study reports the results of myocardial MIBG studies in untreated patients with cancer to assess the influence of age on myocardial MIBG uptake.     

Iodine-131 metaiodobenzylguanidine intra- and extravesicular accumulation in the rat heart

In order to establish the appropriate time for [123I]MIBG human myocardial imaging to assess the adrenergic nerve activity, the time courses of metaiodobenzylguanidine (MIBG) intra- and extravesicular accumulation in the rat heart were estimated by using [131I]MIBG and reserpine. In the heart, the intravesicular accumulation was relatively constant, while the extravesicular accumulation decreased rapidly from 5 min to 6 hr. The intravesicular percentage of the total cardiac tissue concentration reached a plateau value of 50% at 4 hr after i.v. injection of [131I]MIBG. In the spleen, similar time courses were observed as those in the heart, both of these organs being richly innervated by adrenergic nerves. Along with the time activity difference previously observed in the human hearts, these results suggest that at 4 hr post i.v. injection, [123I]MIBG myocardial imaging will best express the neuronal accumulation of the tracer and may be useful for the assessment of adrenergic function in various pathological conditions of the human heart.     

Novel iodinated tracers, MIBG and BMIPP, for nuclear cardiology

With the rapid growth of molecular biology, in vivo imaging of such molecular process (i.e., molecular imaging) has been well developed. The molecular imaging has been focused on justifying advanced treatments and for assessing the treatment effects. Most of molecular imaging has been developed using PET camera and suitable PET radiopharmaceuticals. However, this technique cannot be widely available and we need alternative approach. ¹²³I-labeled compounds have been also suitable for molecular imaging using single-photon computed tomography (SPECT) ¹²³I-labeled meta-iodobenzylguanidine (MIBG) has been used for assessing severity of heart failure and prognosis. In addition, it has a potential role to predict fatal arrhythmia, particularly for those who had and are planned to receive implantable cardioverter-defibrillator treatment. ¹²³I-beta-methyl-iodophenylpentadecanoic acid (BMIPP) plays an important role for identifying ischemia at rest, based on the unique capability to represent persistent metabolic alteration after recovery of ischemia, so called ischemic memory. Since BMIPP abnormalities may represent severe ischemia or jeopardized myocardium, it may permit risk analysis in CAD patients, particularly for those with chronic kidney disease and/or hemodialysis patients. This review will discuss about recent development of these important iodinated compounds.     

Regional alterations of myocardial norepinephrine transporter density in streptozotocin-induced diabetic rats: implications for heterogeneous cardiac accumulation of MIBG in diabetes

Cardiac scintigraphic studies using iodine-123 labeled metaiodobenzylguanidine ([123I]MIBG) have previously demonstrated the heterogeneous myocardial accumulation of radioactivity in diabetes. In this study, we investigated the myocardial regional distribution of [125I]MIBG and the effects of regional myocardial blood flow, myocardial norepinephrine (NE) content, and norepinephrine transporter (NET) function on regional [125I]MIBG accumulation in streptozotocin-induced diabetic (STZ-D) rats. Dual-isotope autoradiographic studies using [125I]MIBG and technetium-99m labeled hexakis (2-methoxy-2-isobutylisonitrile) (99mTc-MIBI), a tracer for the measurement of myocardial blood flow, were carried out to investigate the changes in regional myocardial blood flow in STZ-D rats. Uptake of [125I]MIBG was similar between the anterior wall and the inferior wall in control rats. On the other hand, in STZ-D rats, uptake of [125I]MIBG in the inferior wall was significantly less than that in the anterior wall. Uptake of 99mTc-MIBI was not significantly different between the anterior and inferior walls in control or STZ-D rats, indicating that myocardial blood flow did not change regionally in either control or STZ-D rats, and that the blood flow was not responsible for the heterogeneity of the distribution of [125I]MIBG in STZ-D rats. In STZ-D rats, cardiac NE concentrations determined using an HPLC-electrochemical detection (ECD) system were significantly increased in both the anterior and the inferior wall, although there was no significant difference in NE concentration between the anterior and inferior walls in control or STZ-D rats. Furthermore, the density and affinity of NET were investigated by studying the binding of [3H]desipramine to cardiac membranes. The Bmax values of the NET in the anterior wall were not significantly different between control and STZ-D rats, but the Bmax value of the NET in the inferior wall was significantly lower in STZ-D rats than in controls. In conclusion, myocardial MIBG uptake was reduced in the inferior wall of STZ-D rats compared with control rats; this decrease was correlated with the decrease in NET density, but was not dependent on the regional myocardial blood flow and NE concentration. These results suggest that regional fluctuations in NET levels in the inferior wall contribute to heterogeneous MIBG accumulation in diabetes.     

Scatter correction based on an artificial neural network for99mTc and123I dual-isotope SPECT in myocardial and brain imaging

The aim of this study was to elucidate the clinical usefulness of scatter correction with an artificial neural network (ANN) in 99mTc and 123I dual-isotope SPECT. METHODS: Two algorithms for ANN scatter correction were tested: ANN-10 and ANN-3 employing 10 and 3 energy windows for data acquisition, respectively. Three patients underwent myocardial or brain SPECT with one of the following combinations of radiopharmaceuticals administered: 99mTc-tetrofosmin and 123I-metaiodobenzylguanidine (MIBG), 99mTc-methoxyisobutylisonitrile (MIBI) and 123I-beta-methyl-paraiodophenyl-pentadecanoic acid (BMIPP), or 99mTc-ethyl-cistainate dimmer (ECD) and 123I-iomazenil. The patients were also referred for single-isotope imaging incorporating conventional triple-energy window (TEW) scatter correction. Crosstalk- and scatter-corrected 99mTc- and 123I-SPECT images in dual-isotope acquisition with ANN were compared with those in single-isotope acquisition. RESULTS: The ANN method well separated 123I and 99mTc primary photons. Although ANN-10 yielded images of poor quality, ANN-3 offered comparable image quality with the single-isotope scan without significant increase of acquisition time. CONCLUSION: The proposed method is clinically useful because it provides various combinations of information without anatomical misregistration with one acquisition.     

Quantitation of iodine-123 MIBG uptake by normal adrenal medulla in hypertensive patients

Eighteen hypertensive patients with a clinical suspicion of pheochromocytoma and raised or borderline raised plasma catecholamine and urinary vanillyl mandelic acid (VMA) levels were studied by scintigraphy using 123I-labeled metaiodobenzylguanidine (MIBG). None of these patients had any scintigraphic evidence of pheochromocytoma at the time of study or on subsequent clinical follow-up. A quantitative approach was taken to calculate the adrenal medullary uptake of [123I]MIBG in these patients. Three different methods of quantitation were evaluated using data acquired from an anthropomorphic phantom and analysed by three independent observers. In the patient studies 34 out of 35 adrenal medullas were visualized with uptake in the range of 0.01-0.22% of the administered dose 22 hr postinjection which was calculated using the preferred quantitation method. This is an appropriate control group range for comparison with patients who have proven norepinephrine and epinephrine secreting tumors. A quantitative approach to [123I]MIBG imaging provides an important tool for studying adrenomedullary pathophysiology.     

Portrayal of pheochromocytoma and normal human adrenal medulla by m-[123I]iodobenzylguanidine: concise communication

The radiopharmaceutical m-[131I]iodobenzylguanidine (I-131 MIBG), which is readily taken up by adrenergic vesicles, produces scintigraphic images of pheochromocytomas in man but rarely visualizes normal adrenal glands. Iodine-123 has many potential advantages over I-131 as a radiolabel for MIBG, including shorter half-life, freedom from beta emissions, and increased gamma-camera efficiency. In this study, diagnostic doses of MIBG labeled with I-131 and I-123, with nearly equivalent radiation dosimetry, were compared as imaging agents in eight patients with known or suspected pheochromocytoma. Images of superior quality were obtained with I-123 MIBG, and lesions not visualized using I-131 MIBG were portrayed. In addition, the normal adrenal medullae were visualized on the I-123 MIBG scintigrams in six out of eight patients.     

The effect of gadolinium contrast media on radioiodine uptake by the thyroid gland

OBJECTIVE: Patients with thyroid cancer may require detailed anatomic imaging before 131I therapy. Imaging by contrast-enhanced CT is contraindicated because it may result in saturation of tissues with iodine, decreasing the avidity of thyroid or thyroid cancer cells to subsequent radioiodine for extended intervals. Gadolinium-enhanced MRI offers an alternative to CT for detailed anatomic imaging. However, it is not known whether gadolinium contrast affects uptake of iodine by the thyroid gland since lanthanides affect ion transport in a variety of ways. The objective of this project was to determine whether the gadolinium MRI contrast injection alters thyroid uptake of radioiodine. METHODS: Radioiodine uptake by the thyroid gland was measured at 6 h and 24 h after the oral administration of 100 microCi 123I-Na-I. Three to seven days later, a standard dose (20 mL) of Magnevist (gadolinium DTPA) was administered intravenously. Another capsule of 100 microCi 123I Na-I immediately was given orally, and 6-h and 24-h radioiodine uptake by the thyroid gland was again measured and compared to baseline values. RESULTS: There was no statistically significant difference in uptake of radioiodine uptake by the thyroid gland between baseline values and those acquired immediately after the administration of Magnevist. CONCLUSION: Contrast-enhanced MRI may be safely performed before contemplated determinations of thyroid uptake of radioiodine, 131I therapy for hyperthyroidism, and postsurgical 131I imaging and therapy for well-differentiated thyroid cancer.     

Comparison of the distribution and binding of monoclonal antibodies labeled with 131-iodine or 111-indium

The distribution of two monoclonal antibodies with reactivity against human leukemia/lymphoma associated antigens (BA-1 antibody) and carcinoembryonic antigen (202 antibody) when labeled with 131I or 111In was studied in normal Balb/c mice. The BA-1 antibody of the IgM subclass was labeled with 131I by the micro iodine monochloride method at a 12:1 molar ratio and with 111In by the cyclic DTPA anhydride method at a 10:1 molar ratio. In vitro, the 131I-labeled BA-1 antibody bound 35.5% to 10(7) KM-3 leukemic cells while the 111In-labeled BA-1 antibody bound 29.9% to the same number of KM-3 cells. In vivo, the 111In-labeled BA-1 antibody showed a higher accumulation in liver, spleen, and kidney than the 131I-labeled BA-1 antibody. The 202 antibody of the IgG1 subclass was labeled with 131I at a 5:1 molar ratio and with 111In at a 7:1 molar ratio. In vitro, the 131I-labeled 202 antibody bound 30.9%, 27.4%, and 30.0% to 10(7) CO-112, WIDR, and LS-174T colon cancer cells, respectively. The 111In-labeled 202 antibody bound 20.5%, 30.2%, and 33.6%, respectively to the same number of colon cancer cells. In vivo, the 131I-labeled 202 antibody showed a higher tissue to blood ratio in liver, spleen, and kidney than the 111In-labeled 202 antibody. The data indicate that the relative distribution of 131I-labeled versus 111In-labeled monoclonal antibody may depend on the immunoglobulin subclass of the antibody and the molar ratio used in labeling.