Evaluation of cellular viability by quantitative autoradiographic study of myocardial uptake of a fatty acid analogue in isoproterenol-induced focal rat heart necrosis.

Previous studies led us to hypothesize that a fatty acid analogue, 15-p-iodophenyl-beta-methyl pentadecanoic acid (IMPPA or BMIPP), which is taken up but not quickly metabolized by heart cells, would be a more suitable tracer of cellular viability than thallium-201. Biodistribution studies of 1-14C-IMPPA in conscious, freely moving rats showed that the concentration ratio of radioactivity in the heart with respect to the blood was about 8 for at least 60 min after intravenous administration, permitting its use as a putative tracer in these conscious, freely moving rats. Thereafter, the myocardial uptake of 14C-IMPPA was studied in isoproterenol-treated rats (daily treatment for 10 days in order to induce cardiac hypertrophy and necrotic foci) with respect to control ones. Comparison of myocardial localizations by quantitative autoradiography of the uptake of 201Tl and 14C-IMPPA with that of triphenyltetrazolium chloride (TTC) staining enabled comparative evaluation of nutritional blood flow, localization and uptake of 14C-IMPPA and necrotic foci size. Distributions of 14C-IMPPA and 201Tl in control rats' hearts were homogeneous, like TTC staining. In infarcted hearts, areas of decreased 14C-IMPPA uptake were nearly the same (100% +/- 5%) as those unstained by TTC. These areas were larger than those showing a decrease in thallium uptake (about 70% +/- 5% of the total scar size). Therefore, IMPPA seems to be a more accurate and sensitive indicator of necrosis localization compared with thallium. It may be a useful agent for assessment of myocardial viability by single photon emission tomography (SPET) imaging.     

Kinetics of radioiodinated species in subcellular fractions from rat hearts following administration of iodine-123-labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP)

It is recognized that iodine-123-labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (¹²³IBMIPP) slowly washes out of the myocardium. The mechanism for the washout was investigated in normal rat hearts by analyses of the subcellular distribution and lipid classes based on the BMIPP metabolism. Rat hearts were excised at 1–120 min after intravenous injection of¹²³I-BMIPP. After counting the radioactivity, the hearts were digested with Nagarse and homogenized, and then fractionated into the cytosolic, mitochondrial, microsomal and crude nuclear fractions by centrifugations. The radioactivity of each fraction was counted, and the lipid classes were analysed by radio-thin-layer chromatographic and high-performance liquid chromatographic methods. The heart uptake of 1231-BMIPP was maximal at 5 min (6.81%±0.36% ID/g), and 41% of the radioactivity disappeared within 120 min. The myocardial radioactivity was immediately distributed into the cytosolic, mitochondrial, microsomal and crude nuclear fractions. The distribution (%) of each fraction was almost identical from 5 min through 120 min. The cytosolic fraction was always the major site of radioactivity deposition (60%), and the time-activity curve of the cytosolic fraction paralleled that of the whole heart throughout the 120-min study period. In the cytosolic fraction, most of the radioactivity was incorporated into the triglyceride class, and the rest was present in the free fatty acid, phospholipid (phosphatidylcholine) and diglyceride classes. In the mitochondrial fraction, the radioactivity was mostly incorporated into the phospholipid class (phosphatidylethanolamine), followed by free fatty acids. The final metabolite of¹²³I-BMIPP,¹²³I-p-iodophenylacetic acid (¹²³I-PIPA), initially appeared in the mitochondrial fraction as early as 1 min, and subsequently in the cytosolic fraction at 5 min. Another intermediary metabolite,¹²³I-p-iodophenyldodecanoic acid (¹²³I-PIPC₁₂), was found only in the mitochondrial fraction after 5 min. In conclusion, the slow washout kinetics of¹²³I-BMIPP from the myocardium mainly reflects the turnover rate of the triglyceride pool in the cytosol. The BMIPP metabolism, i.e. initial -oxidation followed by subsequent cycles of -oxidation, was confirmed in vivo. The participation of the mitochondria in the metabolism was also proven.     

Use of iodine-123 metaiodobenzylguanidine myocardial imaging to predict the effectiveness of β-blocker therapy in patients with dilated cardiomyopathy

It is crucial to predict drug effectiveness in chronic disease, such as dilated cardiomyopathy (DCM), in which the left ventricular (LV) function might be improved by -blocker therapy. As the functional improvement effected by -blocker therapy takes more than 2 months, we investigated whether iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) imaging could be used to predict drug effectiveness. We studied 13 patients (11 men and two women; mean age, 43±13 years) with DCM and seven normal subjects (six men and one woman; mean age, 48±16 years). We obtained myocardial single-photon emission tomography (SPET) images 15 min and 4 h after administration of¹²³I-MIBG (111 MBq). Studies were performed in the patients with DCM before and 1 and 3 months after the administration of metoprolol and in the normal subjects. We calculated the regional¹²³I-MIBG washout rate (r-WR) in the SPET image, and the global¹²³I-MIBG washout rate (g-WR) and heart-mediastinum activity ratio (H/M) using the anterior planar image. We classified patients into those showing a 5% increase in LV ejection fraction (LVEF) at 3 months compared with LVEF values before the treatment (group 1,n=7) and those showing a <5% increase in LVEF (group 11,n=6). In group I, the r-WR values at pretreatment and at 1 month and 3 months of treatment, respectively, were 36%±19%, 29%±14%* and 25%±13%* in the anterior segment, 39%±17%, 33%±17%** and 28%±17%* in the lateral segment, 36%±16%, 31%±14%* and 22%±12%** in the septal segment and 40%±11%, 37%±19% and 31%±18%* in the inferior segment; the g-WR was 45%±11%, 43%±10% and 34%±9%^*, respectively (*P<0.05, **P<0.01 vs pretreatment). In group II, there were no significant changes in regional or global parameters during the 3-month period. In normal subjects, the r-WR values in each of the anterior, lateral, septal and inferior segments were significantly lower than those in groups I and II. These values were 18%±9%, 18%±15%, 20%±12% and 21%±15%, respectively. This study demonstrated that with regional assessment¹²³I-MIBG SPET imaging can be used to predict the functional improvement of LVEF at 1 month of -blocker therapy in patients with DCM.     

A comparison of resting images from two myocardial perfusion tracers

We have compared stress-redistribution and delayed rest thallium-201 with rest technetium-99m methoxyisobutylisonitrile (MIBI) tomograms in order to compare the tracers for the assessment of myocardial viability and to validate a rapid protocol combining the two tracers. We studied 30 consecutive patients with known or suspected coronary artery disease [group 1: 16 with normal left ventricular function, mean left ventricular ejection fraction (LVEF) 55%, SD 6%; group 2: 14 with abnormal function, mean LVEF 28%, SD 8%].²⁰¹Tl was injected during infusion of adenosine followed by acquisition of conventional stress and redistribution tomograms. On a separate day,²⁰¹Tl was injected at rest with imaging 4 h later.^99mTc-MIBI was then given at rest and imaging was performed. Three images were compared: redistribution²⁰¹Tl, rest²⁰¹Tl, and rest^99mTc-MIBI. Tracer activity was classified visually and quantitatively in nine segments and segments with>50% activity were defined as containing clinically significant viable myocardium. Mean (±SD) global tracer uptake as a percentage of maximum was similar in group 1 (rest²⁰¹Tl 69%±12%, redistribution²⁰¹Tl 69%±15%, rest^99mTc-MIBI 70%±13%, ANOVAP>0.05), but in group 2 mean tracer uptake was significantly greater in the rest²⁰¹Tl images (59%±16%) than in redistribution²⁰¹Tl images (53%±17%) or rest^99mTc-MIBI images (53%±19%) (ANOVAP=0.02). Overall agreement for regional uptake score was excellent ( from 0.79 to 0.84), although there were a significant number of segments with less uptake shown by redistribution²⁰¹Tl and by rest^99mTc-MIBI than by rest²⁰¹Tl in group 2 (P<0.001). The number of segments with significant viable myocardium in group 1 was very similar between the three images (P>0.05) but in group 2 rest²⁰¹Tl identified significantly more segments as viable than the other images (McNemarP<0.001). Thus²⁰¹Tl and^99mTc-MIBI provide similar information in patients without prior infarction and with normal left ventricular function (group 1), and a rapid protocol with stress²⁰¹Tl injection and imaging followed immediately by rest^99mTc-MIBI injection and imaging is feasible. In patients with abnormal left ventricular function and prior infarction (group 2),^99mTc-MIBI may underestimate the extent of clinically significant viable myocardium.     

Fatty acid myocardial imaging using 123I-β-methyl-iodophenyl pentadecanoic acid (BMIPP): comparison of myocardial perfusion and fatty acid utilization in canine myocardial infarction (Occlusion and reperfusion model)

To evaluate the relationship between myocardial perfusion and fatty acid metabolism in canine myocardial infarction, 16 dogs were studied using thallium and ¹²³I--methyl-iodophenyl pentadecanoic acid (BMIPP). Eight dogs (group A) had left anterior coronary arterial occlusion (6 h ligation), 6 dogs (group B) had reperfusion (3 h ligation and 1 h reperfusion) and 2 dogs served as the normal control. Myocardial imaging with BMIPP was excellent, owing to its higher uptake and longer retention in myocardium and rapid blood disappearance in addition to diminished liver and lung uptake. The mean half time value which was generated from the BMIPP myocardial washout curve, was significantly larger in the reperfused myocardium. The gamma camera imaging showed uncoupling of BMIPP and thallium (BMIPP uptake greater than thallium uptake) in five dogs in group B. On the other hand, all dogs in group A had a persistent defect in BMIPP and thallium uptake. Our findings indicate that the combination of BMIPP and thallium for myocardial imaging supply different information about the zone of infarction and ischemia, which may be useful for the assessment of myocardial viability.     

A comparison of rest sestamibi and rest-redistribution thallium single photon emission tomography: Possible implications for myocardial viability detection in infarcted patients

Thirty patients (26 men, 4 women, mean age 61 ± 8 years) who had suffered myocardial infarction 15 ± 6 months previously, were submitted to (1) standard stress-redistribution thallium-201 single photon emission tomography (SPET), (2) rest-redistribution²⁰¹Tl SPET and (3) stress-rest technetium-99m sestamibi SPET. Uptake modifications in relation to exercise-induced defects were evaluated in a total of 390 myocardial segments. Tracer uptake was scored as normal (=0), mildly reduced (=1), apparently reduced (=2), severely reduced (=3) or absent (=4). Comparison of stress studies failed to show any statistical difference (58% segmental abnormalities with sestamibi vs 61% with thallium). Uptake abnormalities (score 1–4) were detected in 55% of the segments wiliest sestamibi, 55% with standard thallium redistribution, 55% with early imaging after thallium injection at rest and 54% with 3-h delayed rest imaging (P = NS). Absence of tracer uptake (score = 4) under resting conditions was recorded in 75 (19%) segments with standard²⁰¹Tl redistribution, 75 (19%) with rest sestamibi, 70 (18%) with rest²⁰¹Tl imaging and 62 (16%) with rst-rdistruion²⁰¹Tl (P<0.05 vs other imaging modalities). Thus, 3-h delayed rest thallium imaging detected reversibility of uptake defects in a significantly higher number of myocardial segments. This finding might have important implications for both tracer and technique selection when myocardial viability is the main clinical issue.     

Comparison of [123I]ß-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

Single-photon emission tomographic (SPET) imaging with the radiotracer [¹²³I]2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity,-CIT also binds with high affinity to serotonin (5-HT) transporters. 2-Carboisopropoxy-3-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [¹²³I]-CIT and [¹²³I]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [¹²³I]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma¹²³I activity) of lipophilic radiolabeled metabolites at 420 min. [¹²³I]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [¹²³I]-CIT and [¹²³I]IPCIT were 52%±7% and 14%±6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [¹²³I]-CIT (1.7±0.5) was higher than that of [¹²³I]IPCIT (0.4±0.2). Consistent with its greater lipophilicity, [¹²³I]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [¹²³I]IPCIT was about twice that of [¹²³I]-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [¹²³I]-CIT compared to [¹²³I]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different. In conclusion, [¹²³I]IPCIT demonstrated in vivo a higher DA transporter selectivity and higher level of nonspecific uptake.     

Nitrate administration to enhance the detection of myocardial viability by technetium-99m tetrofosmin single-photon emission tomography

A comparison was performed between technetium-99m tetrofosmin myocardial perfusion tomography at baseline and after nitrate administration, using a 2-day protocol, and rest-reinjection thallium-201 single-photon emission tomography (SPET) studies in order to assess whether nitrates enhance the detection of viable myocardium with^99mTc-tetrofosmin. Fifteen patients with coronary artery disease, previous myocardial infarction and a left ventricular ejection fraction <40% underwent²⁰¹T1 rest-injection and^99mTc-tetrofosmin. baseline-postnitroglycerin (0.4 mg sublingually) SPET studies, within 48 h. Tomograms based on the three spatial planes were divided into 15 segments and regional tracer uptake was quantitatively analysed. Viability was defined as presence of tracer uptake >50% of peak activity on baseline studies or after reversibility. The percentage of peak activity of^99mTc-tetrofosmin at baseline correlated with that of 201T1 (r=0.82,P <0.001). On baseline^99mTc-tetrofosmin studies, 73 of the 225 segments that were analysed had <50% of peal. activity. Fifteen percent of these segments showed reversibility after nitrate administration, with an increase in^99mTc-tetrofosmin uptake from 40%±9% to 57%±9% of peak activity (P=0.003). All reversible segments after nitrate administration had viability criteria on²⁰¹Tl studies, but 20 segments that were non-viable on^99mTc-tetrofosmin. studies were viable on²⁰¹Tl studies. Using a threshold value of >40% of peak activity, only seven segments remained non-viable on^99mTc-tetrofosmin studies. Overall agreement between^99mTc-tetrofosmin with nitrates and²⁰¹Tl-reinjection regarding the presence of myocardial viability was 90%. Detection of myocardial viability with^99mTc-tetrofosmin. was enhanced after nitrate administration, correlating with viability criteria observed on thallium studies.     

Recovery of impaired left ventricular function in patients with acute myocardial infarction is predicted by the discordance in defect size on123I-BMIPP and201TI SPET images

A discrepancy between myocardial perfusion defect and wall motion abnormalities is frequently found early after coronary reperfusion in patients with acute myocardial infarction. The purpose of this study was to assess recovery of impaired left ventricular function by reference to the discordance in defect size between myocardial fatty acid uptake and myocardial perfusion using combined single-photon emission tomographic (SPET) imaging early after coronary perfusion therapy. In 37 patients with acute myocardial infarction, iodine-123 15(p-iodophenyl)-3(R, S)-methylpentadecanoic acid (BMIPP) and thallium-201 SPET scans were performed early after coronary reperfusion. A severity score was determined from the extent of the imaging defect with each tracer. Left ventricular wall motion score (WMS) and ejection fraction (EF) were obtained at admission and at 4 weeks after the onset of infarction. In 32 of the 37 patients, discordance in defect sizes delineated with the two SPET studies was found during the acute stage. The severity score for BMIPP was larger than that for²⁰¹Tl during the acute stage (7.7±2.4 vs 4.4±2.5,P <0.001). There was a fair correlation between the severity score for BMIPP and WMS (r=0.82,P <0.0001), but a poor correlation between that for²⁰¹Tl and WMS. The extent of discordance in severity scores between BMIPP and²⁰¹Tl during the acute stage correlated well with the extent of the improvement in WMS (r=0.86,P <0.0001) and that of EF (r=0.85,P <0.0001). We conclude that the discordance in defect size on BMIPP and²⁰¹TI SPET images during the acute stage of infarction is an early predictor of the viability of the myocardium at risk of infarction.     

Time course of technetium-99m sestamibi myocardial distribution in dogs with a permanent or transient coronary occlusion

The influence of duration of coronary occlusion and reperfusion on technetium-99m hexakis-2-methoxyisobutylisonitrile (^99mTc-sestamibi) myocardial redistribution between necrotic, salvaged and non-ischaemic myocardium was investigated in dogs submitted either to a 90-min or a 24-h permanent left descending coronary artery occlusion (groups 1 and 2) or to a 90-min occlusion followed by 30 min, 6 h or 22.5 h of reperfusion (groups 3, 4 and 5). In all groups, ^99mTc-sesta-mibi and radiolabelled microspheres were injected at 45 min of occlusion. After delimiting the area at risk and the infarct by Evans blue perfusion and triphenyltetrazolium chloride staining, radioactivity of heart slices from normal, viable-ischaemic and necrotic myocardium was measured in a gamma counter. A significant (P<0.001) linear relationship between ^99mTc-sestamibi distribution and myocardial blood flow was observed in the area at risk of groups 1 (r=0.92), 2 (r=0.84), 3 (r=0.90), 4 (r=0.93) and 5 (r=0.58). In all groups, the mean percentage of ^99mTc-sestamibi uptake in the ischaemic over normal zone overestimated significantly (P<0.05) the mean percentage of the ratio in myocardial blood flow measured with microspheres (group 1: 13.3±1.4 vs. 7.7±1.2; group 2: 15.9±2.0 vs 5.6±1.2; group 3: 14.9±1.6 vs 6.2±1.0; group 4:20.9±1.7 vs 10.9±1.8; group 5: 51.0±2.7 vs 14.0±2.0). This overestimation of blood flow by ^99mTc-sestamibi approximated a ratio of 2 after brief (90 min) or sustained (24 h) occlusion and after 30 min or 6 h of reperfusion, but increased to almost 4 in group 5 with prolonged (22.5 h) reperfusion, indicating a significant redistribution of the tracer. In this group, redistribution was more pronounced in the viable-ischaemic zone as indicated by a ^99mTc-sestamibi uptake vs the normal zone of 66.5%±5.5% (P<0.05) as compared to 31.5%±3.3% in the necrotic zone, whereas the uptake in the necrotic zone of the 24 h permanently occluded group averaged 22.1%±3.4%. We conclude that upon 6 h of reperfusion, ^99mTc-sestamibi myocardial distribution is still flow dependent, with a net overestimation of the ischaemic myocardial blood flow. Prolonged reperfusion redistributes the tracer to the viable and necrotic myocardium in a 2:1 ratio. In these conditions, reperfusion may be overestimated and infarct size underestimated.     

Experimental studies on myocardial glucose metabolism of rats with 18F-2-fluoro-2-deoxy-d-glucose

The myocardial uptake of ¹⁸F-FDG was investigated under various conditions, and compared with brain and tumor uptake as a function of blood glucose level. The uptake by the heart of normal feeding rats was rapid and remained essentially unchanged up to 2 h after ¹⁸F-FDG injection, approximately 3%–4% dose/g tissue. On the other hand, the myocardial uptake of fasted rats was significantly lower than that of control rats throughout the course of the study, and it was about 0.3%–0.4% dose/g tissue. Myocardial uptake of ¹⁸F-FDG was relatively constant at glucose levels under about 120 mg/100 ml and increased steeply at higher blood glucose levels. In contrast, brain uptake decreased linearly with increasing levels of blood glucose, revealing a strong negative correlation between brain uptake of ¹⁸F-FDG and blood glucose levels. The tumor uptake pattern remained relatively unchanged, irrespective of blood glucose levels. It was revealed that the glucose demands of brain, heart, and tumor were entirely different. After a glucose load, the myocardial uptake of fasted rats increased only slightly from 0.4% to 0.6% dose/g tissue, in spite of transitional hyperglycemia. In contrast, insulin caused myocardial uptake to increase extraordinarily, although it caused a decrease in blood glucose levels.     

Myocardial uptake of thallium-201 diethyldithiocarbamate (201TI-DDC) in cultured heart cells and in humans

We assessed the feasibility of SPECT imaging with ²⁰¹Tl-diethyldithiocarbamate (²⁰¹Tl-DDC), a new cerebral blood flow tracer with little redistribution, expecting to observe less extensive redistribution than with ²⁰¹Tl-chloride. Myocardial sections were obtained in three patients presenting with documented coronary artery disease and injected at peak exercise with 100 MBq ²⁰¹Tl-DDC. In two patients there was a clear redistribution phenomenon at four h after injection. In cultured myocardial cells of newborn rats, the uptake and washout of ²⁰¹Tl-chloride and ²⁰¹Tl-DDC were compared. The ²⁰¹Tl-DDC uptake was lower than ²⁰¹Tl-chloride (transmembrane gradients were respectively 89±10 and 4.1±0.2, mean±sem, n=14, P<0.001). After 2 h washout in a Tl free medium, the retention of ²⁰¹Tl-chloride in the cells was 4% vs 19% for ²⁰¹Tl-DDC. It is concluded that although myocardial imaging is feasible with ²⁰¹Tl-DDC, this agent redistributes significantly with time.     

In vivo and in vitro evaluation of [<Superscript>18</Superscript>F]FETO with respect to the adrenocortical and GABAergic system in rats

11-Hydroxylase (CYP11B1, P450₁₁) plays an important role in the biosynthesis of cortisol and aldosterone and has been shown to be a good target for the in vivo imaging of adrenocortical incidentalomas in nuclear medicine. [¹¹C]Metomidate (MTO), a potent inhibitor of this enzyme, is used for positron emission tomography (PET) imaging of adrenocortical pathology. The synthesis of (R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid 2-[¹⁸F]fluoroethylester (FETO), a close analogue to MTO and etomidate (ETO), has been presented recently, and the present investigation aimed to characterise the in vivo distribution of FETO. Since ETO is a well-known anaesthetic drug acting via the GABAergic system, the interaction of FETO with GABA_A receptors was also evaluated. Eighteen male Sprague-Dawley rats were injected with 1.73–3.06 MBq of FETO into a tail vein after venodilatation in a 40°C water bath. Rats were sacrificed by exsanguination from the abdominal aorta under deep ether anaesthesia after 10 (n=6), 30 (n=6) or 60 min (n=6); organs were removed, weighed and counted. For binding experiments, rat cerebellar membranes were incubated for 90 min at 4°C in TC-50 buffer, 150 mM NaCl and 2 nM of [³H]flunitrazepam in the absence or presence of 10 µM diazepam or various concentrations of ETO, MTO and FETO. In vivo evaluation evinced very high uptake in the adrenal glands (7.52%±1.19% ID/g at 30 min), followed by lung (1.18%±0.19% ID/g, 10 min), liver (0.59%±0.13% ID/g, 10 min) and duodenum (0.7%±0.29% ID/g, 60 min). No defluorination nor fluoroethyl-ester cleavage was observed. When brain regions were compared with the thalamus (the reference region), highest relative uptake was seen in the cortex (2.34), followed by "rest brain" (2.13) and cerebellum (1.96). FETO and ETO were able to increase the binding of [³H]flunitrazepam with similar potencies and to a comparable extent. It is concluded that FETO shows characteristics suitable for the imaging of adrenocortical pathology with PET. Binding experiments on GABA receptors demonstrate a comparable effect of FETO and ETO. Hence, FETO possibly could also be used to elucidate the function, dynamics and kinetics of narcotic drugs with PET.     

Whole-body kinetics and dosimetry ofl-3-[123I]iodo-α-methyltyrosine

The synthetic amino acidl-3-[¹²³I]iodo--methyltyrosine (IMT) is currently under clinical evaluation as a single-photon emission tomography (SPET) tracer of amino acid uptake in brain tumours. So far, dosimetric data in respect of IMT are not available. Therefore we investigated the whole-body distribution of IMT in six patients with cerebral gliomas and the radiation doses were estimated. Whole-body scans were acquired at 1.5, 3 and 5 h after i.v. injection of 370–550 MBq IMT. The bladder was voided prior to each scan and the radioactivity excreted in the urine was measured. Based on the MIRD-11 method and the updated MIRDOSE3, the mean absorbed doses for various organs and the effective dose were calculated from geometric means of the anterior and posterior whole-body scans using seven source organs and the residence time. IMT was predominantly excreted by the kidneys (52.8%±11.5% at 1.5 h p.i., 63.0%±15.7% at 3 h p.i. and 74.6%±9.8% at 5 h p.i.). No organ system other than the urinary tract showed significant retention of the tracer. Early whole-body scans revealed slightly increased tracer uptake in the liver and in the bowel. Highest absorbed doses were found for the urinary bladder wall (0.047 mGy/MBq), the kidneys (0.010 mGy/MBq), the lower large intestinal wall (0.011 mGy/MBq) and the upper large intestinal wall (0.008 mGy/MBq). The effective dose according to ICRP 60 was estimated to be 0.0073 mSv/MBq for adults. This leads to an effective dose of 3.65 mSv in a typical brain SPET study using 500 MBq IMT. The MIRDOSE3 scheme yielded similar results. Thus, in spite of the relatively high tracer dose required for optimal brain scanning, radiation exposure in SPET studies with IMT is in the normal range of routine nuclear medicine investigations.     

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     

Comparison of uptake of99mTc-MIBI,99mTc-tetrofosmin and99mTc-012 into human breast cancer cell lines

Technetium-99m hexakis-2-methoxyisobutylisonitrile (MIBI),^99mTc-tetrofosmin and^99mTc-Q12 were all introduced for myocardial imaging but found additional applications as they are taken up by different tumours, enabling imaging of these lesions in patients. The aim of this study was to compare the uptake characteristics of these compounds in vitro in the human adenocarcinoma breast cell lines MCF-7 and ZR-75. It was shown that^99mTc-MIBI had the highest cellular uptake (15.9%±0.5% dose/mg protein after 60 min in MCF-7, and 14.2%±0.4% dose/mg protein in ZR-75), followed by^99mTc-tetrofosmin (6.8%±0.6% dose/mg protein in MCF-7, and 8.2%±0.2% dose/mg protein in ZR-75) and^99mTc-Q12 (3,2%±0. I% dose/mg protein in MCF-7, and 3.5%±0.3% dose/mg protein in ZR-75 cells). For all three compounds tenfold differences in specific activity did not influence total cell-associated radioactivity. Uptake of^99mTc-MIBI and^99mTc-tetrofosmin was obviously lower at 4° C than at 37° C, whereas^99mTc-Q12 uptake showed only slight temperature dependence. When uptake was compared in cells grown to different cell densities (1 mg/ml cellular protein versus 0.3 mg/ml), no differences in uptake were detected when uptake was corrected for the amount of cellular protein present in the dishes. Furthermore, for all compounds it was shown that cellular radioactivity decreased rapidly after washing. Apart from the differences in cellular uptake of the three compounds after 60 min, no differences in residual cellular radioactivity after washing were found between the different compounds when expressed as a percentage of their 60-min uptake, suggesting that the efflux process of the radiolabelled compounds was similar. The differences in cell-associated activity after 60 min were thus presumably caused by differences in uptake. It was concluded that of the Tc-labelled compounds tested,^99mTc-MIBI had the highest cellular retention in both human breast tumour cell lines. However, for imaging in vivo not only radioactivity in the target organ is important, but also the ratio of radioactivity in the target versus that in the background. Therefore, further studies in vivo need to be performed to investigate which compound is the optimal imaging agent     

Uptake of 18F-fluorocholine, 18F-fluoro-ethyl-L-tyrosine and 18F-fluoro-2-deoxyglucose in F98 gliomas in the rat

Introduction The positron emission tomography (PET) tracers ¹⁸F-fluoro-ethyl-L-tyrosine (FET), ¹⁸F-fluorocholine (N,N-dimethyl-N-[¹⁸F]fluoromethyl-2-hydroxyethylammonium (FCH]) and ¹⁸F-fluoro-2-deoxyglucose (FDG) are used in the diagnosis of brain tumours. The aim of this study was threefold: (a) to assess the uptake of the different tracers in the F98 rat glioma, (b) to evaluate the impact of blood-brain barrier (BBB) disruption and microvessel density (MVD) on tracer uptake and (c) to compare the uptake in the tumours to that in the radiation injuries (induced by proton irradiation of healthy rats) of our previous study.Methods F98 gliomas were induced in 26 rats. The uptake of FET, FCH and FDG was measured using autoradiography and correlated with histology, disruption of the BBB and MVD.Results The mean FET, FCH and FDG standardised uptake values (SUVs) in the tumour and the contralateral normal cortex (in parentheses) were 4.19±0.86 (1.32±0.26), 2.98±0.58 (0.51±0.11) and 11.02±3.84 (4.76±1.77) respectively. MVD was significantly correlated only with FCH uptake. There was a trend towards a negative correlation between the degree of BBB disruption and FCH uptake and a trend towards a positive correlation with FET uptake. The ratio of the uptake in tumours to that in the radiation injuries was 1.97 (FCH), 2.71 (FET) and 2.37 (FDG).Conclusion MVD displayed a significant effect only on FCH uptake. The degree of BBB disruption seems to affect the accumulation of FET and FCH, but not FDG. Mean tumour uptake for all tracers was significantly higher than the accumulation in radiation injuries.     

99mTc-glucarate imaging for the early detection of infarct in partially reperfused canine myocardium

Purpose ^99mTc-glucarate is an imaging agent developed for the detection of acutely infarcted myocardium. The purposes of the current study were to (1) determine whether ^99mTc-glucarate can detect acute infarct in the setting of only partial minimal reperfusion, (2) study the persistence and time course of scan positivity following coronary occlusion and intravenous tracer injection, (3) assess the ability of ^99mTc-glucarate to determine infarct size, and (4) compare these data with previous results obtained using a 100% reperfusion model.Methods Six dogs underwent left circumflex (LCx) coronary occlusion for 90 min, followed by 10% epicardial blood flow reperfusion. Fifteen mCi (555 MBq) ^99mTc-glucarate was injected intravenously 30 min later. Serial gamma camera images were acquired over 240 min. Microsphere blood flow determinations were performed at baseline, during occlusion, during tracer administration, and just before euthanasia. Ex vivo gamma camera images were obtained. Triphenyltetrazolium chloride (TTC) staining was performed to assess infarct size.Results Qualitatively, ^99mTc-glucarate images showed a well-defined hot spot in all six dogs by 30 min after tracer injection (150 min following coronary occlusion), which persisted for 240 min following tracer administration. Quantitatively, there was a significant increase in the LCx/LAD (left anterior descending) counts ratio beginning 10 min after tracer administration (130 min after occlusion), and continuing to 240 min after tracer administration. Tracer retention was 12.0±0.9% for the LAD and 39.0±4.1% for the LCx hot spot zone (p<0.05) at 240 min after ^99mTc-glucarate injection. The correlation coefficient was 0.90 for infarct size by TTC versus ^99mTc-glucarate.Conclusion In the setting of only partial minimal coronary reperfusion following infarction, ^99mTc-glucarate myocardial uptake is delayed and less intense compared with the setting of complete reperfusion. Nevertheless, infarcts can still be reliably detected in dogs using qualitative in vivo imaging, and significant abnormalities in quantitative parameters are observed. Thus, ^99mTc-glucarate imaging may be useful for the clinical detection and relative sizing of acute myocardial infarction, even in the setting of only minimal coronary reperfusion.Ban-An Khaw is a shareholder in Molecular Targeting Technologies, Inc.     

Resting technetium-99m methoxyisobutylisonitrile cardiac imaging in chronic coronary artery disease: comparison with rest-redistribution thallium-201 scintigraphy

We studied 19 patients with angiographically proven coronary artery disease and left ventricular dysfunction (ejection fraction 33% ± 8%) by resting technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI) and rest-redistribution thallium-201 cardiac imaging. Thallium and (^99mTc-MIBI) studies were visually analysed. Of 285 segments, 203 (71%) had normal thallium uptake, 48 (17%) showed reversible thallium defects and 34 (12%) showed irreversible thallium defects. Of these 34 irreversible thallium defects, 19 (56%) were moderate and 15 (44%) were severe. Of the corresponding 285 segments, 200 (70%) had normal ^99mTc-MIBI uptake, while 37 (13%) showed moderate and 48 (17%) showed severe reduction of 99 ^99mTc-MIBI uptake. Myocardial segmental agreement for regional uptake score between initial thallium and resting (^99mTc-MIBI) images was 90% (=0.78). Segmental agreement between delayed thallium and resting ⁹⁹Tc-MIBI images was 77% (=0.44). In particular, in 26 (9%) segments ^99mTc-MIBI uptake was severely reduced while delayed thallium uptake was normal or only moderately reduced. These data suggest that although rest-redistribution thallium and resting (^99mTc-MIBI) cardiac imaging provide concordant results in the majority of myocardial segments, some segments with severely reduced resting ^99mTc-MIBI uptake may contain viable but hypoperfused myocardium. Thus, conclusions on myocardial viability based on ^99mTc-MIBI uptake should be made with caution in chronic coronary artery disease.     

99mTc-sestamibi thyroid uptake in euthyroid individuals and in patients with autoimmune thyroid disease

Purpose We investigated the biokinetics of ^99mTc-sestamibi in the thyroid of euthyroid volunteers (EVs) and in patients with autoimmune thyroid diseases and determined the best time interval between ^99mTc-sestamibi injection and calculation of uptake.Methods Forty EVs, 30 patients with Graves disease (GD), 15 patients with atrophic Hashimotos thyroiditis (AHT) and 15 patients with hypertrophic Hashimotos thyroiditis (HHT) underwent ^99mTc-sestamibi thyroid scintigraphy. Dynamic images were acquired for 20 min, and static images were obtained 20 min, 60 min and 120 min post injection. Five-, 20-, 60- and 120-min uptake, time to maximal uptake (T_max) and T_1/2 of tracer clearance were calculated. Thyroid hormones and antibodies were measured. ^99mTc-pertechnetate uptake was investigated in GD patients.Results T_max was approximately 5 min in all four groups. The mean T_1/2 value for EVs was similar to the GD value and lower than the HHT and AHT values. The mean (±SD) 5-min uptake was 0.13% (±0.05%) for EVs. The 5-min uptake in GD was higher than that in EVs(P<0.001) and correlated with free thyroxine (r=0.54) and with ^99mTc-pertechnetate uptake (r=0.68). Uptake in HHT was higher than that in AHT (P=0.0003) and EVs (P=0.002). Uptake in AHT was lower than uptake in EVs (P=0.0001).Conclusion Five minutes is the optimal time interval between ^99mTc-sestamibi injection and calculation of thyroid uptake. Five-minute uptake differentiates euthyroid individuals from GD patients. There is a high correlation between ^99mTc-sestamibi and ^99mTc-pertechnetate uptake in GD. The reduced ^99mTc-sestamibi uptake in AHT patients is probably due to glandular destruction and fibrosis. Inflammatory infiltrate and high mitochondrial density in thyrocytes possibly explain the increased uptake in GD and HHT.