A 4-methyl-substituted <Emphasis Type="Italic">meta</Emphasis>-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells

Purpose As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[¹³¹I]iodo-4-methyl-benzylguanidine ([¹³¹I]MeIBG) has been developed. The purpose of this study was to evaluate [¹³¹I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts.Methods The ability of SK-N-SH human neuroblastoma cells to retain [¹³¹I]MeIBG in vitro over a period of 4 days, in comparison to [¹²⁵I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [¹³¹I]MeIBG and [¹²⁵I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts.Results Retention of [¹³¹I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [¹²⁵I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [¹³¹I]MeIBG in the heart was similar to that of [¹²⁵I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [¹³¹I]MeIBG was 1.6-fold higher than that of [¹²⁵I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [¹³¹I]MeIBG was two- to threefold lower than that of [¹²⁵I]MIBG. On the other hand, blood levels of [¹³¹I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [¹³¹I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [¹²⁵I]MIBG. However, [¹³¹I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [¹²⁵I]MIBG over 4–48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated.Conclusion Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.     

Metabolism of 15 (p123I iodophenyl-)pentadecanoic acid in heart muscle and noncardiac tissues

The uptake and turnover of (p¹²³I iodophenyl-) pentadecanoic acid (I-PPA), a radioiodinated free-fatty-acid analog, was examined in the heart, lung, liver, kidneys, spleen, and skeletal muscle of rats. At 2 min post injection, a high cardiac uptake of 4.4% dose per gram had already been achieved; this was followed by a rapid, two-component, tracer clearance. The kinetics of tissue concentrations of labeled hydrophilic catabolites indicated a rapid oxidation of I-PPA and the subsequent washout of I-PPA catabolites from heart-muscle tissue. The fractional distribution of the labeled cardiac lipids compared favorably with previously reported values for ³H-oleic-or ¹⁴C-palmitic-acid-labeled myocardial lipids. Typical patterns of I-PPA metabolism were observed in tissues depending on primary fatty-acid oxidation, lipid metabolism regulation, or I-PPA-catabolite excretion. The tissue concentrations and kinetics of I-PPA and its metabolites in the heart muscle indicated that general pathways of cardiac-lipid metabolism are traced by this new -emitting isotope-labeled radiopharmaceutical.     

Metabolism of radioiodinated fatty acid analogs in ischemic and hypoxic canine myocardium.

Myocardial metabolism of 17-[123I]-iodoheptadecanoic acid (IHDA), 15-(p-[131I]-iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[125I]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) was assessed during ischemia and hypoxia. The simultaneous investigation allowed us to evaluate differences in metabolic handling of these three fatty acids. METHODS: In 17 open-chest dogs, the left ascending coronary artery was cannulated and extracorporeal bypass (ECB) perfused. In 3 dogs, ECB flow was kept normal, and these control experiments showed that kinetics of the radioiodinated fatty acids were not affected by the ECB technique itself. In 9 dogs, ECB flow was reduced to one third (ischemia), and in 5 dogs, the ECB area was perfused with venous blood and was kept at control values (hypoxia). After simultaneous intravenous injection of IHDA, pIPPA and DMIPP, seven paired biopsy specimens from the native and ECB-perfused myocardium were taken over an assay period of 35 min. Total activity and the distribution in the aqueous phase and lipid fractions were determined, and time-activity curves were constructed. RESULTS: In ischemic (Is) but not in hypoxic (Hy) myocardium, peak total activity of IHDA, pIPPA and DMIPP decreased significantly versus normal (N) myocardium (IHDA: N = 700 +/- 267 versus Is = 335 +/- 158 dpm/mg/mCi; pIPPA: N = 988 +/- 318 versus Is = 438 +/- 180 dpm/mg/mCi; DMIPP: N = 352 +/- 146 versus Is = 179 +/- 82 dpm/mg/mCi; all P values < 0.001). The relative decrease was similar for IHDA, pIPPA or DMIPP. Half-time values of total activity were prolonged for IHDA and pIPPA but were shortened for DMIPP in ischemic and hypoxic myocardium (IHDA: N = 22, Is = 44 and Hy = 50 min; pIPPA: N = 24, Is = 95 and Hy = 169 min; DMIPP: N = 528, Is = 409 and Hy = 115 min). The aqueous phase activity for IHDA, pIPPA and DMIPP decreased significantly versus normal myocardium in both ischemic (IHDA: N = 71% +/- 9% versus Is = 36% +/- 9%, P < 0.001; pIPPA: N = 62% +/- 10% versus Is = 25% +/- 8%, P < 0.001; DMIPP: N = 26% +/- 11% versus Is = 18% +/- 3%, P < 0.05) and hypoxic (IHDA: N = 76% +/- 8% versus Hy = 62% +/- 8%, P < 0.05; pIPPA: N = 66% +/- 8% versus Hy = 46% +/- 10%, P < 0.05; DMIPP: N = 32% +/- 6% versus Hy = 24% +/- 4%, P < 0.05) myocardium. The relative decrease was significantly highest for pIPPA and lowest for DMIPP. Incorporation into triacylglycerols increased significantly for IHDA, pIPPA and DMIPP in both ischemic and hypoxic myocardium. In normal myocardium, DMIPP was already mainly incorporated into triacylglycerols. Activity of IHDA and pIPPA in acylcarnitine increased significantly in ischemic and hypoxic myocardium. CONCLUSION: Kinetics of the radioiodinated fatty acid analogs in myocardium are altered during oxygen deprivation in a similar fashion as documented in literature for natural fatty acids. However, the changes were different between IHDA, pIPPA and DMIPP, suggesting different metabolic handling and thus reflecting different aspects of myocardial fatty acid metabolism.     

Influence of propranolol on uptake of radioiodinated heptadecanoic acid and thallium-201 in the dog heart

In an experimental study, the influence of propranolol on myocardial uptake of radioiodinated heptadecanoic acid (¹³¹I-HDA) and thallium-201 (²⁰¹Tl) in the dog heart was assessed. Uptake of ¹³¹I-HDA and ²⁰¹Tl was evaluated in ten control dogs and in ten dogs 20 min after IV administration of propranolol (0.15 mg/kg). In both groups, four healthy dogs were studied and six dogs were studied after coronary artery occlusion. It was shown that both total uptake of ¹³¹I-HDA and ²⁰¹Tl did not alter significantly, regardless of significant changes in hemodynamic parameters and total arterial plasma FFA levels. However, distribution of both ¹³¹I-HDA and ²⁰¹Tl was markedly affected by propranolol, since the endocardial to epicardial ratio showed significantly higher values in the ischemic myocardial regions. The results of our study indicate that propranolol (1) preserves myocardial perfusion in the normal and acutely ischemic dog heart, and (2) gives a more favorable distribution in the ischemic myocardial region towards the subendocardial layers.     

External detection of regional myocardial metabolism with radioiodinated hexadecenoic acid in the dog heart

In a previous study we have demonstrated that terminally iodinated hexadecenoic acid (¹³¹I-HA) and Thallium-201 (²⁰¹Tl) are comparable in myocardial uptake and distribution in the ischemic dog heart (Westera et al. 1980). In the present study the potential value of ¹³¹I-HA was proved in determining regional myocardial metabolism in 19 dog experiments.In ten dogs, ¹³¹I-HA was administered 5 min after occlusion of a coronary artery (group II), in six dogs after a 90 min occlusion period (group III). Three dogs served as controls (group I). The turnover rates (t1/2) of ¹³¹I-HA were calculated from mono-exponential time-activity curves, obtained by external detection over ischemic and normally perfused areas during a 30 min period after IV injection of 0.7–1.5 mCi ¹³¹I-HA. The t1/2 values in ischemic regions were found to be significantly longer (group II, 25.1±2.6 min; group III, 22.6±1.8 min) than in nonischemic areas (group II, 12.5±1.8 min; group III, 14.2±1.4 min). The t1/2 values in the control dogs (group I, 13.4±1.4 min) were not significantly different from the turnover rates in the non-ischemic areas of the occluded hearts.We conclude that the study of turnover rates of radioiodinated free fatty acids allows the determination of regional myocardial metabolism and offers a means to distinguish normally perfused from ischemic myocardial tissue.     

Clinical evaluation of no-carrier-added meta-[123I]iodobenzylguanidine for myocardial scintigraphy

In clinical and research studies, images obtained using carrier-added meta-[¹²³I]iodobenzylguanidine (c.a. [¹²³I]MIBG) have shown quite variable quality, with varying levels of uptake in lung, liver and mediastinum; this is a significant problem for quantification of the myocardial uptake by means of region ratios. First experimental and preliminary human data in respect of no-carrier-added (n.c.a.) [¹²³I]MIBG are indicative of improved imaging quality. The aim of the present study was to evaluate the clinical value of myocardial scintigraphy with n.c.a. [¹²³I]MIBG in patients with tachyarrhythmias. The study population comprised 24 patients with tachyarrhythmogenic diseases routinely studied by cardiac single-photon emission tomography (SPET) with [¹²³I]MIBG. Twelve of the 24 patients were studied with c.a. [¹²³I]MIBG (seven females and five males; mean age 42±13 years, range 20–60 years), whereas the other 12 were studied with n.c.a. [¹²³I]MIBG (ten females, two males; mean age 41±11 years, range 18–60 years, P=NS). For quantification of the specific uptake in the different organs, count ratios were calculated on SPET images acquired 4 h p.i. Visual analysis of all [¹²³I]MIBG scans showed improved image quality (improved contrast between heart and neighbouring organs) in n.c.a. studies as compared with c.a. studies. A significantly higher heart/left atrial blood ratio was found in the n.c.a. studies as compared with the c.a. studies (10.3±3.2 vs 5.3±1.3, P=0.0003); furthermore, significantly higher heart/lung and heart/liver ratios (2.5±0.6 vs 1.5±0.3, P=0.0002, and 0.8±0.2 vs 0.6±0.1, P=0.0006, respectively) were obtained in the c.a. studies, whereas lung/left atrial blood and liver/left atrial blood ratios showed no significant differences (4.2±1.3 vs 3.6±1.1, P=0.39, and 13.7±5.2 vs 9.6±2.2, P=0.21, respectively). In conclusion, the use of n.c.a. [¹²³I]MIBG yields a significantly higher myocardial uptake associated with improvement in contrast between the heart and neighbouring organs and is therefore superior to the commercially available c.a. [¹²³I]MIBG for use in clinical and research studies of the myocardial presynaptic sympathetic nervous system. Furthermore, our data indicate that for quantification the use of a left atrial blood reference region of interest, which is only available on SPET studies, is to be recommended. Received 22 September and in revised form 2 November 1999     

Renal excretion of iodine-131 labelledmeta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours

Iodine-131 labelledmeta-iodobenzylguanidine ([¹³¹I]MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [¹³¹I]MIBG (3.1–7.5 GBq) to 17 patients (n=32 courses), aged 2–73 years, 56%±10%, 73%±11%, 80%±10% and 83%±10% of the dose was cumulatively excreted as total radioactivity in urine att=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%–18% of [¹³¹I]meta-iodohippuric acid ([¹³¹I]MIHA), the cumulatively excreted radioactivity consisted of >85% [¹³¹I]MIBG, with 6% of the dose excreted as free [¹³¹I]iodide, 4% as [¹³¹I]MINA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [¹³¹I]MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [¹³¹I]meta-iodobenzoic acid in two patients, a possible metabolic pathway for [¹³¹I]MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity.     

Quantifying endogenous glucose production and contributing source fluxes from a single 2H NMR spectrum

Endogenous glucose production (EGP), gluconeogenic and glycogenolytic fluxes by analysis of a single ²H‐NMR spectrum is demonstrated with 6‐hr and 24‐hr fasted rats. Animals were administered [1‐²H, 1‐¹³C]glucose, a novel tracer of glucose turnover, and ²H₂O. Plasma glucose enrichment from both tracers was quantified by ²H‐NMR analysis of monoacetone glucose. The 6‐hr fasted group (n = 7) had EGP rates of 95.6 ± 13.3 μmol/kg/min, where 56.2 ± 7.9 μmol/kg/min were derived from PEP; 12.1 ± 2.1 μmol/kg/min from glycerol, and 32.1 ± 4.9 μmol/kg/min from glycogen. The 24‐hr fasted group (n = 7) had significantly lower EGP rates (52.8 ± 7.2 μmol/kg/min, P = 0.004 vs. 6 hr) mediated by a significantly reduced contribution from glycogen (4.7 ± 5.9 μmol/kg/min, P = 0.02 vs. 6 hr) while PEP and glycerol contributions were not significantly different (39.5 ± 3.9 and 8.5 ± 1.2 μmol/kg/min, respectively). These estimates agree with previous assays of EGP fluxes in fasted rats obtained by multinuclear NMR analyses of plasma glucose enrichment from ²H₂O and ¹³C‐glucose tracers. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Myocardial uptake of <Superscript>99m</Superscript>Tc-annexin-V and <Superscript>111</Superscript>In-antimyosin-antibodies after ischemia-reperfusion in rats

Objectives Phosphatidylserin exposure on cell surfaces occurs early during apoptosis and is detected in vivo by using ^99mTc-annexin-V (ANX). Cardiomyocyte membrane disruption is detected in vivo by using ¹¹¹In-antimyosin-antibodies (AM). We aimed to determine if ANX and AM allow evaluation of the time-course of these two distinct cell death events after myocardial ischemia-reperfusion. Methods Coronary tying (20 min) followed by reperfusion (IR) was performed in 31 rats. Twelve of the rats were injected with ANX, 11 with AM, and eight with both tracers. Myocardial uptake of tracers was studied 1–2 h, 4 h, or 24 h after IR by scintigraphy (ANX, n = 14) and autoradiography (all cases), and compared to histology and Apostain staining. Results Scintigraphy was positive in all rats 2 h after IR and in three of five rats at 24 h. On autoradiography, ANX activity was intense in myocardial lesions as early as 1 h post-IR, whereas AM activity was mild at 2 h then increased at 4 h post-IR. ANX and AM uptakes evolved from mid-myocardium to endocardial and epicardial regions from 2 h to 24 h post-IR. Apostain staining was significant in myocardial lesions (p < 10⁶ compared to six sham-operated rats). On histology, myocardial lesion was characterized by interstitial oedema, myocytes necrosis, and dramatic thinning at 24 h. Conclusion These data suggest that ANX and AM allow temporal and regional evaluations of PS exposure and membrane disruption, respectively, during myocytes death after 20-min myocardial ischemia followed by reperfusion. Also, (i) apoptosis starts very early in injured myocardium, (ii) myocyte necrosis occurs later (3–4 h post-reperfusion), and (iii) most dead cells are removed from mid-myocardium between 6 h and 24 h after reperfusion.     

Clinical performance and radiation dosimetry of no-carrier-added vs carrier-added 123I-metaiodobenzylguanidine (MIBG) for the assessment of cardiac sympathetic nerve activity

Purpose We hypothesized that assessment of myocardial sympathetic activity with no-carrier-added (nca) ¹²³I-meta-iodobenzylguanidine (MIBG) compared to carrier-added (ca) ¹²³I-MIBG would lead to an improvement of clinical performance without major differences in radiation dosimetry. Methods In nine healthy volunteers, 15 min and 4 h planar thoracic scintigrams and conjugate whole-body scans were performed up to 48 h following intravenous injection of 185 MBq ¹²³I-MIBG. The subjects were given both nca and ca ¹²³I-MIBG. Early heart/mediastinal ratios (H/M), late H/M ratios and myocardial washout were calculated. The fraction of administered activity in ten source organs was quantified from the attenuation-corrected geometric mean counts in conjugate views. Radiation-absorbed doses were estimated with OLINDA/EXM software. Results Both early and late H/M were higher for nca ¹²³I-MIBG (ca ¹²³I-MIBG early H/M 2.46 ± 0.15 vs nca ¹²³I-MIBG 2.84 ± 0.15, p = 0.001 and ca ¹²³I-MIBG late H/M 2.69 ± 0.14 vs nca ¹²³I-MIBG 3.34 ± 0.18, p = 0.002). Myocardial washout showed a longer retention time for nca ¹²³I-MIBG (p < 0.001). The effective dose equivalent (adult male model) for nca ¹²³I-MIBG was similar to that for ca ¹²³I-MIBG (0.025 ± 0.002 mSv/MBq vs 0.026 ± 0.002 mSv/MBq, p = 0.055, respectively). Conclusion No-carrier-added ¹²³I-MIBG yields a higher relative myocardial uptake and is associated with a higher myocardial retention. This difference between nca ¹²³I-MIBG and ca ¹²³I-MIBG in myocardial uptake did not result in major differences in estimated absorbed doses. Therefore, nca ¹²³I-MIBG is to be preferred over ca ¹²³I-MIBG for the assessment of cardiac sympathetic activity.     

Quantitative analysis of myocardial glucose utilization in patients with left ventricular dysfunction by means of 18F-FDG dynamic positron tomography and three-compartment analysis

Purpose Myocardial glucose utilization (MGU) is altered in various heart diseases. The aim of this study was to quantitatively assess regional myocardial glucose utilization in patients with left ventricular (LV) dysfunction by dynamic ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET).Methods A total of 18 subjects were studied, including ten with LV dysfunction (seven with idiopathic dilated cardiomyopathy and three with aortic regurgitation; NYHA II in 8 and III in 2) and eight healthy normal volunteers. Patients with diabetes mellitus were excluded. A dynamic PET study was performed for 40 min following the injection of 370 MBq of FDG after 50-g glucose loading. On the basis of a three-compartment model, MGU, K₁, k₂, and k₃ were computed on a pixel by pixel basis to generate LV myocardial parametric maps. FDG standardized uptake value (SUV) was also calculated using static images obtained 40 min after FDG injection. These metabolic values were compared with myocardial flow distribution (%Flow), LVEF, LV volumes, and LV wall thickening (WT) determined by gated myocardial single-photon emission computed tomography using QGS software in eight myocardial segments.Results MGU correlated positively with LV volumes and negatively with LVEF. K₁ was significantly higher in the segments of the patients than in those of the normal volunteers (0.082±0.055 vs 0.041±0.017 ml min^–1 g^–1, p<0.05), although there was no difference in MGU between the groups. On the other hand, SUV, k₂, and k₃ did not differ significantly between the groups. Among the patients, the K₁ values were significantly higher in the areas with impaired WT (%WT<17%) (0.109±0.063 vs 0.069±0.062 ml min^–1 g^–1, p<0.05) and in the areas with flow reduction (%Flow<71%) (0.112±0.076 vs 0.071±0.046 ml min^–1 g^–1, p<0.05).Conclusion These results indicate that glucose utilization was preserved in the patients with LV dysfunction, mainly due to an increase in glucose transport, particularly in the regions with severely impaired LV function. Thus, the quantitative assessment of myocardial glucose utilization by FDG dynamic PET may provide useful information for assessing the regional myocardial metabolic status in patients with LV dysfunction.     

Structurally modified fatty acids: Clinical potential as tracers of metabolism

Recently 15-p-iodophenyl-β-methyl-pentadecanoic acid (BMPPA) was proposed for use in myocardial scintigraphy, as a possible probe of metabolic processes other than β-oxidation. In 19 patients (CAD/15, St.p. Mi/7; control 4) myocardial scintigraphy was carried out after i.v. I-123-BMPPA (2–4 mCi). Data were collected (LAO 45°/14; anterior/5) for 100 min in the fasted patients. Organ to background (BG) ratios were calculated for the heart (H) and liver (L), and the elimination (E) behaviour was analyzed from BG (vena cava region) corrected time activity curves. In 10 patients plasma and urine were examined. By CHCl₃/MeOH extraction of plasma samples (90 min after injection), both in water and in organic medium soluble catabolites were found. TLC fractionation showed that those were co-migrating, compared to standards, with bencoic acid, BMPPA and trigylcerides. In the urine (0–2 h after injection, 4.1% dose) hippuric acid was found. The mean t-max of BMPPA occurred at 15 min in the heart and at 9 min in the liver (P<0.01), with H/BG and L/BG ratios of 1.8 and 2.1, respectively. The elimination of BMPPA was slower from the heart than from the liver (P<0.01). It was biexponential from the liver in all cases (\(\bar x\): t/2 I, 11.4 min; t/2 II, 92 min; t/2 I uncor., 38 min) with the size of phase I smaller than that of phase II (\(\bar x\): I/II, 0.57). From the heart BMPPA turnover was biexponential in 11 patients (\(\bar x\): t/2 I, 13.8 min; t/2 II, 187 min; t/2 I uncor., 65 min; I/II, 0.34), but monoexponential in 8 (\(\bar x\): t/2, 218 min).

In 13 diseased regions (MI/7) BMPPA uptake was reduced, and the E behaviour was mostly abnormal as compared to the respective undiseased region. We conclude that BMPPA is a useful agent for myocardial scintigraphy. Its longer retention time in the heart compared to unbranched radioiodinated fatty acids may facilitate SPECT studies. E behaviour and plasma analysis indicate that BMPPA is metabolically broken down. Yet, the complexity of the supposed mechanism may impede curve interpretation in terms of specific metabolic pathways.

     

Iodine-123N- methyl-4-iododexetimide: a new radioligand for single-photon emission tomographic imaging of myocardial muscarinic receptors

Cardiac muscarinic receptor ligands suitable for positron emission tomography have previously been characterised. Attempts to develop radioligands of these receptors suitable for single-photon emission tomographic (SPET) imaging have not been successful due to high lung retention and high non-specific binding of previously investigated potential tracers. The purpose of this study was to evaluate the biodistribution and in vivo imaging characteristics of a new radiopharmaceutical, [¹²³I]N-methyl-4-iododexetimide. Biodistribution studies performed in rats showed high cardiac uptake (2.4% ID/g) 10 min after injection with a heart to lung activity ratio of 5:1. Specificity and stereo selectivity of cardiac binding were demonstrated using blocking experiments in rats. Dynamic imaging studies in anaesthetised greyhounds demonstrated rapid and high myocardial uptake and low lung binding with stable heart to lung activity ratios of >2.5:1 between 10 and 30 min, making SPET imaging feasible. Administration of an excess of an unlabelled muscarinic antagonist, methyl-quinuclidinyl benzylate rapidly displaced myocardial activity to background levels and the pharmacologically inactive enantiomer, [¹²³I]N-methyl-4-iodolevetimide, had no detectable cardiac uptake, indicating specific and stereoselective muscarinic receptor binding. SPET revealed higher activity in the inferior than in the anterior wall, this being consistent with previously described regional variation of cardiac parasympathetic innervation. [¹²³I]N-methyl-4-iododexetimide shows promise as an imaging agent for muscarinic receptor distribution in the heart and may be helpful in evaluating diverse cardiac diseases associated with altered muscarinic receptor function, including heart failure and diabetic heart disease.     

A procedure for wall detection in [18F]FDG positron emission tomography heart studies

Quantitative positron emission tomography (PET) heart studies require the accurate localization of regions of interest (ROIs) on the myocardial wall (MW) and left ventricle (LV). The procedure is often inaccurate, especially when there is low tracer uptake. We implemented a data processing technique to improve the accuracy of the localization of ROIs on the MW and LV in fluorine-18 labelled deoxyglucose ([¹⁸F]FDG) PET heart studies. This technique combines transmission data, acquired before tracer administration and used for attenuation correction, and dynamic emission data (DY), acquired to obtain myocardial time-activity curves and used to calculate regional myocardial glucose utilization, to generate a new set of transmission images (TRDY) with enhanced contrast between MW and LV. These new transmission images identify the extravascular myocardial tissue and can be used for ROI placement. Validation of the method was performed in 25 patients, studied after an oral glucose load, by drawing irregular ROIs on three transaxial slices outlining the septum and anteriorapical and lateral wall on the last frame of the DY images (steady state) and then on the TRDY images. Two kinds of analysis were performed on a total of 225 myocardial segments: (1) mean counts per pixel in the DY images from ROIs independently drawn on DY and TRDY images were compared; (2) TRDY ROIs were copied onto DY images and repositioned in the event of mismatch between ROIs and myocardial tissue edge. Mean counts per pixel in the DY images from the original and the repositioned TRDY ROIs were compared. An excellent correlation was found in both cases (using TRDY and DY ROIs:y=0.908x+0.068,r=0.97; using TRDY ROIs alone:y=0.975x+0.006,r=0.99). This technique can be used for clinical applications in physiological and pathological conditions in which the myocardial [¹⁸F]FDG uptake is reduced or minimal, including diabetes and myocardial infarction.     

Decreased uptake of therapeutic doses of iodine-131 after 185-MBq iodine-131 diagnostic imaging for thyroid remnants in differentiated thyroid carcinoma

We performed a prospective random study to assess possible thyroid stunning by a 185-MBq iodine-131 dose used to diagnose thyroid remnants. Patients with differentiated thyroid carcinoma were included after total or near-total thyroidectomy. They were randomly assigned to two groups. In group 0 (G0, 32 patients), iodine-123 administration only was used to diagnose thyroid remnants and/or metastasis, so that no thyroid stunning by ¹³¹I would occur. In group 1 (G1, 19 patients), diagnostic imaging was performed with ¹²³I and 185 MBq ¹³¹I. ¹²³I imaging was less sensitive than ¹³¹I imaging in identifying thyroid remnants in both groups (94%). Thyroid uptake of ¹²³I was measured in both groups (at 2 h) and was not significantly different between the groups. Patients with thyroid remnants who remained in the study (28/32 in G0, 17/19 in G1) were treated with 370 MBq ¹³¹I, 5 weeks after treatment (mean time, range 12–84 days). In 12/17 G1 patients thyroid uptake measurement was repeated immediately before treatment. Uptake was equal to 1.97%±0.71% and significantly lower (P<0.05) than the previous measurement (3.76%±1.50%). Patients were imaged 7 days after administration of the therapeutic dose and the images were compared with the diagnostic images. In 28/28 G0 patients thyroid remnants were unchanged and clearly seen. In 5/17 G1 patients, however, the remnants were hardly identified, although they had been clearly seen at the time of diagnosis. We conclude the following: (1) a diagnostic dose of 185 MBq ¹³¹I decreases thyroid uptake for several weeks after administration and can impair immediate subsequent ¹³¹I therapy; (2) ¹²³I is slightly less sensitive than ¹³¹I in identifying thyroid remnants; and (3) the need to scan for thyroid remnants remains to be confirmed, since only 2/51 patients enrolled in this study were not treated with ¹³¹I. Received 6 August and in revised form 24 October 1997     

Specific targeting of infectious foci with radioiodinated human recombinant interleukin-1 in an experimental model

In the present study, radioiodinated human recombinant interleukin-1 (IL-1) was investigated for its potential to image infectious foci in vivo in an animal model of infection. Twenty-four hours after induction of aStaphylococcus aureus abscess in the left calf muscle, mice were i.v. injected with both iodine-125 labelled IL-1 and iodine-131 labelled myoglobin, a size-matched control agent. The animals were killed for tissue biodistribution studies at 2, 6, 12, 24 and 48 h p.i. Gamma camera images were obtained at 6, 24 and 48 h after injecting mice with¹²³I-IL-1. Radioiodinated IL-1 rapidly cleared from the body; after 12 h the abscess was the organ with the highest activity. The absolute abscess uptake of¹²⁵I-IL-1 remained high compared to¹³¹I-myo-globin, resulting in significantly higher abscess-to-muscle ratios of¹²⁵I-IL-1 compared to 1311-myoglobin. The ratios of¹²⁵I-IL-1 reached the ultimate value of 44.4±10.8 at 48 h p.i., whereas the ratios of¹³¹I-myoglobin did not exceed 5.9±0.7. Gamma camera imaging revealed clearly visible abscesses. In conclusion, our results demonstrate specific retention of radioiodinated IL-1 in the abscess, presumably by interaction of IL-1 with its receptor on the inflammatory cells. The high target to-background ratios that were obtained over the course of time indicate that the IL-1 receptor may be a valuable target for the imaging of infectious foci.     

Radioiodine-131 in differentiated thyroid cancer: a retrospective analysis of an uptake-related ablation strategy

In our hospital, a 24-h radioiodine-131 (¹³¹I) uptake-related ablation strategy is used in patients with differentiated thyroid cancer to destroy thyroid remnants after primary surgery. In this strategy, low doses of ¹³¹I are used, but data in the literature on its efficacy are conflicting. Therefore, we performed the present study to evaluate the clinical outcome of this ablation strategy. In this study, patients (n=235) were selected who underwent thyroidectomy for differentiated thyroid cancer, followed by an ablative dose of ¹³¹I. Approximately 6 months after ablation, treatment efficacy was evaluated using radioiodine scintigraphy and thyroglobulin (Tg) measurements. Successful ablation was defined as the absence of radioiodine uptake in the neck region (criterion 1). Tg values were determined 3–12 months after ablation (criterion 2). Based on criterion 1, unsuccessful ablation was found in 43.0% of cases. Pre-treatment uptake values were statistically significantly lower (P=0.003) in successfully ablated patients (mean 5.4%) than in unsuccessfully ablated patients (mean 8.2%). Based on criterion 2, unsuccessful ablation was found in 52.4% of patients. The uptake-related ablation strategy, using low doses of ¹³¹I, shows a relatively high treatment failure rate. Based on these results it is suggested that a lower ablation failure rate could be achieved by applying higher ¹³¹I doses in the ablation of thyroid remnants in differentiated thyroid carcinoma patients. In the case of lymph node metastases a further dose adjustment may be advisable.     

Cardiac 17O MRI: Toward direct quantification of myocardial oxygen consumption

A new ¹⁷O‐labeled blood contrast agent was injected intravenously in control dogs. Electrocardiogram (ECG)‐triggered myocardial T₁ρ imaging was performed to obtain spin‐locking T₁ρ‐weighted myocardial signals for the detection of resultant metabolite H₂¹⁷O water in the heart. Bolus and slow injection methods of various doses of the ¹⁷O‐labeled and ¹⁶O‐labeled agents were carried out in order to evaluate the sensitivity of this method and determine the optimal injection method. Bolus injection provided approximately 1% signal reduction, whereas slow injection with larger amount of agent yielded 11.9 ± 0.6% signal reduction. Myocardial oxygen consumption rate was determined by a technique to quantify cerebral oxygenation consumption rate previously developed in ¹⁷O brain studies. With either injection method, myocardial oxygen consumption rate at rest was 5.0 – 5.6 μmol/g/min. Therefore, it appears feasible to detect metabolically generated HO water in vivo in the heart, using the ¹⁷O‐labeled blood tracer. Myocardial oxygen consumption rate can then be quantified in vivo, which may open new doors for the assessment of myocardial metabolism. Magn Reson Med 63:1442–1447, 2010. © 2010 Wiley‐Liss, Inc.     

Kinetics of 131I-o-Iodohippurate in rats

The organ distribution of ¹³¹I-o-iodohippurate (OIH) was studied in rats in the time interval of 1–1440 min. The mean decrease of OIH in plasma was fitted with a function composed of three exponential terms. A three-compartment model describing kinetics of OIH in rats was suggested and its parameters were computed. Comparison of organ and plasma concentrations of OIH showed that the liver, up to 30 min, and the heart and lungs, up to 15 min after administration, form with plasma a common central compartment.     

Technetium-99m tetrofosmin myocardial perfusion scan: comparison of 1-day and 2-day protocols

Nineteen patients with angina were recruited in this study for comparison of two 1-day protocols (stress-4 h rest and rest-4-h stress) and a 2-day protocol of technetium-99m tetrofosmin single-photon emission tomography (SPET). All of them underwent coronary angiography before or after the study. Exercise stress-rest study and rest-stress study were performed on two consecutive days. Delayed imaging was performed before the rest injection on the 2nd day. The stress study on the 1 st day and rest study on the 2nd day were considered as a 2-day protocol. The 1-day stress-rest protocol had a sensitivity of 100% (18/18) and an accuracy of 100% (19/19) in diagnosing ischaemic heart disease. The 1-day rest-stress protocol had a sensitivity of 94.4% (17/18) and an accuracy of 94.7% (18/19). These differences were not statistically significant (P=0.5 for sensitivity and accuracy). There was also no statistically significant difference between the two protocols in the diagnosis of ischaemic heart disease in individual artery territories. For the left descending artery, sensitivity was 88.2% (15/17) vs 76.5% (13/17) (P=0.48) for the stress-rest and rest-stress studies respectively. For the left circumflex artery, sensitivity was 90% (9/10) vs 80% (8/10) (P=1) and specificity was 66.7% (6/9) vs 77.8% (7/9) (P=1) respectively. For the right coronary artery, the sensitivity was 100% (16/16) vs 94% (15/16) (P=1) respectively, while the specificity was 33.3% (1/3) in both studies. Three hundred and forty-two myocardial segments were analysed. The stress-rest and 2-day protocols showed no statistically significant difference in the overall identification of segments with reversible ischaemia (48/141 segments vs 48/141 segments) or in respect of individual artery territories. There was also no significant difference in the identification of reversible ischaemic segments between the rest-stress and 2-day protocols (48/141 segments vs 34/135 segments,P=0.14). Abdominal activity was seen in 36 studies and interpretation was affected in five of them. Five patients with 24-h delayed images were evaluated and 24 segments with washout were identified. It is concluded that^99mTc-tetrofosmin is a valuable new tracer in the investigation of ischaemic heart disease. The 1-day stress-rest protocol is as good as the 1-day rest-stress protocol in diagnosing coronary heart disease. The 1-day protocols and the 2-day protocol display no difference in identifying segments with reversible ischaemia.