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     

Quantitation of myocardial iodine-123 MIBG uptake in SPET studies: a new approach using the left ventricular cavity and a blood sample as a reference

In patients with chronic heart failure increased sympathetic activity is related to unfavourable prognosis. Since myocardial iodine-123 metaiodobenzylguanidine ([¹²³I]MIBG) uptake is related to myocardial noradrenaline content, i.e. cardiac sympathetic activity, measurement of myocardial [¹²³I]MIBG uptake may be of clinical use in determining prognosis or the effect of pharmacological intervention in these patients. The aim of the present study was to evaluate a new method to quantitate myocardial [¹²³I]MIBG uptake with respect to reproducibility and accuracy. Eighteen [¹²³I]MIBG planar and single-photon emission tomography (SPET) studies of patients with chronic heart failure were evaluated. Myocardial uptake was calculated from the myocardial (MYO) to left ventricular cavity (C) count density ratio and the¹²³I activity in a blood sample. This was performed employing planar LAO images, a single-slice SPET method using the midventricular myocardial short-axis slice, and finally a multi-slice SPET method analysing semi-automatically drawn volumes of interest (VOIs). The accuracy of the multi-slice SPET method was verified using a cardiac phantom. The planar method was found to be reproducible [intra- and interobserver coefficients of variation (IACV and IRCV) were 0.025 and 0.012 respectively] but the mean MYO/C count density ratio was only 1.31±0.16 as a consequence of overprojection. For the single-slice SPET method IACV was 0.2 and IRCV was 0.13, representing poor reproducibility. For the multi-slice SPET method IACV was 0.051, IRCV was 0.047 and the mean MYO/C count density ratio was 5.4±2.42. Accuracy was 81% at a true MYO/C count density ratio of 6 in the phantom. It is concluded that the multi-slice SPET method using the left ventricular cavity VOI and a blood sample as a reference is a reproducible and accurate method for assessing myocardial [¹²³I]MIBG uptake.     

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.     

The kinetics of beta-methyl-substituted labelled fatty acids in ischaemic myocardium: an analysis in man and with a blood-perfused isolated heart model.

beta-Methyl-substituted free fatty acids (FFAs) have been developed for myocardial single-photon emission tomography (SPET) imaging, but little is known about their kinetics in ischaemic conditions. The aim of this study was to determine the changes in the myocardial kinetics of a beta-methyl-branched FFA, [123I]16-iodo-3-methyl-hexadecanoic acid (MIHA), under ischaemic conditions. The kinetics of MIHA were analysed: (a) using a blood-perfused isolated heart model subjected to moderate ischaemia (50% flow reduction) and (b) in patients who had an exercise thallium-201 SPET defect corresponding to either necrotic (n = 13) or chronically ischaemic and viable (n = 15) myocardium, and who underwent two consecutive SPET studies after MIHA injection. In animals, the myocardial early retention fraction of MIHA, but not its clearance rate, was dependent on coronary flow, the early retention fraction being higher in ischaemic than in normoxic conditions (0.24 +/- 0.10 vs 0.14 +/- 0.04, P = 0.004). In the patient SPET studies, the uptake of MIHA calculated in ischaemic and viable areas (G1: 74% +/- 9% of maximal left ventricular value) was different from that calculated in necrotic (G2: 59% +/- 7%, P < 0.001) or normal (G3: 88 +/- 6%, P < 0.001) areas. By contrast, MIHA-clearance calculated between the two consecutive SPET studies was not different in G1, G2 and G3. Unlike in the case of other FFAs, the myocardial clearance of MIHA is not decreased by ischaemia. However, the early retention of MIHA is increased in the case of a moderate reduction in coronary flow, a property which might help in the detection of viability in chronically ischaemic myocardium.     

Norepinephrine transporter density as a causative factor in alterations in MIBG myocardial uptake in NIDDM model rats

Cardiac scintigraphic studies with iodine-123 labeled metaiodobenzylguanidine ([(123)I]MIBG) have demonstrated global and regionally pronounced decreases in myocardial accumulation of radioactivity in diabetes. The aim of this study was to investigate the cause of the regional differential decrease in accumulation. To this end, we investigated the global and regional myocardial distribution of [(125)I]MIBG in GK/Crj (GK) rats [a model of non-insulin-dependent diabetes mellitus (NIDDM)] and assessed the responsibility of regional myocardial blood flow, myocardial and plasma norepinephrine (NE) content, and norepinephrine transporter (NET) function for the regional variations in [(125)I]MIBG accumulation. To investigate the responsibility of myocardial blood flow for the alterations in MIBG accumulation, dual-isotope autoradiographic studies with [(125)I]MIBG and technetium-99m hexakis-2-methoxy-2-isobutylisonitrile (MIBI), a tracer for the measurement of myocardial blood flow, were carried out in GK rats and control rats. The results in respect of the uptake of radioactivity into various myocardial regions were expressed as distribution absorption ratios [DAR = (radioactivity of tissue/g of tissue) x (body weight/total injected dose)]. In control rats, uptake of [(125)I]MIBG was significantly higher in the inferior wall than in the anterior wall (anterior wall, 6.35 +/- 0.90; inferior wall, 8.12 +/- 1.27: P < 0.001). On the other hand, in GK rats, uptake of [(125)I]MIBG was similar between the anterior wall and the inferior wall (anterior wall, 4.91 +/- 0.71; inferior wall, 4.81 +/- 0.69). Compared with control rats, uptake of [(125)I]MIBG in GK rats was decreased in both the anterior wall and the inferior wall. Uptake of (99m)Tc-MIBI was not significantly different between the anterior and inferior walls in control (anterior wall, 17.9 +/- 4.42; inferior wall, 18.1 +/- 4.52) and GK rats (anterior wall, 16.6 +/-8.03; inferior wall, 16.7 +/- 7.90), indicating that myocardial blood flow did not change regionally in either control or GK rats, and that the blood flow was not responsible for the differential decrease in MIBG accumulation in GK rats. Cardiac and plasma NE levels were measured using an HPLC-electrochemical detection system. The cardiac and plasma NE concentrations were not significantly different between control (anterior wall, 347 +/- 56 ng/g; inferior wall, 354 +/- 31 ng/g; plasma 9.38 +/- 2.10 ng/ml) and GK rats (anterior wall, 323 +/- 62 ng/g; inferior wall, 344 +/- 35 ng/g; plasma, 9.41 +/- 2.39 ng/ml). The density and affinity of NET were investigated by studying the binding of [(3)H]desipramine to cardiac membranes. The B(max) (fmol/mg protein) in the inferior wall was significantly higher than that in the anterior wall in the control rats (anterior wall, 364 +/- 28; inferior wall, 459 +/- 36: P < 0.05). On the other hand, there was no significant difference in the B(max) value between the anterior and inferior walls in GK rats (anterior wall, 263 +/- 42; inferior wall, 251 +/- 27). In conclusion, myocardial MIBG uptake was differentially reduced in GK rats, and this decrease was associated with a decrease in NET density, but the regional myocardial blood flow and the NE concentration were not responsible for the alterations in MIBG uptake. Thus, NET density was identified as the factor responsible for decreases in MIBG accumulation.     

Differential alteration of the nigrostriatal dopaminergic system in Wilson's disease investigated with [123I]ss-CIT and high-resolution SPET.

Wilson's disease (WD) is a copper deposition disorder which can result in a number of extrapyramidal motoric symptoms such as parkinsonism. Therefore, this study was carried out to investigate, for the first time, nigrostriatal dopaminergic function in WD in relation to different courses and severity of the disease. Using high-resolution single-photon emission tomography (SPET) after administration of 2ss-carbomethoxy-3ss-(4[123I]iodophenyl)tropane ([123I]ss-CIT), striatal dopamine transporters (DAT) were imaged in 43 WD patients and a control group of ten subjects. From the SPET images, specific [123I]ss-CIT binding ratios were obtained for the caudate heads, putamina and entire corpus striatum. In addition, to evaluate a putative dissociation between the caudate and putaminal [123I]ss-CIT binding ratios, the ratio between these binding ratios was calculated (CA/PU ratio). The SPET data were compared with clinical data on the course of the disease (CD), the severity of neurological symptoms and the degree of hepatic alteration. Whereas the specific regional [123I]ss-CIT binding ratios in patients with asymptomatic/hepatic CD did not differ from those in the control group (e.g. striatal ratios: 13.4+/-3.0 vs 11.7+/-2.8), in patients with neurological CD the ratios were significantly reduced for all striatal substructures (P=0.003 after one-factor ANOVA). For the different subgroups a tendency was detected towards a stepwise decrease in the specific [123I]ss-CIT binding ratios from pseudo-sclerosis CD (9.4+/-2.3), through pseudo-parkinsonian CD (9.1+/-2.1) to arrhythmic-hyperkinetic CD (8.5+/-1.6). However, these group differences reached significance only for the comparison with asymptomatic/hepatic CD (P=0.02). The CA/PU ratio was significantly higher in WD than in the control group (1.30+/-0.19 vs 1.11+/-0.08; P=0.003). Severity of neurological symptoms was significantly correlated with all specific regional [123I]ss-CIT binding ratios (r=-0.49 to -0.57). For degree of liver alteration, significant correlations were obtained with the putaminal binding ratio (r=-0.37) and the CA/PU ratio (r=0.44). From these results is concluded that in WD the nigrostriatal dopaminergic function is compromised to varying extents. The degree of this presynaptic alteration of dopaminergic neurotransmission depends on the clinical course and severity of this copper deposition brain disorder and also varies in the different striatal substructures.     

Is abnormal iodine-123-MIBG kinetics associated with left ventricular dysfunction in patients with diabetes mellitus?

BACKGROUND: Although autonomic neuropathy is frequently recognized in patients with diabetes mellitus, it is uncertain whether cardiac sympathetic neuropathy may play a role in the development of diabetic cardiomyopathy. METHODS AND RESULTS: In 10 control subjects and 61 patients with diabetes mellitus who did not have coronary artery disease, cardiac sympathetic function and left ventricular ejection fraction (LVEF) were evaluated by using iodine-123-metaiodobenzylguanidine (MIBG) imaging and echocardiography, respectively. Dynamic acquisitions and planar images obtained 15 and 150 minutes after injection were used as a means of measuring early and late myocardial uptake and clearance rates of MIBG from the heart. Eight patients with an LVEF less than 50% demonstrated a lower late myocardial MIBG uptake (0.0043% +/- 0.0017% vs. 0.0024% +/- 0.0009%/pixel, P = .002) and a higher clearance rate (22.9% +/- 17.7% vs. 49.3% +/- 12.2%, P<.0001) than the 53 patients with an LVEF of 50% or greater, although the age, sex, type of diabetes mellitus, and frequency of neuropathy, retinopathy, and nephropathy were not significantly different between the 2 subgroups. The LVEF correlated weakly but significantly with early and late myocardial uptake and clearance rate (r = 0.277, P = .03; r = 0.421, P = .001; r = 0.382, P = .002; respectively) in patients with diabetes mellitus. CONCLUSION: Marked MIBG abnormalities are associated with left ventricular dysfunction in patients with diabetes mellitus. However, long-term follow-up of patients with diabetes mellitus who have marked MIBG abnormalities and normal LVEF will be required to determine whether these patients would demonstrate systolic dysfunction earlier than patients without an MIBG abnormality.     

Concordance between rest MIBG and exercise tetrofosmin defects: possible use of rest MIBG imaging as a marker of reversible ischaemia

Perfusion imaging combined with pharmacological stress is the study of choice in patients with ischaemic heart disease who are incapable of exercising. Some medical conditions, however, can preclude the use of pharmacological stress. In these particular situations, availability of a diagnostic test which allows for the assessment of ischaemic territory at rest would be desirable. With the purpose of providing a marker of reversible ischaemia, we evaluated myocardial iodine-123 metaiodobenzylguanidine (MIBG) uptake in regions with fixed and reversible defects defined by exercise/rest perfusion study. Fifty-four male patients with ischaemic heart disease and previous myocardial infarction were studied by means of exercise/rest tetrofosmin and MIBG single-photon emission tomography (SPET). Regional tracer uptake was quantified and expressed as a percentage of maximum peak activity. Areas with denervated but perfused myocardium and areas with ischaemic myocardium were calculated. Regions with<75% of peak activity in the exercise perfusion study were divided into two groups according to whether the increase in peak activity in the respective rest study was >10% (reversible regional defect) or <10% (fixed regional defect). These percentages were compared with the percentages of the innervation study. The area of the innervation defect was significantly larger when the perfusion defect was reversible than when it was fixed. In regions with reversible perfusion defects, the size of the area of denervated but perfused myocardium was similar to the size of the area of ischaemic myocardium. In regions with reversible defects, the percentage of myocardial MIBG uptake was not significantly different from the percentage of tetrofosmin uptake at exercise, while it was significantly lower than the percentage of tetrofosmin uptake at rest. In regions with fixed defects, the percentage of myocardial MIBG uptake was significantly lower than the percentage of tetrofosmin uptake at exercise and at rest. In patients who developed angina during exercise test, the area of denervated but perfused myocardium was significantly larger than in patients without angina (4.1+/-2.4 vs 3.4+/-2.5, P=0.02). The same trend was observed with regard to the size of the innervation defect (8.6+/-2.4 vs 5.7+/-2.2, P=0.02). It is concluded that when the use of pharmacological stress is not possible in patients incapable of exercising, rest studies with MIBG combined with rest myocardial perfusion studies may be useful as a marker of reversible ischaemia.     

Myocardial sympathetic innervation in the athlete's sinus bradycardia: Is there selective inferior myocardial wall denervation?

BACKGROUND: Sinus bradycardia in trained athletes is predominantly a manifestation of increased vagal tone, but it is not known whether an alteration in the cardiac sympathetic system can contribute to blunted chronotropic response. This study assessed the integrity of the sympathetic system in trained athletes with sinus bradycardia by means of the iodine-123-metaiodobenzylguanidine (123I-MIBG) procedure. METHODS AND RESULTS: Fourteen athletes with sinus bradycardia and 8 athletes with a normal heart rate were explored by means of planar and single photon emission computed tomography MIBG studies. The heart/mediastinum ratio, regional myocardial distribution, and percent of regional myocardial MIBG uptake were evaluated. The heart/mediastinum ratio in athletes with sinus bradycardia was 1.87+/-0.10, and in athletes with a normal heart rate, the heart/mediastinum ratio was 1.86+/-0.16 (P = not significant). In athletes with sinus bradycardia, the regional distribution of MIBG showed an inferior and apical uptake defect in 8 athletes, an inferior, apical, and septal defect in 3 athletes, an inferior defect in 1 athlete, and normal distribution in 2 athletes (14%). In athletes with a normal heart rate, the regional distribution of MIBG showed an apical uptake defect in 3 athletes and normal distribution in 5 athletes (63%). The percent of regional MIBG uptake in the inferior region was significantly reduced in athletes with sinus bradycardia (44%+/-13% vs. 72%+/-11%, P<.01). CONCLUSION: These results show severely reduced myocardial MIBG distribution in the inferior region in athletes with sinus bradycardia, suggesting selective inferior myocardial wall sympathetic denervation, which may be related to increased vagal tone.     

Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: relationship to regional wall motion and myocardial perfusion abnormalities

BACKGROUND: Iodine 123-labeled metaiodobenzylguanidine (MIBG) has been used to study cardiac adrenergic nerve activity. Cardiac MIBG uptake is diminished in patients with heart failure. However, it is not known how this reduction is related to regional abnormalities of myocardial wall motion or perfusion. METHODS AND RESULTS: We studied 24 patients with idiopathic dilated cardiomyopathy (ejection fraction <45%) and 15 healthy control subjects using I-123 MIBG cardiac imaging, echocardiographic assessment of wall motion abnormalities, technetium 99m sestamibi perfusion scintigraphy, and hemodynamic assessment. Cardiac MIBG was significantly correlated with ejection fraction (r = 0.67), cardiac index (r = 0.57), left ventricular wall motion score index (r = -0.68), and systolic wall stress (r = -0.61). MIBG was lower in patients than in control subjects (1.43 +/- 0.19 vs 2.05 +/- 0.02; P <.01), whereas the washout rate was higher (P <.01). Moreover, a significant correlation was found between the reduction in MIBG uptake and the severity of echocardiographic wall motion abnormalities in the anterior wall (r = 0.543), apex (r = 0.530), and septum (r = 0.675), as well as with the severity of decrease in resting myocardial perfusion in the anterior wall (r = 0.480) and septum (r = 0.580). CONCLUSIONS: Patients with idiopathic dilated cardiomyopathy show not only global but also regional abnormalities of cardiac sympathetic innervation. The severity of these changes is partially correlated with abnormalities of regional wall motion and myocardial perfusion.     

Metaiodobenzylguanidine to map scintigraphically the adrenergic nervous system in man

Metaiodobenzylguanidine (MIBG) localizes in adrenergic neurons; MIBG labeled with 123I then serves as an analog of norepinephrine, and concentrations of [123I]MIBG reflect sites of adrenergic neurons in organs. Movements of [123I]MIBG into and out of organs were measured by quantitative scintigraphy in man. We perturbed adrenergic neuron function in several ways, and [123I]MIBG concentrations in the heart were subsequently altered in patterns consistent with the concept that [123I]MIBG resides mostly in adrenergic neurons. Uptake of [123I]MIBG into the heart was inhibited by the tricyclic drug, imipramine, and this agent also accelerated the rate of loss of [123I]MIBG. Phenylpropanolamine, a sympathomimetic drug that acts by displacing norepinephrine from neurons, increased the rates of loss of [123I]MIBG from the heart. Exercise was followed by a movement of [123I]MIBG into blood and urine. Generalized autonomic neuropathies were associated with marked diminutions of [123I]MIBG uptake into the heart. We conclude that quantitative scintigraphy in patients will enable determinations of regional disturbances in integrity (by measuring uptake of [123I]MIBG) and function (by measuring rates of loss of [123I]MIBG) of the adrenergic nervous system in the heart.     

Interaction of metaiodobenzylguanidine with cardioactive drugs: an in vitro study

Metaiodobenzylguanidine (MIBG), an analogue of noradrenaline, is used to explore the functional integrity of sympathetic nerve endings in the human heart. Various drugs inhibit noradrenaline transport systems and may block the uptake of MIBG. As in vivo studies of the effect of these drugs on myocardial [¹²³I]MIBG uptake are often difficult to perform, we used an in vitro human blood platelet model for this purpose. A platelet preparation from healthy volunteers was incubated with [¹²⁵I]MIBG alone or different concentrations of drugs currently used in cardiology. Labetalol and propranolol inhibited [¹²⁵I]MIBG uptake, whereas all other drugs tested (other -blockers, calcium inhibitors, digoxin and amiodarone) had no effect even at doses exceeding 50 M. The labetalol dose inhibiting 50% of [¹²⁵I]MIBG uptake was lower than the plasma concentration of this drug in treated patients, whereas the propranolol dose was higher. This in vitro study of the effect of drugs on MIBG uptake by human blood platelets is predictive of their in vivo effect on myocardial uptake of [¹²³I]MIBG in treated patients, provided that plasma concentration is taken into account.     

High uptake of L-3-[123I]iodo-alpha-methyl tyrosine in pilocytic astrocytomas

Despite a favourable prognosis, pilocytic astrocytomas may exhibit signs of malignancy on various neuroimaging modalities. This retrospective analysis was conducted to determine whether scintigraphic features of malignancy are also found on single-photon emission tomography (SPET) using L-3-[123I]iodo-alpha-methyl tyrosine (IMT) as a tracer. Twenty patients with pilocytic astrocytomas were retrospectively selected from a large series of patients referred for the evaluation of primary or recurrent brain tumours. IMT SPET was performed in 16 patients, positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was available in 10 of the patients and SPET using technetium-99m tetrofosmin or thallium-201 had been performed in 11. Image analysis was performed using standard protocols to determine how many patients exceeded the respective thresholds of malignancy. Features of malignancy were found in 7/16 IMT SPET studies, in 7/10 FDG PET studies and in 7/11 of the residual SPET investigations. A significant correlation of tumour size and IMT uptake in primary pilocytic astrocytomas indicated partial volume effects to partly account for the differential uptake behaviour (n = 10, r = 0.87, P < 0.05). Differences in IMT uptake in primaries (1.7 +/- 0.6, n = 10) and in recurrent tumours (2.3 +/- 0.7, n = 6) did not attain statistical significance. IMT SPET results indicative of malignancy are regularly found in pilocytic astrocytomas, despite their good prognosis. No uptake may be detected in largely cystic or in small tumours.     

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.     

Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants

Iodine-123 metaiodobenzylguanidine ([123I]MIBG) is a norepinephrine analog which can be used to image the sympathetic innervation of the heart. In this study, cardiac imaging with [123I]MIBG was performed in patients with idiopathic congestive cardiomyopathy and compared to normal controls. Initial uptake, half-time of tracer within the heart, and heart to lung ratios were all significantly reduced in patients compared to normals. Uptake in lungs, liver, salivary glands, and spleen was similar in controls and patients with cardiomyopathy indicating that decreased MIBG uptake was not a generalized abnormality in these patients. Iodine-123 MIBG imaging was also performed in cardiac transplant patients to determine cardiac nonneuronal uptake. Uptake in transplants was less than 10% of normals in the first 2 hr and nearly undetectable after 16 hr. The decreased uptake of MIBG suggests cardiac sympathetic nerve dysfunction while the rapid washout of MIBG from the heart suggests increased cardiac sympathetic nerve activity in idiopathic congestive cardiomyopathy.     

Sympathetic reinnervation of cardiac allografts evaluated by 123I-MIBG imaging.

Some heart-transplant patients present with improved heart rate response to exercise and anginal pain suggesting reinnervation of allografts. Studies performed up to 5 y post-transplantation have suggested that reinnervation is a slow process that occurs only after 1 y post-transplantation. The purpose of this study was to evaluate the extent of sympathetic reinnervation in heart-transplant patients and its relation to cardiac function. METHODS: We performed 123I-metaiodobenzylguanidine (MIBG) studies and rest/exercise radionuclide ventriculography in 31 heart-transplant patients 6 mo to 12 y post-transplantation. Intensity of myocardial MIBG uptake was quantified by a heart-to-mediastinum ratio (HMR), and the regional distribution of MIBG was determined by tomographic studies. RESULTS: HMR correlated positively with time after transplantation (r = 0.607, P < 0.001). Patients studied from 2 to 12 y post-transplantation had an HMR significantly higher than patients studied before 2 y post-transplantation (1.62 +/- 0.2 versus 1.34 +/- 0.2, P < 0.05). Myocardial MIBG uptake was anterolateral in 16 patients, anterior in 3 and anterolateral and septal in 3. Myocardial MIBG uptake was absent in 9 patients. Vasculopathy developed in 8 patients, and 5 of them (63%) had decreased myocardial MIBG uptake. Peak filling rate was higher in patients studied from 2 to 12 y post-transplantation (2.7 +/- 0.8 end-diastolic volume (EDV)/s versus 2.16 +/- 0.5 EDV/s, P = 0.02). CONCLUSION: Sympathetic reinnervation increases with time after heart transplantation and is seen more frequently after 2 y post-transplantation. Complete reinnervation of the transplanted heart does not occur even up to 12 y post-transplantation. Early vasculopathy may delay the process of sympathetic reinnervation.     

Activity of the uptake-1 norepinephrine transporter as measured by I-123 MIBG in heart failure patients with a loss-of-function polymorphism of the presynaptic α2C-adrenergic receptor

BACKGROUND: Patients with a deletion of 4 consecutive amino acids in the gene encoding for the alpha(2C)-adrenergic receptor (alpha(2C)Del322-325) have an increased prevalence of clinical heart failure, worse clinical status, and a lower left ventricular ejection fraction compared with patients without this deletion. We postulated that patients with the alpha(2C)Del322-325 polymorphism would have a compensatory increase in norepinephrine uptake-1 transporter activity as measured by iodine 123 metaiodobenzylguanidine (MIBG). METHODS AND RESULTS: Thirty-nine patients with heart failure related to idiopathic dilated cardiomyopathy were studied. Demographic characteristics, left ventricular ejection fraction, maximum oxygen consumption, exercise duration, and plasma norepinephrine levels did not differ between patients with the alpha(2C) receptor polymorphism (n = 9) and those without it (n = 30). Patients with the alpha(2C)Del322-325 polymorphism had significantly greater heart-to-mediastinum ratios of I-123 MIBG at 4 hours after tracer injection (1.60 +/- 0.19 vs 1.41 +/- 0.19, P =.0117) and greater background-corrected heart counts per pixel at 4 hours compared with patients without the polymorphism. CONCLUSIONS: Patients with genetic impairment of the alpha(2C)-adrenergic receptor have augmented activity of the norepinephrine uptake-1 transporter as measured by I-123 MIBG. Further studies are needed to clarify the mechanism by which uptake-1 transporter activity is increased in this setting.     

Potential of iodine-123 metaiodobenzylguanidine single-photon emission tomography to detect abnormal functional status of the pulmonary neuroadrenergic system in irradiated lung.

The potential of iodine-123 metaiodobenzylguanidine (MIBG) to detect functional abnormalities of the pulmonary neuroadrenergic system (PNS) in irradiated lung areas (ILAS) was preliminarily explored using single-photon emission tomography (SPET). The subjects included five healthy subjects and a total of 31 patients with peripheral-type lung cancer treated by radiation; 15 patients (group A) had received a dose of less than 36 Gy (mean +/- SD: 28.2 +/-6.2 Gy), and 16 patients (group B) had received a higher dose (mean +/- SD: 51.2 +/- 3.5 Gy) at the time of examination. MIBG SPET scans acquired 15 min and 3 h after injection were used to measure the MIBG uptake ratio (count ratio of the ILA to the contralateral non-ILA) and the clearance rate [percentage of (early counts - delayed counts)/early counts] from the ILAs without noticeable abnormal opacities on chest computed tomography scan. Lung perfusion changes were also assessed by technetium-99m macroaggregated albumin SPET. By contrast to the homogeneous MIBG uptake in the lungs of the healthy subjects, MIBG uptake was folcally decreased in correspondence with the ILAs in all patients, including 11 patients (73.3%) of group A with relatively preserved lung perfusion. The reduction MIBG uptake was significant (P<0.0001), and the MIBG clearance rate from the ILAs was also significantly faster than the clearance rates from the normal lungs and contralateral non-ILAs (both P<0.01). Group B patients showed significantly lower MIBG uptake and faster clearance from the ILAs than group A patients (P<0. 001 and P<0.05, respectively), although there was no significant difference in the clearance from the non-ILAs. Overall, MIBG uptake/clearance from the ILAs correlated significantly with the radiation dose in the 31 patients (r = -0.656; P<0.0001 and r = 0. 387; P<0.05, respectively). Perfusion changes were inversely correlated with the clearance from the ILAs (r = -0.432, P<0.05), but did not correlate with MIBG uptake. These preliminary results suggest that MIBG may have the potential to be a marker of abnormal functional status of the PNS produced by irradiation and may facilitate investigation of irradiation lung injury independently of morphological or lung perfusion changes.     

Rapid clearance of iodine-131 MIBG from the heart and liver of patients with adrenergic dysfunction and pheochromocytoma

Iodine-131 MIBG, a radiolabeled adrenergic neuron-blocking agent, decreased rapidly from the heart and liver of patients with adrenergic dysfunction (n = 3) and pheochromocytoma (n = 2) when compared with eight controls. The 4-hr activity expressed as percentages (mean +/- s.d.) of the 20-min counts were as follows: 80 +/- 3.0% in the controls compared with 60 +/- 7.6% in the patients over the heart (p less than 0.01) and 79 +/- 3.2% in the controls compared with 51 +/- 17% in the patients over the liver (p less than 0.02). However, there was no significant difference in the rate of [131I]MIBG decrease in these organs between controls and patients in the intervals subsequent to 4 hr (p greater than 0.05). These findings suggest that adrenergic neuronal uptake of [131I]MIBG in these organs is smaller in the patients than in the controls. Measurements of time-activity relationships of radioiodinated MIBG may be useful for assessment of adrenergic function of these organs and thus of generalized disorders of adrenergic innervation.     

Effect of long-term atrial-demand ventricular pacing on cardiac sympathetic activity

It has been shown that either dual-chamber or atrial pacing may be better than ventricular single-chamber pacing, but the long-term effect of dual-chamber pacing on cardiac sympathetic activity is unclear. The aim of this study was to assess the effect of long-term dual-chamber pacing on cardiac sympathetic activity, compared with atrial pacing and unpaced individuals. We studied 11 patients with dual-chamber pacemakers (Group D), nine with atrial single-chamber pacemakers (Group A) over the long term (mean 44 +/- 36 months) and 10 normal individuals without cardiac pacing. All underwent myocardial 123I-metaiodobenzylguanidine (MIBG) imaging to assess cardiac sympathetic activity. The heart-to-mediastinum (H/M) MIBG uptake ratio and the MIBG washout rate from the myocardium were calculated. Echocardiography was performed in all patients with cardiac pacing to assess left ventricular function. In Group D, the H/M ratio on delayed images was significantly lower than that of Group A (1.82 +/- 0.51 vs 2.56 +/- 0.50, P < 0.001) and normal individuals (2.65 +/- 0.35, P < 0.05). The myocardial MIBG washout rate of Group D was significantly higher than that of either Group A (52 +/- 13% vs 36 +/- 8%, P < 0.01) or normal individuals (31 +/- 7%, P < 0.05). Neither the H/M ratio nor MIBG washout rate differed significantly between patients in Group A and normal individuals. Furthermore, the echocardiographic parameters did not differ significantly between the two pacing groups. We conclude that long-term ventricular pacing, even in the presence of atrioventricular synchrony, accelerates cardiac sympathetic activity without deteriorating left ventricular function.