Radiochemical purity of iodine-131 labelled metaiodobenzylguanidine infusion fluids: a report from clinical practice

Iodine-131 labelled metaiodobenzylguanidine ([¹³¹I]MIBG) has a diagnostic and therapeutic role in the management of neural crest tumours, particularly neuroblastoma, malignant phaeochromocytoma and paraganglioma. With therapeutic amounts of [¹³¹I]MIBG it is essential that the amount of free [¹³¹I]iodide, the most important impurity, is known. In clinical practice the percentage of free [¹³¹I]iodide seen in a [1311]MIBG infusion concentrate increased from 2.2%±0.67% to 3.6%±0.39% (mean ± SD; n=23) 1 day after production. At the time of use the percentage of free [¹³¹I]iodide was always below our upper limit of acceptance of 5%. Since 5% of free [¹³¹I]iodide is within practical reach in our environment, a higher percentage at the time of pre-administration quality control is not accepted in the Netherlands Cancer Institute. Correspondence to: A.R. Wafelman     

Non-invasive in vivo imaging with radiolabelled FIAU for monitoring cancer gene therapy using herpes simplex virus type 1 thymidine kinase and ganciclovir

An experimental cancer gene therapy model was employed to develop a non-invasive imaging procedure using radiolabelled 2'-fluoro-2'-deoxy-5-iodo-1--d-arabinofuranosyluracil (FIAU) as an enzyme substrate for monitoring retroviral vector-mediated herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) transgene expression. Iodine-131 labelled FIAU was prepared by a no-carrier-added (n.c.a.) synthesis process and lyophilised to give "hot kits". The labelling yield was over 95%, with a radiochemical purity of more than 98%. The stability of [¹³¹I]FIAU in the form of lyophilised powder (the hot kit) was much better than that in the normal saline solution. The shelf life of the final [¹³¹I]FIAU hot kit product is as long as 4 weeks. Cellular uptake of [¹³¹I]FIAU after different periods of storage was investigated in vitro with HSV1-tk-retroviral vector transduced NG4TL4-STK and parental non-transduced NG4TL4 murine sarcoma cell lines over an 8-h incubation period. The NG4TL4-STK cells accumulated more radioactivity than NG4TL4 cells in all conditions, and accumulation increased with time up to 8 h. The kinetic profile of the cellular uptake of n.c.a. [¹³¹I]FIAU formulated from the lyophilised hot kit or from the stock solution was qualitatively similar. For animal model cancer gene therapy studies, FVB/N mice were inoculated subcutaneously with the HSV1-tk(+) and tk(–) sarcoma cells into the flank to produce tumours. Biodistribution studies showed that tumour/blood ratios were 2, 3.5, 8.2 and 386.8 at 1, 4, 8 and 24 h post injection, respectively, for the HSV1-tk(+) tumours, and 0.5, 0.5, 0.7 and 5.4, respectively, for the HSV1-tk(–) tumours. Radiotracer clearance from blood was completed in 24 h and was bi-exponential. A significant difference in radioactivity accumulation was revealed among the HSV1-tk(+) tumours, the tk(–) tumours and other tissues. At 24 h p.i., higher activity retention was observed in HSV1-tk(+) tumours (9.67%±3.89%ID/g) than in HSV1-tk(–) tumours (0.48%±0.19%ID/g). After seven consecutive daily treatments with the prodrug ganciclovir, planar gamma camera imaging showed HSV1-tk(+) tumour regression at day 4, and complete tumour regression at day 7. These results clearly demonstrate that the simplified n.c.a. synthesis process developed in this study is reliable and that the [¹³¹I]FIAU product is useful for in vivo monitoring of HSV1-tk gene transfer, expression and gene therapy.     

Is MIBG a substrate of P-glycoprotein?

Purpose Radionuclide therapy with ¹³¹I-labelled meta-iodobenzylguanidine ([¹³¹I]MIBG) is effective in cases where it is difficult to carry out surgical resection or debulking of neuroendocrine tumours (NETs). However, it has recently been reported that P-glycoprotein (P-gp) is expressed in these NETs. Therefore, it is important to clarify whether MIBG is a substrate of P-gp or not. In this study, using a human cell line which overexpresses P-gp, LLC-GA5-COL150, we investigated this question. Methods The transcellular transport and accumulation of [¹²⁵I]MIBG were measured using monolayer cultures grown in Transwell chambers. [¹²⁵I]MIBG was added to either the basolateral or the apical side, aliquots of the incubation medium on the other side were taken at specified times, and the radioactivity was measured. For accumulation experiments, the cells on the filters were solubilised and the radioactivity in aliquots was measured. Results There were no significant differences in the transport of MIBG between LLC-PK₁ and LLC-GA5-COL150 monolayers in either direction until 60 min. With respect to the accumulation of MIBG, there were no significant differences between LLC-PK₁ and LLC-GA5-COL150 cells in either direction. Conclusion MIBG is not a substrate of P-gp. Therefore, radionuclide therapy with MIBG would be useful in the treatment of NETs expressing P-gp.     

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.     

Comparisons of [18F]-1-deoxy-1-fluoro-scyllo-inositol with [18F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice

Introduction

The aim of the study was to evaluate the uptake of [¹⁸F]-1-deoxy-1-fluoro-scyllo-inositol ([¹⁸F]-scyllo-inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [¹⁸F]-2-fluoro-2-deoxy-d-glucose ([¹⁸F]-FDG) under the same conditions were also performed.

Methods

Radiosynthesis of [¹⁸F]-scyllo-inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [¹⁸F]-scyllo-inositol and [¹⁸F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation.

Results

The radiosynthesis of [¹⁸F]-scyllo-inositol was automated with good radiochemical yields (24.6%±3.3%, uncorrected for decay, 65±2 min, n=5) and high specific activities (≥195 GBq/μmol at end of synthesis). Uptake of [¹⁸F]-scyllo-inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [¹⁸F]-FDG (4.6±0.5 vs. 5.5±2.1 %ID/g, respectively; P=.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [¹⁸F]-scyllo-inositol in inflammation was lower than [¹⁸F]-FDG. While uptake of [¹⁸F]-scyllo-inositol in intracranial U-87 MG xenografts was significantly lower than [¹⁸F]-FDG, the tumour-to-brain ratio was significantly higher (10.6±2.5 vs. 2.1±0.6; P=.001).

Conclusions

Consistent with biodistribution studies, uptake of [¹⁸F]-scyllo-inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [¹⁸F]-FDG. The tumour-to-brain ratio of [¹⁸F]-scyllo-inositol was also significantly higher than that of [¹⁸F]-FDG for visualizing intracranial glioma xenografts in NOD SCID mice, giving a better contrast.     

Metabolic fate of L-[methyl-11C]methionine in human plasma

The metabolites of L-[methyl-¹¹C]methionine in the plasma of 8 patients with tumor were measured for 60 min after injection. In the plasma, after a rapid clearance, the total radioactivity remained constant, and protein-bound radioactivity increased rapidly. Non protein metabolites detected by HPLC as at least two components besides methionine, increased with time. Significant individual variations for the metabolism were observed. AT 60 min after injection, 36.5% (range: 16%–72%) and 45.3% (range: 13%–74%) of the ¹¹C was measured as methionine and labeled proteins, respectively.     

Feasibility of sodium/iodide symporter gene as a new imaging reporter gene: comparison with<Emphasis Type="Italic"> HSV1-tk</Emphasis>

Positron emission tomography (PET) imaging reporter genes, such as HSV1-tk and D₂ receptor genes, make it possible to visualise gene expression non-invasively and repetitively in vivo. However, these systems require the synthesis of complicated substrates and the availability of expensive PET equipment. Expression of the sodium/iodide symporter (NIS) gene can be easily monitored with radioiodines and technetium-99m using a gamma camera. To evaluate the possibility of using NIS as an imaging reporter gene, we compared its characteristics with those of the conventional HSV1-tk gene. The CM cell line was made by transfecting the HSV1-tk gene into CT-26 (mouse colon carcinoma cell line). The CTN and CMN cell lines were then made by transfecting the NIS gene into CT-26 and CM. We measured the uptake of iodine-125 iodovinyldeoxyuridine ([¹²⁵I]IVDU) and ¹²⁵I to evaluate the expression of the HSV1-tk and NIS genes, respectively. Each cell line was injected into four flank sites in Balb/c mice. The biodistribution study was performed after intravenously injecting [¹²⁵I]IVDU and ¹³¹I, and ¹³¹I scintigraphy was performed for the evaluation of NIS expression. In vitro studies indicated that CTN and CMN had 40- to 79-fold and 150- to 256-fold higher uptake of ¹²⁵I than CT-26 and CM, respectively. Furthermore, CM and CMN showed 57- to 69-fold higher uptake of [¹²⁵I]IVDU than CT-26 and CTN. NIS gene expression and ¹²⁵I accumulation were found to be directly correlated (R ²=0.923), as were HSV1-tk gene expression and [¹²⁵I]IVDU accumulation (R ²=0.956). Calculated signal per unit NIS and HSV1-tk mRNA expression was 23,240±3,755 cpm and 34,039±5,346 cpm, respectively. In vivo study indicated that CTN and CMN had 2.3- and 5.8-fold higher uptake of ¹³¹I than CT-26 and CM, and 1.8- and 3.5-fold higher uptake of [¹²⁵I]IVDU than CT-26 and CTN. Scintigraphy using ¹³¹I easily visualised CTN and CMN tumours. In conclusion, the NIS gene may be viewed as an imaging reporter gene with comparable performance to the HSV1-tk gene for monitoring target gene expression.     

Cardiac sympathetic nerve function assessed by [131I]metaiodobenzylguanidine after ischemia and reperfusion in anesthetized dogs

Background  Accumulation of ¹³¹I-labeled metaiodobenzylguanidine ([¹³¹I]MIBG), a radiolabeled norepinephrine analog, is reduced in infarcted myocardium, suggesting loss of cardiac sympathetic nerve viability. Histopathologic studies, however, indicate that the nerve endings are morphologically intact. Experiments were therefore designed to determine the mechanism of reduced MIBG accumulation. Methods and Results  Desipramine, a specific blocker of neuronal norepinephrine reuptake, was used to separate the portions of total myocardial [¹³¹I]MIBG accumulation attributable to neuronal and nonneuronal uptake mechanisms. Sixteen dogs underwent circumflex coronary artery occlusion for 60 minutes followed by a 5-hour reperfusion. [¹³¹I]MIBG was injected intravenously 1 hour after reperfusion. The left ventricle was removed and incubated in triphenyltetrazolium chloride to identify infarcted and viable myocardium within the zone at risk. Preliminary studies is sham-operated dogs showed that pretreatment with desipramine (5 mg/kg) reduced [¹³¹I]MIBG accumulation 4 hours after injection to 38.9% of untreated controls. Chemical sympathectomy by topical phenol resulted in a similar decrease in [¹³¹I]MIBG accumulation (to 45.7% of normal), and desipramine did not produce further inhibition of [¹³¹I]MIBG accumulation over that produced by phenol alone, indicating that the inhibitory effect of desipramine on neuronal accumulation of [¹³¹I]MIBG was essentially complete. In dogs undergoing ischemia-reperfusion, myocardial samples from infarcted and viable postischemic areas showed 64.5%±11.8% and 84.7%±9.1% of normal [¹³¹I]MIBG activity, respectively (both, p<0.01 vs normal area, n=9). With desipramine pretreatment (n=7), accumulation of [¹³¹I]MIBG decreased in all areas. Neuronal accumulation was reduced uniformly in infarcted, viable postischemic, and normal areas by 30% to 35% compared with sham-operated controls. In contrast, nonneuronal accumulation was only 39.3% in infarcted areas and 84.6% in viable postischemic areas compared with normal areas, and these decreases accounted entirely for the reduced total [¹³¹I]MIBG accumulation. Conclusions  Reduced [¹³¹I]MIBG accumulation in infarcted myocardium after 60 minutes of ischemia and 5 hours of reperfusion, is attributable to a deficit in nonneuronal accumulation and not to decreased accumulation by sympathetic nerves. Supported by United States Public Health Service grants 17655 (Specialized Center of Research in Ischemic Heart Disease) and RO1-33360 from the National Heart, Lung and Blood Institute (Bethesda, Md.).     

The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels

Purpose The aim of this study was to investigate the role of thymidine kinase 1 (TK₁) protein in 3-deoxy-3-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) studies.Methods We investigated the in vivo kinetics of [¹⁸F]FLT in TK₁+/– and TK₁–/– L5178Y mouse lymphoma tumours that express different levels of TK₁ protein.Results [¹⁸F]FLT-derived radioactivity, measured by a dedicated small animal PET scanner, increased within the tumours over 60 min. The area under the normalised tumour time–activity curve were significantly higher for the TK₁+/– compared with the –/– variant (0.89±0.02 vs 0.79±0.03 MBq ml^–1 min, P=0.043; n=5 for each tumour type). Ex vivo gamma counting of tissues excised at 60 min p.i. (n=8) also revealed significantly higher tumour [¹⁸F]FLT uptake for the TK₁+/– variant (6.2±0.6 vs 4.6±0.4%ID g^–1, P=0.018). The observed differences between the cell lines with respect to [¹⁸F]FLT uptake were in keeping with a 48% higher TK₁ protein in the TK₁+/– tumours versus the –/– variant (P=0.043). On average, there were no differences in ATP levels between the two tumour variants (P=1.00). A positive correlation between [¹⁸F]FLT accumulation and TK₁ protein levels (r=0.68, P=0.046) was seen. Normalisation of the data for ATP content further improved the correlation (r=0.86, P=0.003).Conclusion This study shows that in vivo [¹⁸F]FLT kinetics depend on TK₁ protein expression. ATP may be important in realising this effect. Thus, [¹⁸F]FLT-PET has the potential to yield specific information on tumour proliferation in diagnostic imaging and therapy monitoring.     

Comparison of the biodistribution of two hypoxia markers [<Superscript>18</Superscript>F]FETNIM and [<Superscript>18</Superscript>F]FMISO in an experimental mammary carcinoma

The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([¹⁸F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([¹⁸F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O₂) or carbogen gas (95% O₂ + 5% CO₂). The gassing procedure was begun 5 min before the intravenous injection of either [¹⁸F]FETNIM or [¹⁸F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [¹⁸F]FETNIM (4.9±2.6 vs 1.8±0.5; P<0.01) and [¹⁸F]FMISO (4.4±1.0 vs 1.5±0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [¹⁸F]FETNIM and [¹⁸F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [¹⁸F]FMISO than for [¹⁸F]FETNIM in normal tissues.     

111In-tropolonate labelled platelets; studies in normals and in patients with thrombocytopenia

Human platelets were labelled with aqueous ¹¹¹In-tropolonate in comparison with ¹¹¹In-oxinate. In normals the labelling efficiency with ¹¹¹In-tropolonate was higher (93%±2%) than with ¹¹¹In-oxinate (67%±8%) (P<0.05). In cases of severe thrombocytopenia, lower labelling efficiencies were obtained. In six normals a mean platelet life of 9 days ±3 days and an initial recovery of 59%±15% were obtained. In twelve patients with trombocytopenia the mean platelet life was 4 days±4 days and the initial recovery was 58%±20%. The absolute uptake of radioactivity in spleen and in liver in both groups are reported.     

Excretion of radioiodine in human milk following a therapeutic dose of I-131

An investigation of ¹³¹I excretion into human milk after a therapeutic dose of 5142 MBq (139 mCi) ¹³¹I, in a patient who has had a thyroidectomy is presented. During the first 36 h, 17.4% of the administered dose was excreted into the milk. In addition to the known radiation risk, this may affect the quantity of ¹³¹I retained by the thyroid and metastases.     

Effects of nicorandil on cardiac sympathetic nerve activity after reperfusion therapy in patients with first anterior acute myocardial infarction

Purpose Ischaemic preconditioning (PC) is a cardioprotective phenomenon in which short periods of myocardial ischaemia result in resistance to decreased contractile dysfunction during a subsequent period of sustained ischaemia. Nicorandil, an ATP-sensitive potassium channel opener, can induce PC effects on sympathetic nerves during myocardial ischaemia. However, its effects on cardiac sympathetic nerve activity (CSNA) and left ventricular remodelling have not been determined. In this study, we sought to determine whether nicorandil administration improves CSNA in patients with acute myocardial infarction (AMI).Methods We studied 58 patients with first anterior AMI, who were randomly assigned to receive nicorandil (group A) or isosorbide dinitrate (group B) after primary coronary angioplasty. The nicorandil or isosorbide dinitrate was continuously infused for >48 h. The extent score (ES) was determined from ^99mTc-pyrophosphate scintigraphy, and the total defect score (TDS) was determined from ²⁰¹Tl scintigraphy 3–5 days after primary angioplasty. The left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) were determined by left ventriculography 2 weeks later. The delayed heart/mediastinum count (H/M) ratio, delayed TDS and washout rate (WR) were determined from ¹²³I-meta-iodobenzylguanidine (MIBG) images 3 weeks later. The left ventriculography results were re-examined 6 months after treatment.Results Fifty patients originally enrolled in the trial completed the entire protocol. After treatment, no significant differences were observed in ES or left ventricular parameters between the two groups. However, in group A (n=25), the TDSs determined from ²⁰¹Tl and ¹²³I-MIBG were significantly lower (26±6 vs 30±5, P<0.01, and 32±8 vs 40±6, P<0.0001, respectively), the H/M ratio significantly higher (1.99±0.16 vs 1.77±0.30, P<0.005) and the WR significantly lower (36%±8% vs 44%±12%, P<0.005) than in group B (n=25). Moreover, 6 months after treatment, LVEDV and LVEF were better in group A than in group B.Conclusion These findings indicate that nicorandil can have beneficial effects on CSNA and left ventricular remodelling in patients with first anterior AMI.     

Reproducibility of cerebral glucose utilization measured by PET and the [18F]-2-fluoro-2-deoxy-d-glucose method in resting,healthy human subjects

The stability of cerebral glucose utilization was examined in nine right-handed, healthy men (age, 24.88±2.93 years) using positron emission tomography (PET) and the [¹⁸F]-fluorodeoxyglucose (FDG) method. Each study was run twice at intervals of 1–12 weeks with the subject at rest. The average cerebral metabolic rate for glucose (CMRGlu) was 5.40±0.71 mg/100 g per min (coefficient of variance, 13.08). The average intraindividual variation of CMRGlu was 7.91%±15.46% (P=0.13). Metabolic indices (MI: regional/mean cortical CMRGlu) were used to determine the regional cerebral metabolic distribution. The interindividual (coefficient of variance, 7.13) and intraindividual variabilities (average variation, –0.12%±8.76%) of MI were smaller than those of metabolic rates. No reproducible significant asymmetry was observed. The FDG method used with subjects at rest thus yields low intraindividual variability of both cerebral glucose consumption and regional metabolic distribution, even at an interval of several weeks. Cerebral glucose utilization measured under such conditions may act as a reliable reference for determination of the influences of physiological (activation), pharmacological or pathological processes on cerebral glucose metabolism.Abbreviations FDG [¹⁸F]-fluorodeoxyglucose - CMRGlu cerebral metabolic rates for glucose - MI metabolic indices - EEG electroencephalogram - FWHM full width at half maximum     

Regional uptake of iodine-125-metaiodobenzylguanidine in the rat heart

Regional uptake of iodine- 125-metaiodobenzylguanidine ([¹²⁵I]MIBG) was evaluated in normal (n=12) and reserpinized (n=12) rat hearts. At 15 min and 1, 3 and 6 h after injection of [¹²⁵I]MIBG, tissue activities were calculated for the right ventricular myocardium (RV), the whole left ventricular myocardium (whole LV), the epicardial layer of the left ventricular myocardium (Ep LV), the endocardial layer of the left ventricular myocardium (En LV), the basal segment of the left ventricular myocardium and the apical segment of the left ventricular myocardium. The uptake of [¹²⁵I]MIBG at 6 h after injection in the normal rat heart was higher in RV than in whole LV (0.45 ± 0.09% vs 0.30 ± 0.06% kg dose/g), and in Ep LV than in En LV (0.32 ± 0.07% vs 0.25 ± 0.05%). In the reserpinized rat heart, the difference in the uptake between Ep LV and En LV was smaller. This suggests that the difference in the regional [¹²⁵I] MIBG uptake might reflect different intravesicular uptake in the layers of the heart. To our knowledge, the low uptake in the endocardial layer was a new finding which seems to indicate a difference in innervation between the epicardial and endocardial layers of the left ventricle in the rat heart. Autoradiographic study also showed the low uptake of [¹²⁵I] MIBG in the endocardial layer, while homogeneous perfusion was observed with thallium-201, supporting the tissue uptake study. Thus, the endocardial and epicardial layers of the left ventricle in the rat heart were considered to be differently innervated.     

Imaging platelet deposition on Dacron bifurcation grafts in man: Quantification by a dual-tracer method using 111In-labeled platelets and 99mTc-labeled human serum albumin

A dual tracer technique using ¹¹¹In-labeled platelets and ^99mTc-labeled human serum albumin was applied to evaluate the thrombogenicity of Dacron bifurcation arterial grafts. The level of platelet accumulation over the whole of the graft was estimated from the ratio of ¹¹¹In-platelet radioactivity deposited on the vascular wall to these radioactivity circulating in the blood pool, i.e., the platelet-accumulation index (PAI). Furthermore, the PAI value was calculated for each pixel in digitized images and the PAI distribution image (PAI image) was reconstructed. Eighteen patients with DeBakey knitted Dacron bifurcation grafts and 11 normal volunteers were studied. Of the 18 patients, 11 had no graft occlusion (group I) and the remaining 7 (group II) had occlusion. The mean PAI value (±SD) over the whole of the graft in group I was 32.6%±33.7% as compared to -8.8%±4.5% in the control group (P<0.01). In group I, the PAI value over the entire graft decreased with the age of the fraft (r=-0.763; P<0.01). In contrast, in group II, platelet accumulation did not diminish with time and persisted beyond the time of which platelet accumulation was no longer found in group I. Moreover, analysis of the PAI images revealed enhanced platelet accumulation on the proximal part of the graft to be more frequent in group II than in group I (6/7 vs 0/11; _c ² = 10.55; P<0.005). The method used for platelet imaging in the present study may be useful in the study of platelet reactions on Dacron arterial prostheses.     

Use of <Superscript>123</Superscript>I-MIBG scintigraphy to assess the impact of carvedilol on cardiac adrenergic neuronal function in childhood dilated cardiomyopathy

Iodine-123 metaiodobenzylguanidine (MIBG) cardiac scintigraphy is a useful tool for the assessment of cardiac adrenergic neuronal function, which is impaired in children with idiopathic dilated cardiomyopathy (DCM). In adults with DCM, long-term treatment with carvedilol improves both cardiac adrenergic neuronal function and left ventricular function. The aim of this prospective study was to evaluate the impact of carvedilol on cardiac adrenergic neuronal function using ¹²³I-MIBG scintigraphy and on left ventricular function using equilibrium radionuclide angiography in children with DCM. Seventeen patients (11 female, six male; mean age 39±57 months, range 1–168 months) with DCM and left ventricular dysfunction underwent ¹²³I-MIBG cardiac scintigraphy and equilibrium radionuclide angiography before and after a 6-month period of carvedilol therapy. A static anterior view of the chest was acquired 4 h after intravenous injection of 20–75 MBq of ¹²³I-MIBG. Cardiac neuronal uptake of ¹²³I-MIBG was measured using the heart to mediastinum count ratio (HMR). Radionuclide left ventricular ejection fraction (LVEF) was assessed following a standard protocol. MIBG cardiac uptake and left ventricular function respectively increased by 38% and 65% after 6 months of treatment with carvedilol (HMR=223%±49% vs 162%±26%, P<0.0001, and LVEF=43%±17% vs 26%±11%, P<0.0001). Carvedilol can improve cardiac adrenergic neuronal and left ventricular function in children with dilated cardiomyopathy. Further studies are needed to assess the relationship between improvement in MIBG cardiac uptake and the beneficial effects of carvedilol on morbidity and mortality.     

Serial change of iodine-123 metaiodobenzylguanidine (MIBG) myocardial concentration in patients with dilated cardiomyopathy

Serial change of the metaiodobenzylguanidine iodine-123 (¹²³I-MIBG) myocardial concentration was investigated in patients with dilated cardiomyopathy (DCM). Eight DCM patients and 6 control subjects were examined. After the injection of thallium-201 and ¹²³I-MIBG, planar chest images were obtained simultaneously for both tracers in every 30–60 min over 5 h. Serial changes of myocardial uptake ratio (MUR) were compared for both tracers. In DCM, the initial MUR of ¹²³I-MIBG did not differ significantly from that of the controls. The washout of ¹²³I-MIBG from the myocardium, however, was significantly increased in DCM. In particular, the decrease in the early phase (15–45 min) was significantly larger in DCM than in the controls (21.2%±7.5% vs. 5.3%±4.0%, P <0.01), showing a significant negative correlation with the left ventricular ejection fraction (r = –0.72 P < 0.05). For ²⁰¹TI, neither the initial MUR nor the washout rate different significantly between the two. Thus, an early rapid decrease of the ¹²³I-MIBG myocardial concentration might characterize DCM and reflect the severity of this disease. Offprint requests to: K. Yamakado     

Effects of perindopril on cardiac sympathetic nerve activity in patients with congestive heart failure: comparison with enalapril

Purpose The production of aldosterone in the heart is suppressed by the angiotensin-converting enzyme (ACE) inhibitor perindopril in patients with congestive heart failure (CHF). Moreover, perindopril has been reported to have more cardioprotective effects than enalapril.Materials and methods Forty patients with CHF [left ventricular ejection fraction (LVEF) <45%; mean 33±7%] were randomly assigned to perindopril (2 mg/day; n=20) or enalapril (5 mg/day; n=20). All patients were also treated with diuretics. The delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS) and washout rate (WR) were determined from ¹²³I-meta-iodobenzylguanidine (MIBG) images, and plasma brain natriuretic peptide (BNP) concentrations were measured before and 6 months after treatment. The left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and LVEF were also determined by echocardiography.Results After treatment, in patients receiving perindopril, TDS decreased from 39±10 to 34±9 (P<0.01), H/M ratios increased from 1.62±0.27 to 1.76±0.29 (P<0.01), WR decreased from 50±14% to 42±14% (P<0.05) and plasma BNP concentrations decreased from 226±155 to 141±90 pg/ml (P<0.0005). In addition, the LVEDV decreased from 180±30 to 161±30 ml (P<0.05) and the LVESV decreased from 122±35 to 105±36 ml (P<0.05). Although the LVEF tended to increase, the change was not statistically significant (from 33±8% to 36±12%; P=NS). On the other hand, there were no significant changes in these parameters in patients receiving enalapril.Conclusion Plasma BNP concentrations, ¹²³I-MIBG scintigraphic and echocardiographic parameters improved after 6 months of perindopril treatment. These findings indicate that perindopril treatment can ameliorate the cardiac sympathetic nerve activity and the left ventricular performance in patients with CHF.     

Evaluation of 99mTc-dextran as a lymphoscintigraphic agent in rabbits

Dextran (clinical grade, average mol. wt. 82,200) was labelled with ^99mTc and the labelling efficiency was checked by paper and thin-layer chromatography and electrophoresis. The amount of free ^99mTcO ₄ ^- was always less than 1%. The radiopharmaceutical was injected ID into the web space in hind legs of ten rabbits (200–600 Ci/0.05 ml). Scintigrams were taken at 10-min intervals up to 3 h in three rabbits. The injection site and the hind legs were massaged after injection in the other seven rabbits and scintigrams were taken at 10-min intervals up to 2 h. Blood samples were obtained at 5, 15, 30, 90 and 120 min in both groups. In addition a 180-min sample, was also taken in the first group. At the end of the study the rabbits were killed and the popliteal lymph nodes and the organs were removed to be weighed, and counted. Our results indicated a high concentration of radioactivity in the popliteal lymph nodes and massage at the injection site increased the average uptake of the popliteal lymph node from 1.12%±0.77% to 4.28%±1.57% at 3 and 2 h, respectively (P<0.001). In scintigrams the lymph channels and the nodes were very well visualised. The blood radioactivity levels were too low to present a background problem. With massage 30% of the injected dose was removed from the injection site in 2 h. We have shown that ^99mTc-dextran is a good radiopharmaceutical for the visualisation of the lymph system and deserves further experimental and clinical studies.