Functional imaging of multidrug resistance in an orthotopic model of osteosarcoma using 99mTc-sestamibi

Purpose The purpose of this work was the development of an orthotopic model of osteosarcoma based on luciferase-expressing tumour cells for the in vivo imaging of multidrug resistance (MDR) with ^99mTc-sestamibi. Methods Doxorubicin-sensitive (143B-luc⁺) and resistant (MNNG/HOS-luc⁺) osteosarcoma cell lines expressing different levels of P-glycoprotein and carrying a luciferase reporter gene were inoculated into the tibia of nude mice. Local tumour growth was monitored weekly by bioluminescence imaging and X-ray. After tumour growth, a ^99mTc-sestamibi dynamic study was performed. A subset of animals was pre-treated with an MDR inhibitor (PSC833). Images were analysed for calculation of ^99mTc-sestamibi washout half-life (t _1/2), percentage washout rate (%WR) and tumour/non-tumour (T/NT) ratio. Results A progressively increasing bioluminescent signal was detected in the proximal tibia after 2 weeks. The t _1/2 of ^99mTc-sestamibi was significantly shorter (p < 0.05) in drug-resistant MNNG/HOS-luc⁺ tumours (t _1/2 = 87.3 ± 15.7 min) than in drug-sensitive 143B-luc⁺ tumours (t _1/2 = 161.0 ± 47.4 min) and decreased significantly with PSC833 (t _1/2 = 173.0 ± 24.5 min, p < 0.05). No significant effects of PSC833 were observed in 143B-luc⁺ tumours. The T/NT ratio was significantly lower (p < 0.05) in MNNG/HOS-luc⁺ tumours than in 143B-luc⁺ tumours at early (1.55 ± 0.22 vs 2.14 ± 0.36) and delayed times (1.12 ± 0.11 vs 1.62 ± 0.33). PSC833 had no significant effects on the T/NT ratios of either tumour. Conclusion The orthotopic injection of tumour cells provides an animal model suitable for functional imaging of MDR. In vivo bioluminescence imaging allows the non-invasive monitoring of tumour growth. The kinetic analysis of ^99mTc-sestamibi washout provides information on the functional activity of MDR related to P-glycoprotein expression and its pharmacological inhibition in osteosarcoma.     

Acute oral trimetazidine administration increases resting technetium 99m sestamibi uptake in hibernating myocardium

Background  Trimetazidine is an antiischemic drug protecting the myocardium from ischemic damage through the preservation of mitochondrial oxidative metabolism, without any hemodynamic effect. ^99mTc-sestamibi is accumulated by myocytes according to mitochondrial function. As mitochondrial metabolism is thought to be present in hibernating myocardium, the aim of the study was to investigate trimetazidine effects on infarcted and eventually hibernating myocardial areas by means of ^99mTc-sestamibi perfusional scintigraphy, comparing them to postoperative recovery of wall motion. Methods and Results  Twelve patients with previous myocardial infarction underwent 2 perfusion imaging tomographic studies at rest with ^99mTc-sestamibi, receiving placebo or trimetazidine (60 mg orally), and subsequently underwent revascularization procedures. An echocardiographic study was carried out before and >3 months after revascularization. At polar map analysis of placebo scan, infarcted vascular territories (wall motion score index: 2.65±0.31) showed 73.7%±10.4% of the territory with activity <2.5 SD from the mean of normals, for a severity (expressed as the sum of the standard deviations below average normal values in all abnormal pixels) of 833.8±345.7. Polar map analysis of the trimetazidine scan showed tracer uptake increased significantly in 11 of them, by 8.2%±3.0% (p<0.001) and by 180.3±111.0 SD (p<0.001), respectively. Postoperative wall motion score index improved significantly in 9 of these territories (−0.9±0.4, p<0.001). Conclusions  Trimetazidine-associated increase in ^99mTc-sestamibi uptake in infarcted but viable myocardial areas is probably related to an improvement in mitochondrial oxidative metabolism that is essential to ^99mTc-sestamibi retention. Additionally, coupling trimetazidine administration to ^99mTc-sestamibi perfusional scintigraphy may represent a means of detecting viable myocardium.     

Infarct size in primary angioplasty without on-site cardiac surgical backup versus transferal to a tertiary center: a single photon emission computed tomography study

Background  Primary percutaneous coronary intervention (PCI) performed in large community hospitals without cardiac surgery back-up facilities (off-site) reduces door-to-balloon time compared with emergency transferal to tertiary interventional centers (on-site). The present study was performed to explore whether off-site PCI for acute myocardial infarction results in reduced infarct size. Methods and results  One hundred twenty-eight patients with acute ST-segment elevation myocardial infarction were randomly assigned to undergo primary PCI at the off-site center (n = 68) or to transferal to an on-site center (n = 60). Three days after PCI, ^99mTc-sestamibi SPECT was performed to estimate infarct size. Off-site PCI significantly reduced door-to-balloon time compared with on-site PCI (94 ± 54 versus 125 ± 59 min, respectively, p < 0.01), although symptoms-to-treatment time was only insignificantly reduced (257 ± 211 versus 286 ± 146 min, respectively, p = 0.39). Infarct size was comparable between treatment centers (16 ± 15 versus 14 ± 12%, respectively p = 0.35). Multivariate analysis revealed that TIMI 0/1 flow grade at initial coronary angiography (OR 3.125, 95% CI 1.17–8.33, p = 0.023), anterior wall localization of the myocardial infarction (OR 3.44, 95% CI 1.38–8.55, p < 0.01), and development of pathological Q-waves (OR 5.07, 95% CI 2.10–12.25, p < 0.01) were independent predictors of an infarct size > 12%. Conclusions  Off-site PCI reduces door-to-balloon time compared with transferal to a remote on-site interventional center but does not reduce infarct size. Instead, pre-PCI TIMI 0/1 flow, anterior wall infarct localization, and development of Q-waves are more important predictors of infarct size.     

Myocardial kinetics of <Superscript>201</Superscript>Thallium, <Superscript>99m</Superscript>Tc-tetrofosmin,and <Superscript>99m</Superscript>Tc-sestamibi in an acute ischemia–reperfusion model using isolated rat heart

Objective ²⁰¹Thallium (TL), ^99mTc-tetrofosmin (TF), and ^99mTc-sestamibi (MIBI) are extensively used as myocardial perfusion agents. The objective of the present study was to evaluate their kinetics under acute ischemia–reperfusion. Methods Isolated rat hearts, perfused by the Langendorff method at a constant flow rate of 10 ml/min, were allotted to normal control, mild ischemia, and severe ischemia groups, in which 20-min tracer wash-in was conducted followed by a 25-min tracer washout. No-flow ischemia (15 min for mild ischemia groups; 30 min for severe ischemia groups) was induced before conducting wash-in and washout in the ischemia groups. Whole-heart radioactivity was determined with an external gamma detector. Myocardial flow rate (K ₁, ml/min) and clearance rate (k ₂, min⁻¹) were calculated. Results K _1TL, K _1TF, and K _1MIBI decreased according to the severity of ischemia (K _1TL 5.32 ± 0.53, 4.76 ± 0.70, and 1.44 ± 0.59; K _1TF 3.80 ± 0.70, 2.73 ± 0.99, and 1.09 ± 0.45; and K _1MIBI 3.45 ± 1.10, 2.15 ± 0.82, and 1.05 ± 0.13, in the normal control, mild, and severe ischemia groups, respectively). K ₁ was significantly higher for TL than for the ^99mTc tracers (P < 0.05), but the ^99mTc tracers had equivalent K ₁ values. k _2TL increased significantly (P < 0.05) in the ischemia groups (k _2TL 0.062 ± 0.013, 0.11 ± 0.045, and 0.12 ± 0.035), but showed no significant difference between the ischemia groups. k _2MIBI and k _2TF were significantly (P < 0.05) lower than k _2TL and increased significantly (P < 0.05) in the severe ischemia group (k _2TF 0.0056 ± 0.0022, 0.0037 ± 0.0015, and 0.024 ± 0.015; and k _2MIBI 0.00072 ± 0.0011, 0.00038 ± 0.00076, and 0.042 ± 0.034). k _2MIBI was significantly (P < 0.05) lower than k _2TF in the normal control and mild ischemia groups. Conclusions Tracer extraction was higher for TL than for the ^99mTc tracers and all tracers decreased according to the severity of ischemia–reperfusion in the three tracer groups. The clearance kinetics of not only MIBI but also TF is possibly useful for the evaluation of the severity of ischemia, and the Langendorff method and a methodological approach by continuous determinations of radioactivity may serve for the quantitative analysis of tracer kinetic profiles.     

Comparison of <Superscript>99m</Superscript>Tc-annexin A5 with <Superscript>18</Superscript>F-FDG for the detection of atherosclerosis in ApoE−/− mice

Purpose ^99mTc-annexin A5, a marker of ongoing apoptosis, and ¹⁸F-FDG, a marker of the increased metabolism of inflammatory cells, are supposed to be useful in the detection of metabolically active atheroma. This study reports a comparison of the intralesional distribution of these tracers in relation to lesion development in ApoE−/− mice. Methods Male ApoE−/− mice (n = 12–14/group) were maintained on a Western-type diet after the age of 5 weeks. At 25 weeks, ^99mTc-annexin A5 or ¹⁸F-FDG was injected and the aortas were harvested for autoradiography (ARG) and Oil Red O staining. Regional radioactivity accumulation was compared in relation to the Oil Red O staining score (ranging from 0 to 3, a semiquantitative parameter for evaluating lesion development). Results Both ^99mTc-annexin A5 and ¹⁸F-FDG showed preferential uptake into atherosclerotic lesions, with higher uptake levels for ¹⁸F-FDG (mean, 56.07 %ID×kg/m²) than for ^99mTc-annexin A5 (mean, 10.38 %ID×kg/m²). The regional uptake levels of each tracer correlated with the Oil Red O staining score (r = 0.65, p < 0.05 for ^99mTc-annexin A5; r = 0.56, p < 0.05 for ¹⁸F-FDG). The uptake ratios of advanced lesions (score >0.5) to early lesions (score <0.5) were significantly higher for ^99mTc-annexin A5 than for ¹⁸F-FDG (f = 4.73, p = 0.03). Conclusion Both ^99mTc-annexin A5 and ¹⁸F-FDG accumulate in atherosclerotic lesions and correlate with the severity of each lesion. The higher absolute uptake levels of ¹⁸F-FDG may be advantageous for lesion detection, whereas the preferential uptake of ^99mTc-annexin A5 in advanced lesions may be a useful indicator of late-stage lesions or vulnerable plaque transformation.     

The effect of collateral flow and myocardial viability on the distribution of technetium-99m sestamibi in a closed-chest model of coronary occlusion and reperfusion

Myocardial uptake of technetium-99m sestamibi at low coronary flow rates overestimates blood flow, but the relative impact of flow and viability on ^99mTc-sestamibi kinetics is unclear. The objective of this study was to determine the effect of myocardial viability and the degree of collateral blood flow on the uptake and retention of ^99mTc-sestamibi by examining three animal models of coronary occlusion and reperfusion, each reflecting a different state of viability and collateral blood flow. Three closed-chest animal models were studied: canine (high collateral flow, preserved viability), porcine (low collateral flow, absent viability) and porcine with slowly occlusive coronary stents producing infarction and enhanced collateral blood flow (high collateral flow, absent viability). There were seven dogs, seven pigs and six pigs, respectively, in each animal model. Animals from all three models were subjected to a 40-min total left anterior descending artery (LAD) occlusion followed by 2 h of reperfusion. ^99mTc-sestamibi and radiolabelled microspheres were injected during LAD occlusion 10 min prior to reperfusion. Animals were sacrificed after 2 h of reperfusion flow. Ex situ heart slice imaging to determine risk area was followed by viability staining to determine infarct size. Slices were subsequently sectioned into equally sized radial segments and placed in a gamma well counter. Risk area as determined by ex situ ^99mTc-sestamibi imaging was not significantly different by model. Pathological infarct size differed significantly by model [canine = 1%±1% of the left ventricle (LV); porcine = 13%±8% LV; porcine with stent = 14%±7% LV; P=0.002)]. Collateral blood flow by microspheres during occlusion tended to differ among models (overall P=0.08), with the canine and porcine with stent models having relatively high flow rates compared with the acute porcine model. ^99mTc-sestamibi activity correlated with microsphere blood flow in all three models, with r values for individual animals (n=20) ranging from 0.86 to 0.96 (all P<0.0001). There was a significant difference in the regression line intercepts (P<0.0001) and slopes (P<0.01) among the three models comparing ^99mTc-sestamibi uptake with myocardial blood flow. ^99mTc-sestamibi uptake overestimated blood flow to a greater extent in the canine model (high flow with viability) than in the porcine model (low flow, absent viability). Despite enhanced collateral flow, there was significantly less overestimation of flow in the porcine stent model (high flow, absent viability). In conclusion, at low flow rates ^99mTc-sestamibi activity overestimates myocardial blood flow. This effect is most pronounced in myocardium with significant collateral flow and preserved viability, consistent with over-extraction or redistribution of the tracer. The effect is markedly decreased in non-viable myocardium regardless of blood flow. Received: 18 October and in revised form 18 December 1999     

Estimate of myocardial salvage in late presentation acute myocardial infarction by comparing functional and perfusion abnormalities in predischarge gated SPECT

Purpose We hypothesized that, because of persistent stunning, the extent of post-treatment functional abnormalities detected using gated single-photon emission computed tomography (SPECT) could be representative of the initial risk area in acute myocardial infarction (AMI) treated by reperfusion therapy. Materials and methods In 48 AMI patients, we acquired two ^99mTc-sestamibi gated SPECT studies (at admission with tracer injection before treatment and at discharge 5 to 10 days later). We assessed the myocardial salvage defined by the admission minus predischarge summed rest score, and we compared it with the value obtained by subtracting the extent of perfusion defect from the extent of wall motion or wall thickening abnormalities in predischarge gated SPECT. Myocardial salvage was expressed as salvage index (salvaged myocardium divided by initial risk area). Results There was a good correlation between summed rest score salvage index and wall motion (Spearman’s ρ = 0.754, p < 0.0001) or wall thickening salvage index (Spearman’s ρ = 0.798, p < 0.0001). The wall thickening salvage index was able to classify correctly the patients that had a summed rest score salvage index ≥ 0.10 with 73% sensitivity, 88% specificity, and 83% accuracy. The wall motion salvage index was highly sensitive (91%) but poorly specific (13%, p < 0.002 vs wall thickening salvage index) and less accurate (69%, p < 0.05 vs wall thickening salvage index). Conclusions ^99mTc-sestamibi gated SPECT allows assessing myocardial salvage using only post-treatment data. The salvage index derived using wall thickening as surrogate of admission perfusion defect correlates well with the salvage index measured by comparing pre- and post-treatment perfusion defects.     

Agreement and disagreement between contrast-enhanced magnetic resonance imaging and nuclear imaging for assessment of myocardial viability

Purpose  The purpose of this study was to compare contrast-enhanced MRI and nuclear imaging with ^99mTc-tetrofosmin and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) single photon emission computed tomography (SPECT) for assessment of myocardial viability. Methods  Included in the study were 60 patients with severe ischaemic left ventricular (LV) dysfunction who underwent contrast-enhanced MRI, ^99mTc-tetrofosmin and ¹⁸F-FDG SPECT. Myocardial segments were assigned a wall motion score from 0 (normokinesia) to 4 (dyskinesia) and a scar score from 0 (no scar) to 4 (76–100% transmural extent). Furthermore, ^99mTc-tetrofosmin and ¹⁸F-FDG segmental tracer uptake was categorized from 0 (tracer activity >75%) to 3 (tracer activity <25%). Dysfunctional segments were classified into viability patterns on SPECT: normal perfusion/¹⁸F-FDG uptake, perfusion/¹⁸F-FDG mismatch, and mild or severe perfusion/¹⁸F-FDG match. Results  Minimal scar tissue was observed on contrast-enhanced MRI (scar score 0.4±0.8) in segments with normal perfusion/¹⁸F-FDG uptake, whereas extensive scar tissue (scar score 3.1±1.0) was noted in segments with severe perfusion/¹⁸F-FDG match (p < 0.001). High agreement (91%) for viability assessment between contrast-enhanced MRI and nuclear imaging was observed in segments without scar tissue on contrast-enhanced MRI as well as in segments with transmural scar tissue (83%). Of interest, disagreement was observed in segments with subendocardial scar tissue on contrast-enhanced MRI. Conclusion  Agreement between contrast-enhanced MRI and nuclear imaging for assessment of viability was high in segments without scar tissue and in segments with transmural scar tissue on contrast-enhanced MRI. However, evident disagreement was observed in segments with subendocardial scar tissue on contrast-enhanced MRI, illustrating that the nonenhanced epicardial rim can contain either normal or ischaemically jeopardized myocardium.     

In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients

Technetium-99m sestamibi is a transport substrate recognised by the multidrug-resistant P-glycoprotein (Pgp). To test whether^99mTc-sestamibi efflux is enhanced in breast carcinomas overexpressing Pgp, we determined the efflux rates of^99mTc-sestamibi and Pgp levels in tumours from 30 patients with untreated breast carcinoma. Patients were intravenously injected with 740 MBq of^99mTc-sestamibi and underwent a 15-min dynamic study followed by the acquisition of static planar images at 0.5, 1, 2 and 4 h. Tumour specimens were obtained from each patient 24 h after^99mTc-sestamibi scan and Pgp levels were determined using¹²⁵I-MRK16 monoclonal antibody and in vitro quantitative autoradiography. All breast carcinomas showed high uptake of^99mTc-sestamibi and data from region of interest analysis on sequential images were fitted with a monoexponential function. The efflux rates of^99mTc-sestamibi, calculated from decay-corrected time-activity curves, ranged between 0.00121 and 0.01690 min⁻¹ and were directly correlated with Pgp levels measured in the same tumours (r=0.62;P<0.001). Ten out of 30 breast carcinomas (33%) contained 5 times more Pgp than benign breast lesions and showed a mean concentration of 5.73±1.63 pmol/g of tumour (group A). The remaining 20 breast carcinomas had a mean Pgp concentration of 1.29±0.64 pmol/g (group B), equivalent to that found in benign breast lesions.^99mTc-sestamibi efflux from tumours of group A was 2.7 times higher than that observed in tumours of group B (0.00686±0.00390 min⁻¹ vs 0.00250±0.00090 min⁻¹,P<0.001). The in vivo functional test with^99mTc-sestamibi showed a sensitivity and a specificity of 80% and 95%, respectively. In conclusion, the efflux rate of^99mTc-sestamibi may be used for the in vivo identification of the multidrug resistant (MDR1) phenotype in untreated breast cancer patients.     

Assessment of coronary flow reserve by sestamibi imaging in patients with typical chest pain and normal coronary arteries

Purpose We assessed coronary flow reserve (CFR) by sestamibi imaging in patients with typical chest pain, positive exercise stress test and normal coronary vessels. Methods Thirty-five patients with typical chest pain and normal angiogram and 12 control subjects with atypical chest pain underwent dipyridamole/rest ^99mTc-sestamibi imaging. Myocardial blood flow (MBF) was estimated by measuring first transit counts in the pulmonary artery and myocardial counts from SPECT images. Estimated CFR was expressed as the ratio of stress to rest MBF. Rest MBF and CFR were corrected for rate–pressure product (RPP) and expressed as normalised MBF (MBF_n) and normalised CFR (CFR_n). Coronary vascular resistances (CVR) were calculated as the ratio between mean arterial pressure and estimated MBF. Results At rest, estimated MBF and MBF_n were lower in controls than in patients (0.98 ± 0.4 vs 1.30 ± 0.3 counts/pixel/s and 1.14 ± 0.5 vs 1.64 ± 0.6 counts/pixel/s, respectively, both p < 0.02). Stress MBF was not different between controls and patients (2.34 ± 0.8 vs 2.01 ± 0.7 counts/pixel/s, p=NS). Estimated CFR was 2.40 ± 0.3 in controls and 1.54 ± 0.3 in patients (p < 0.0001). After correction for the RPP, CFR_n was still higher in controls than in patients (2.1 ± 0.5 vs 1.29 ± 0.5, p < 0.0001). At baseline, CVR values were lower (p < 0.01) in patients than in controls. Dipyridamole-induced changes in CVR were greater (p < 0.0001) in controls (−63%) than in patients (−35%). In the overall study population, a significant correlation between dipyridamole-induced changes in CVR and CFR was observed (r = −0.88, p < 0.0001). Conclusion SPECT might represent a useful non-invasive method for assessing coronary vascular function in patients with angina and a normal coronary angiogram.     

Early detection and monitoring of cartilage alteration in the experimental meniscectomised guinea pig model of osteoarthritis by <Superscript>99m</Superscript>Tc-NTP 15-5 scintigraphy

Purpose This study in the meniscectomised guinea pig aimed to demonstrate that the radiotracer ^99mTc-NTP 15-5 would have pathophysiological validity for in vivo osteoarthritis imaging. Methods The specificity of ^99mTc-NTP 15-5 for cartilage was determined in healthy animals (n = 13), by tissue radioactivity counting, joint autoradiography and scintigraphy. ^99mTc-NTP 15-5 scintigraphy was performed at 20, 50, 80, 115, 130, 150 and 180 days after medial meniscectomy (n = 10 MNX) or sham operation (n = 5), and scintigraphic ratios (operated/contralateral) were calculated for femoral (F) and tibial (T) areas. F and T ratios were compared with those of ^99mTc-MDP bone scintigraphy. At the study end-point, autoradiographic analysis of joint ^99mTc-NTP 15-5 distribution and macroscopic scoring of cartilage integrity were performed. Results The high and specific accumulation of ^99mTc-NTP 15-5 in normal cartilage (about 5.5 ± 1.7 % of injected dose/g of tissue), which permitted joint imaging with high contrast, was affected by osteoarthritis. In the MNX group, ^99mTc-NTP 15-5 accumulation in cartilage within the operated joint, relative to the contralateral joint, was observed to change in the same animals as pathology progressed. Although F and T ratios were significantly higher in MNX (F = 1.7 ± 0.2; T = 1.6 ± 0.1) than in shams (F = 1.0 ± 0.1; T = 1.0 ± 0.1) at day 50, they were significantly lower in MNX (F = 0.6 ± 0.1; T = 0.7 ± 0.1) than in shams (F = 1.0 ± 0.1; T = 0.9 ± 0.1) at day 180. No change in ^99mTc-MDP uptake was observed over 6 months. Macroscopic analysis confirmed features of osteoarthritis only in MNX knees. Conclusion These results in MNX guinea pigs provide additional support for the use of ^99mTc-NTP 15-5 for in vivo imaging of osteoarthritis.     

Prediction of functional recovery after revascularization using quantitative gated myocardial perfusion SPECT: a multi-center cohort study in Japan

Backgrounds  Prediction of left ventricular functional recovery is important after myocardial infarction. The impact of quantitative perfusion and motion analyses with gated single-photon emission computed tomography (SPECT) on predictive ability has not been clearly defined in multi-center studies. Methods  A total of 252 patients with recent myocardial infarction (n = 74) and old myocardial infarction (n = 175) were registered from 25 institutions. All patients underwent resting gated SPECT using ^99mTc-hexakis-2-methoxy-isobutyl isonitrile (MIBI) and repeated the study after revascularization after an average follow-up period of 132 ± 81 days. Visual and quantitative assessment of perfusion and wall motion were performed in 5,040 segments. Results  Non-gated segmental percent uptake and end-systolic (ES) percent uptake were good predictors of wall motion recovery and significantly differed between improved and non-improved groups (66 ± 17% and 55 ± 18%, p < 0.0001 for non-gated; 64 ± 16% and 51 ± 17% for ES percent uptake, p < 0.0001). The area under the curve of receiver operating characteristics curve for non-gated percent uptake, ES percent uptake, end-diastolic percent uptake and visual perfusion defect score was 0.70, 0.71, 0.61, and 0.56, respectively. Sensitivity and specificity of percent uptake were 68% and 64% for non-gated map and 80% and 52% for ES percent uptake map. An optimal threshold for predicting segmental improvement was 63% for non-gated and 52% for ES percent uptake values. Conclusion  Segmental ^99mTc-MIBI uptake provided a useful predictor of wall motion improvement. Application of quantitative approach with non-gated and ES percent uptake enhanced predictive accuracy over visual analysis particularly in a multi-center study.     

Molecular imaging of vascular cell adhesion molecule-1 expression in experimental atherosclerotic plaques with radiolabelled B2702-p

Purpose VCAM-1 plays a major role in the chronic inflammatory processes present in vulnerable atherosclerotic plaques. The residues 75–84 (B2702-p) and 84–75/75–84 (B2702-rp) of the major histocompatibility complex-1 (MHC-1) molecule B2702 were previously shown to bind specifically to VCAM-1. We hypothesised that radiolabelled B2702-p and B2702-rp might have potential for the molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic plaques. Methods Preliminary biodistribution studies indicated that ¹²⁵I-B2702-rp was unsuitable for in vivo imaging owing to extremely high lung uptake. ¹²³I- or ^99mTc-labelled B2702-p was injected intravenously to Watanabe heritable hyperlipidaemic rabbits (WHHL, n = 6) and control animals (n = 6). After 180 min, aortas were harvested for ex vivo autoradiographic imaging, gamma-well counting, VCAM-1 immunohistology and Sudan IV lipid staining. Results Robust VCAM-1 immunostaining was observed in Sudan IV-positive and to a lesser extent in Sudan IV-negative areas of WHHL animals, whereas no expression was detected in control animals. Significant 2.9-fold and 1.9-fold increases in ¹²³I-B2702-p and ^99mTc-B2702-p aortic-to-blood ratios, respectively, were observed between WHHL and control animals (p < 0.05). Tracer uptake on ex vivo images co-localised with atherosclerotic plaques. Image quantification indicated a graded increase in ¹²³I-B2702-p and ^99mTc-B2702-p activities from control to Sudan IV-negative and to Sudan IV-positive areas, consistent with the observed pattern of VCAM-1 expression. Sudan IV-positive to control area tracer activity ratios were 17.0 ± 9.0 and 5.9 ± 1.8 for ¹²³I-B2702-p and ^99mTc-B2702-p, respectively. Conclusion Radiolabelled B2702-p is a potentially useful radiotracer for the molecular imaging of VCAM-1 in atherosclerosis.     

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

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

Nitrate-enhanced gated SPECT in patients with primary angioplasty for acute myocardial infarction: evidence of a reversible and nitrate-sensitive impairment of myocardial perfusion

Purpose Reperfusion of myocardial infarction (MI) leads to a reversible dysfunction of coronary vessels. We hypothesised that vasodilating drugs such as nitrates might improve sestamibi uptake within viable areas of recently reperfused MI, thereby enhancing prediction of subsequent improvements in perfusion and contractility. This study was aimed at assessing nitrate-enhanced sestamibi gated SPECT after MI reperfusion. Methods Twenty-nine patients underwent rest followed by nitrate sestamibi gated SPECT at 9 ± 3 days after primary angioplasty for acute MI and at follow-up, 4–10 months later. Four MBq/kg of ^99mTc-sestamibi was injected at rest, and 12 MBq/kg after nitroglycerin spray. Results Follow-up improvements were documented for both perfusion (P+) and contractility (C+) in 18% of the 180 initially abnormal segments, in neither perfusion (P−) nor contractility (C−) in 44%, in contractility only (C+P−) in 16% and in perfusion only (C−P+) in 22%. Perfusion improvement was related to lower sestamibi uptake on baseline rest SPECT (P+: 42 ± 15% vs P−: 50 ± 15%, p = 0.001) and, moreover, to a higher increase between rest and nitrate uptake (P+: +9.5 ± 6.5% vs P−: +2.0 ± 5.9%, p < 0.001). Contractility improvement was related to sestamibi uptake on baseline nitrate SPECT (C+: 58 ± 15% vs C−: 38 ± 16%, p < 0.001), a variable enhancing the prediction provided by sestamibi uptake at rest (p < 0.05). Conclusion The improvement in perfusion which is documented in the months following MI reperfusion is predicted by initial nitrate enhancement of sestamibi uptake, suggesting a mechanism of reversible vascular injury. In this particular setting, sestamibi uptake is a better predictor of contractility recovery when determined after nitrate administration rather than under conventional resting conditions.     

Extraction and retention of technetium-99m Q12, technetium-99m sestamibi, and thallium-201 in isolated rat heart during coronary acidemia

Technetium-99m Q12 and ^99mTc-sestamibi are cationic lipophilic myocardial perfusion imaging tracers. Because myocardium in areas of ischemia becomes acidotic, experiments were designed to differentiate the effects of myocardial perfusate pH on radiotracer extraction and retention independent of substrate availability. We hypothesized that ^99mTc-Q12 and ^99mTc-sestamibi single-pass uptake and retention would be unaffected by a modest reduction in coronary perfusate pH. Isolated rat hearts were perfused at constant flow with Krebs-Henseleit buffer enriched with bovine red blood cells (20%). The indicator dilution method was used to measure the maximum extraction (E _max) and net extraction (E _net) of thallium-201 and ^99mTc-Q12 (n = 8) or ²⁰¹Tl and ^99mTc sestamibi (n = 7) during baseline perfusion (pH = 7.4), during acidemic (pH = 6.7) perfusion, and during a restitution period with normal perfusate (pH = 7.4). ²⁰¹Tl E _max (0.71±0.03) was greater than either ^99mTc-Q12 or ^99mTc-sestamibi E _max (0.27±0.02 and 0.26±0.01 respectively, P<0.0001). Acidemia significantly reduced ²⁰¹Tl E _max (0.65±0.03, P<0.02) but not ^99mTc-Q12 or ^99mTc-sestamibi E _max (0.25±0.02 and 0.24±0.02 respectively). During control perfusion E _net of ²⁰¹Tl was greater than that of ^99mTc-Q12 at 3 and 5 min and greater than that of ^99mTc-sestamibi at 3 min. ^99mTc-Q12 E _net was less than ^99mTc-sestamibi E _net at 3, 5, and 10 min. Acidemia decreased ²⁰¹Tl and ^99mTc-sestamibi E _net at 3, 5, and 10 min but had no effect on ^99mTc-Q12 E _net. It is concluded that E _max of ^99mTc-Q12 is less than that of ²⁰¹Tl but is not different from that of ^99mTc-sestamibi. E _net of ^99mTc-Q12 is less than that of ^99mTc-sestamibi. Received 20 May and in revised form 4 August 1997     

Dual-time-point <Superscript>18</Superscript>F-FDG PET imaging for diagnosis of disease type and disease activity in patients with idiopathic interstitial pneumonia

Purpose  Individual clinical courses of idiopathic interstitial pneumonia (IIP) are variable and difficult to predict because the pathology and disease activity are contingent, and chest computed tomography (CT) provides little information about disease activity. In this study, we applied dual-time-point [¹⁸F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) positron emission tomography (PET), commonly used for diagnosis of malignant tumours, to the differential diagnosis and prediction of disease progression in IIP patients. Methods  Fifty patients with IIP, including idiopathic pulmonary fibrosis (IPF, n = 21), non-specific interstitial pneumonia (NSIP, n = 18) and cryptogenic organizing pneumonia (COP, n = 11), underwent ¹⁸F-FDG PET examinations at two time points: scan 1 at 60 min (early imaging) and scan 2 at 180 min (delayed imaging) after ¹⁸F-FDG injection. The standardized uptake values (SUV) at the two points and the retention index (RI-SUV) calculated from them were evaluated and compared with chest CT findings, disease progression and disease types. To evaluate short-term disease progression, all patients were examined by pulmonary function test every 3 months for 1 year after ¹⁸F-FDG PET scanning. Results  The early SUV for COP (2.47 ± 0.74) was significantly higher than that for IPF (0.99 ± 0.29, p = 0.0002) or NSIP (1.22 ± 0.44, p= 0.0025). When an early SUV cut-off value of 1.5 and greater was used to distinguish COP from IPF and NSIP, the sensitivity, specificity and accuracy were 90.9, 94.3 and 93.5%, respectively. The RI-SUV for IPF and NSIP lesions was significantly greater in patients with deteriorated pulmonary function after 1 year of follow-up (progressive group, 13.0 ± 8.9%) than in cases without deterioration during the 1-year observation period (stable group, −16.8 ± 5.9%, p < 0.0001). However, the early SUV for all IIP types provided no additional information of disease progression. When an RI-SUV cut-off value of 0% and greater was used to distinguish progressive IIPs from stable IIPs, the sensitivity, specificity and accuracy were 95.5, 100 and 97.8%, respectively. Conclusion  Early SUV and RI-SUV obtained from dual-time-point ¹⁸F-FDG PET are useful parameters for the differential diagnosis and prediction of disease progression in patients with IIP.     

Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates

Purpose  Myocardial extractions of mitochondria complex I (MC-I) inhibitors were high and well correlated with flow. This study assessed the potential of MC-I inhibitors to be developed as myocardial perfusion imaging (MPI) agents. Methods  RP1003, RP1004, and RP1005 representing three classes of MC-I inhibitor were synthesized and radio-labeled with ¹⁸F. These agents were evaluated for IC₅₀ values, tissue biodistribution, and cardiac PET imaging. ¹⁸F-RP1004 was further examined for first-pass extraction and by imaging in non-human primates (NHP) and rats following coronary ligation. Results  RP1003, RP1004, and RP1005 exhibited high MC-I inhibitory activity with IC₅₀ of 3.7, 16.7, and 14.4 nM. Heart uptakes in rats (percent injected dose per gram tissue) at 15 and 60 min after injection were 3.52 ± 0.36 and 2.68 ± 0.20 for ¹⁸F-RP1003, 2.40 ± 0.21 and 2.67 ± 0.27 for ¹⁸F-RP1004, and 2.28 ± 0.12 and 1.81 ± 0.17 for ¹⁸F-RP1005. The heart to lung and liver uptake ratios were favorable for cardiac imaging with these agents. In isolated perfused rabbit hearts, the uptake of ¹⁸F-RP1004 increased from 0.74 ± 0.19 to 1.68 ± 0.39 mL/min/g at flow rates of 1.66 to 5.06 mL/min/g. These values were higher than or similar to that of ^99mTc-sestamibi. Cardiac imaging with these agents in rats and rabbits allowed visualization of the heart with minimal lung interference and rapid liver activity clearance. Imaging with ¹⁸F-RP1004 also showed clear myocardium and marked liver activity washout in the NHP and clear detection of the perfusion-deficit area associated with left coronary artery ligation in the rat. Conclusion  MC-I inhibitors have the potential to be a new class of MPI agent.     

Assessment of intra- and interobserver reproducibility of rest and cold pressor test-stimulated myocardial blood flow with <Superscript>13</Superscript>N-ammonia and PET

Purpose We investigated the intraobserver reproducibility of myocardial blood flow (MBF) measurements with PET at rest and during cold pressor test (CPT), and the interobserver agreement. Methods Twenty normal volunteers were studied. Using ¹³N-ammonia, MBF was measured at rest and during CPT and measurement was repeated in a 1-day session (short-term reproducibility; SR). After a follow-up of 2 weeks, MBF was measured again at rest and during CPT and compared with the initial baseline measurement (long-term reproducibility; LR). In addition, adenosine-induced hyperemic MBF increases were assessed. Results Assessment of the SR did not show a significant absolute difference in MBF at rest, MBF during CPT or the endothelium-related change in MBF from rest to CPT (ΔMBF) (0.09 ± 0.10, 0.11 ± 0.09, and 0.08 ± 0.05 ml/g/min; p = NS), and they were linearly correlated (r = 0.72, r = 0.76 and r = 0.84; p < 0.0001). Corresponding values for standard error of the estimate (SEE), as indicative for the range of MBF measurement error, were 0.14, 0.14, and 0.09 ml/g/min. The LR yielded relatively higher but non-significant absolute differences in the MBF at rest, MBF during CPT and ΔMBF (0.10 ± 0.10, 0.14 ± 0.10, and 0.19 ± 0.10 ml/g/min; p = NS), and paired MBFs significantly correlated (r = 0.75, r = 0.71, and r = 0.60; p < 0.001). Corresponding SEEs were 0.13, 0.15, and 0.16 ml/g/min. The interobserver analysis yielded a high correlation for MBF at rest, MBF during CPT, and hyperemic MBF (r = 0.96, SEE=0.04; r = 0.78, SEE=0.11; and r = 0.87, SEE=0.28; p < 0.0001, respectively), and also a good interobserver correlation for ΔMBF (r = 0.62, SEE=0.09; p < 0.003). Conclusion Short- and long-term MBF responses to CPT, as an index for endothelium-related coronary vasomotion, can be measured reproducibly with ¹³N-ammonia PET. In addition, the high interobserver reproducibility for repeat analysis of MBF values suggests the measurements to be largely operator independent. Thomas H. Schindler and Xiao-Li Zhang contributed equally to this paper.     

Evaluation of right ventricular function with multidetector computed tomography: comparison with magnetic resonance imaging and analysis of inter- and intraobserver variability

This study was performed to prospectively compare multidetector computed tomography (MDCT) with 16 simultaneous sections and magnetic resonance imaging (MRI) for the assessment of global right ventricular function in 50 patients. MDCT using a semiautomatic analysis tool showed good correlation with MRI for end-diastolic volume (EDV, r = 0.83, p < 0.001), end-systolic volume (ESV, r = 0.86, p < 0.001) and stroke volume (SV, r = 0.74, p < 0.001), but only a moderate correlation for the ejection fraction (EF, r = 0.67, p < 0.001). Bland Altman analysis revealed a slight, but insignificant overestimation of EDV (4.0 ml, p = 0.08) and ESV (2.4 ml, p = 0.07), and underestimation of EF (0.1%, p = 0.92) with MDCT compared with MRI. All limits of agreement between both modalities (EF: ±15.7%, EDV: ±31.0 ml, ESV: ±18.0 ml) were in a moderate but acceptable range. Interobserver variability of MDCT was not significantly different from that of MRI. For MDCT software, the post-processing time was significantly longer (19.6 ± 5.8 min) than for MRI (11.8 ± 2.6 min, p < 0.001). Accurate assessment of right ventricular volumes by 16-detector CT is feasible but still rather time-consuming.