Evaluation of novel cationic 99mTc(I)-tricarbonyl complexes as potential radiotracers for myocardial perfusion imaging

This report describes the evaluation of three cationic ^99mTc(I)–tricarbonyl complexes — [^99mTc(CO)₃(L)]⁺ (L=N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (ME-PNP), N-[15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (15C5-PNP) and N-[18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (18C6-PNP)) — as potential radiotracers for myocardial perfusion imaging. Biodistribution, imaging and metabolism studies were performed using Sprague–Dawley rats. It was found that bisphosphine ligands have a significant impact on the biodistribution characteristics and clearance kinetics of their cationic ^99mTc(I)–tricarbonyl complexes. Among the three radiotracers evaluated in this study, [^99mTc(CO)₃(15C5-PNP)]⁺ has a very high initial heart uptake and is retained in the rat myocardium for >2 h. It also shows rapid clearance from the liver and lungs. The heart/liver ratio of [^99mTc(CO)₃(15C5-PNP)]⁺ is 2.5 times better than that of ^99mTc-sestamibi at 30 min postinjection. [^99mTc(CO)₃(15C5-PNP)]⁺ is almost identical to ^99mTcN-DBODC5 with respect to heart uptake, heart/lung ratio and heart/liver ratio. Results from metabolism studies show that there is no significant metabolism for [^99mTc(CO)₃(15C5-PNP)]⁺ in the urine, but it does show a small metabolite peak (<10%) in the radio high-performance liquid chromatography chromatogram of the feces sample at 120 min postinjection. Results planar imaging studies demonstrate that [^99mTc(CO)₃(15C5-PNP)]⁺ has a much better liver clearance profile than ^99mTc-sestamibi and might give clinically useful images of the heart as early as 30 min postinjection. [^99mTc(CO)₃(15C5-PNP)]⁺ is a very promising candidate for more preclinical evaluations in various animal models.     

<Superscript>99m</Superscript>Tc sestamibi myocardial perfusion scintigraphy with the novel use of metamizol for the detection of perfusion reversibility

PURPOSE: This study aims to investigate whether induction with metamizol, an analgesic-antipyretic drug having spasmolitic activity, could be used to increase the detectability of ischemic/jeopardized myocardium during MPS (myocardial perfusion scintigraphy). MATERIALS AND METHODS: Metamizol-enhanced rest MPS (45 min after administration of 1 g metamizol orally, 740 MBq (99m)Tc sestamibi was injected, MPS was acquired 45 min later) was performed in 21 patients who had perfusion defects on their previous stress-rest (99m)Tc sestamibi MPS. Blood pressure was monitored at 15-min intervals. Stress, rest, metamizol-rest MPS images were interpreted on the model of 20 segments using a visual uptake score (VUS; 0 = normal, 1 = mild, 2 = moderate, 3 = significant decreases, 4 = no uptake). (99m)Tc sestamibi uptake ratios (MIBI-UR; mean counts in the region of the perfusion defect/mean counts in the region of the normal-perfused wall) were obtained on each MPS and compared with each other. Average MIBI-UR in each scintigraphic examination was calculated. MPS were compared with coronary angiography results. RESULTS: VUS and MIBI-UR results showed that metamizol-rest MPS displayed the defect reversibility better than rest MPS. Of the 14 segments with fixed perfusion defects on stress-rest MPS, 8 showed improvement of perfusion after metamizol induction. In 33 segments, lesion reversibility was better delineated on metamizol-rest MPS. Metamizol-induced sestamibi uptake was significantly higher (p < 0.001) than stress/baseline rest examinations as calculated by the MIBI-UR. Blood pressure remained unaltered. Coronary angiography results were in concordance with metamizol induced MPS. CONCLUSIONS: Metamizol-enhanced rest MPS increases detectability of ischemic/viable myocardium during MPS. Metamizol should be discontinued like nitrates before stress MPS since it may mask the visualization of ischemic perfusion defects.     

In vivo imaging of radiation-induced tissue apoptosis by <Superscript>99m</Superscript>Tc(I)-his<Subscript>6</Subscript>-annexin A5

Objective  

A recombinant annexin A5 with the N-terminal extension of six histidine residues was labeled with ^99mTc(I)-tricarbonyl ion to produce the ^99mTc-labeled annexin A5, referred to ^99mTc(I)-his₆-annexin A5. We have explored the agent as an effective imaging probe for in vivo detecting the apoptosis of internal tissue subjected with high radiation doses in a γ-irradiated mouse model.     

[<Superscript>99m</Superscript>Tc]Demobesin 1, a novel potent bombesin analogue for GRP receptor-targeted tumour imaging

Demobesin 1 is a potent new GRP-R-selective bombesin (BN) analogue containing an open chain tetraamine chelator for stable technetium-99m binding. Following a convenient labelling protocol, the radiopeptide, [(99m)Tc]Demobesin 1, formed in nearly quantitative yields and with high specific activities. Both unlabelled and labelled peptide demonstrated high-affinity binding in membrane preparations of the human androgen-independent prostate adenocarcinoma PC-3 cell line. The IC(50) values determined for Demobesin 1 and [Tyr(4)]BN were 0.70+/-0.08 n M and 1.5+/-0.20 n M, respectively, while the K(d) defined for [(99m)Tc/(99g)Tc]Demobesin 1 was 0.67+/-0.10 n M. [(99m)Tc]Demobesin 1 was rather stable in murine plasma, whereas it degraded rapidly in kidney and liver homogenates. After injection in healthy Swiss albino mice, [(99m)Tc]Demobesin 1 accumulated very efficiently in the target organs (pancreas, intestinal tract) via a GRP-R-mediated process, as shown by in vivo receptor blocking experiments. An equally high and GRP-R-mediated uptake was exhibited by [(99m)Tc]Demobesin 1 after injection in PC-3 tumour-bearing athymic mice. The initial high radioligand uptake of 16.2+/-3.1%ID/g in the PC-3 xenografts at 1 h p.i. remained at a similar level (15.61+/-1.19%ID/g) at 4 h p.i. Even after 24 h p.i., when the radioactivity had cleared from all other tissues, a value of 5.24+/-0.67%ID/g was still observed in the tumour. The high and prolonged localization of [(99m)Tc]Demobesin 1 at the tumour site and its rapid background clearance are very promising qualities for GRP-R-targeted tumour imaging in man.     

Single-photon agents for tumor imaging:<Superscript>201</Superscript>TI,<Superscript>99m</Superscript>Tc-MIBI,and<Superscript>99m</Superscript>Tc-tetrofosmin

This review aims at fostering comprehension and knowledge not only for expert physicians who can skillfully handle various techniques for tumor imaging but also for young practitioners in the field of nuclear medicine. As image processing software and hardware become smaller, faster and better, SPECT will adapt and incorporate these advances. A principal advantage of SPECT over PET is the more widespread availability of the equipment and lower cost for the introduction of the system in community-based facilities. Moreover, SPECT has become less dependent on a limited number of acknowledged experts for its interpretation owing to a variety of handy computer tools for imaging analyses. The increasing use of PET in tumor imaging is not necessarily proportional to the decline of SPECT. General physicians' attention to SPECT technology would also increase more by evoking their interest in "tracer imaging."     

Questionnaire survey of hospitals in Saitama Prefecture regarding the shortage of <Superscript>99m</Superscript>Tc-labeled radiopharmaceuticals and <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generators

Objective and methods  

A questionnaire survey was conducted at all 32 hospitals in Saitama Prefecture to investigate the current difficult situation in terms of nuclear medicine management in the face of the ^99mTc shortage due to insufficient supply, and 29 hospitals (90.6%) replied.     

Effect of increased <Superscript>99m</Superscript>Tc/<Superscript>99</Superscript>Tc ratios on count rates in sentinel node procedures: a randomised study

The aim of this study was to evaluate the count rates of sentinel lymph nodes (SLNs) in patients with breast cancer in the operating theatre, using ^99mTc-Nanocoll with different ratios of technetium-99m to technetium-99. After written informed consent had been obtained, we tested different ratios of ^99mTc/⁹⁹Tc-Nanocoll in a double-blinded randomised study performed in 161 patients. Twenty-five MBq/g ^99mTc-colloid albumin was prepared in vacuum. In 87 patients (group A) a 2-h elution was used and in 74 patients (group B) a 24-h elution was used. Patients were subcategorised into subgroups 1 and 3, in which an SLN procedure for breast carcinoma was performed simultaneously with lumpectomy, and subgroups 2 and 4, in which an SLN procedure was performed 2–3 weeks after prior excision biopsy. All patients were injected along the lateral border of the areola (two injections: 50 MBq/0.3 ml intradermally and 50 MBq/2 ml intraparenchymally). Ex vivo measurement of count rates was performed with a gamma probe. Comparing groups A and B in respect of registered counts per second (cps) of excised SLNs, a significant difference was found (P<0.004). When comparisons were made between subgroups 1 and 2 (2-h elution) and between subgroups 3 and 4 (24-h elution) in respect of registered cps of excised SLNs, no significant difference was found (subgroup 1 vs 2, P=0.825; subgroup 3 vs 4, P=0.915). Use of a 2-h elution in vacuum yielded a significantly higher count rate of maximum specific activity of ^99mTc-colloid albumin in SLNs than was achieved using a 24-h elution in vacuum. SLN procedures performed 2–3 weeks after prior excision biopsy proved reliable as compared to SLN procedures performed simultaneously with lumpectomy.     

<Superscript>99m</Superscript>Tc-ECD brain perfusion SPECT in hyperalgesic fibromyalgia

Purpose Neuro-imaging studies with ^99mTc-HMPAO SPECT in fibromyalgia (FM) patients have reported only limited subcortical hypoperfusion. ^99mTc-ECD SPECT is known to provide better evaluation of areas of high cerebral blood flow and regional metabolic rate. We evaluated a homogeneous group of hyperalgesic patients with FM using ^99mTc-ECD SPECT. The aim of this study was to investigate brain processing associated with spontaneous pain in FM patients. Methods Eighteen hyperalgesic FM women (mean age 49 years, range 25–63 years; American College of Rheumatology criteria) and ten healthy women matched for age were enrolled in the study. A voxel-by-voxel group analysis was performed using SPM2 (p<0.05, corrected for multiple comparisons). Visual Analogue Scale score for pain was 82±4 at the time of the SPECT study. Results Compared with control subjects, we observed individual brain SPECT abnormalities in FM patients, confirmed by SPM2 analysis, with hyperperfusion of the somatosensory cortex and hypoperfusion of the frontal, cingulate, medial temporal and cerebellar cortices. Conclusion In the present study, performed without noxious stimuli in hyperalgesic FM patients, we found significant hyperperfusion in regions of the brain known to be involved in the sensory dimension of pain processing and significant hypoperfusion in areas assumed to be associated with the affective-attentional dimension. As current pharmacological and non-pharmacological therapies act differently on the two components of pain, we hypothesise that SPECT could be a valuable and readily available tool to guide individual therapeutic strategy and provide objective follow-up of pain processing recovery under treatment.     

Long-term prognostic value of exercise <Superscript>99m</Superscript>Tc-MIBI SPET myocardial perfusion imaging in patients after percutaneous coronary intervention

The purpose of this study was to evaluate the long-term prognostic value of exercise technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI) single-photon emission tomography (SPET) imaging in patients after percutaneous coronary intervention (PCI). Three hundred and eighteen consecutive post-PCI patients who underwent exercise and rest ^99mTc-MIBI SPET myocardial perfusion imaging (MPI) were followed up for 38±27 months. Patients with early revascularisation (<3 months after MPI) were excluded. A semiquantitative visual analysis employing a 20-segment and four-point scoring system was used to define the summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS). Death and non-fatal myocardial infarction (MI) were considered as hard events, and late revascularisation procedures (3 months after MPI) as soft events. Fifty-one patients (16.0%) suffered from cardiac events during follow-up, including 1 (0.3%) death, 13 (4.1%) non-fatal MIs, 9 (2.8%) coronary artery bypass grafting procedures and 28 (8.8%) PCIs. According to the SPET results, patients were classified into three groups: patients with normal MPI (SSS=0, n=153), patients with irreversible defects (SDS<3 and SRS>1, n=100) and patients with reversible defects (SDS3, n=65). The annual hard cardiac event rate in patients with reversible defects was 3.9%, which was significantly higher than that in patients with normal MPI (0.2%, ²=7.71; P<0.01). The annual soft cardiac event rate in patients with reversible defects was 10.7%, which was significantly higher than that in patients with irreversible defects (2.5% ²=17.69; P<0.001), and also significantly higher than that in patients with normal MPI (1.5%, ²=33.89; P<0.001). In patients with normal and reversible defects, there was no significant difference in soft and hard cardiac event rates according to whether patients were symptomatic or asymptomatic (P>0.05). However, the annual soft event rate in patients with irreversible defects and symptoms was 5.0%, which was higher than that of 0.6% in asymptomatic patients (²=6.11, P<0.05). Multivariate Cox analysis showed that SSS was the best independent predictor for hard cardiac events (²=12.70; P<0.001) and SDS was the strongest independent predictor for soft cardiac events (²=11.72; P<0.001). Post-PCI patients who have normal exercise ^99mTc-MIBI SPET MPI have a good long-term prognosis, while those with reversible defects are at a higher risk for future cardiac events, without correlation to the chest pain symptoms. However, symptomatic patients with irreversible defects have a higher risk for repeat revascularisation, but not for hard events, compared with asymptomatic patients. Exercise ^99mTc-MIBI SPET MPI has important clinical value for risk stratification and management decision-making in post-PCI patients.     

Simultaneous <Superscript>99m</Superscript>Tc/<Superscript>201</Superscript>Tl dual-isotope SPET with Monte Carlo-based down-scatter correction

In simultaneous technetium-99m/thallium-201 dual-isotope (DI) single-photon emission tomography (SPET), down-scatter of (99m)Tc photons contaminates the (201)Tl image, which leads to a decrease in lesion contrast and loss of quantitative accuracy. Correction for down-scatter can be achieved by first reconstructing the (99m)Tc activity distribution. Subsequently, the (99m)Tc down-scatter in the (201)Tl photopeak window is simulated and used for correction during iterative reconstruction of the (201)Tl image. In this work, the down-scatter projections are calculated using a dedicated Monte Carlo simulator which is able to efficiently model the detection of lead X-rays from the collimator. An anthropomorphic torso phantom with a cardiac insert with and without cold lesions was used for evaluation of the proposed method. Excellent agreement in lesion contrast and quantitative accuracy was found between the down-scatter corrected DI-SPET (201)Tl image and the virgin (i.e. separately acquired) (201)Tl image, in particular when the effects of lead X-rays were included. Compensation for the noise added by down-scatter to the (201)Tl image can be achieved by using a 15% lower dose of (99m)Tc, a 15% increase in scan time and a 12% increase in (201)Tl dose. In conclusion, the Monte Carlo-based down-scatter correction recovers lesion contrast and quantitative accuracy in DI-SPET (201)Tl images almost perfectly. In addition, degradations due to the added noise of down-scatter in simultaneous DI-SPET can be prevented by slight adaptations to the data acquisition protocol.     

Regional differences between <Superscript>99m</Superscript>Tc-ECD and <Superscript>99m</Superscript>Tc-HMPAO SPET in perfusion changes with age and gender in healthy adults

A number of studies using single-photon emission tomography (SPET) have shown perfusion changes with age in several cortical and subcortical areas, which might distort the results of perfusion imaging studies of neuropsychiatric disorders. Technetium-99m labelled ethyl cysteinate dimer (ECD) and hexamethylpropylene amine oxime (HMPAO) are both used as markers of cerebral perfusion, but have different pharmacokinetics and retention patterns. The aim of this study was to determine whether age and gender effects on perfusion SPET differ depending on whether ^99mTc-HMPAO or ^99mTc-ECD is used. Forty-five subjects (20 male and 25 female, mean age 52.8±6.6 years) were assigned to ^99mTc-HMPAO SPET (HMPAO group), and 39 subjects (24 male and 15 female, mean age 52.6±6.7 years) to ^99mTc-ECD SPET (ECD group). SPET images were obtained about 10 min after intravenous injection of approximately 800 MBq ^99mTc-HMPAO or ^99mTc-ECD using the same SPET scanner. Three-dimensional volumetric magnetic resonance imaging was performed to as7sess morphological changes in the grey matter. All image processing and statistical analyses were performed using SPM99 software. An area in the right anterior frontal lobe showed an increase in perfusion with age only in the HMPAO group, whereas areas in the bilateral retrosplenial cortex showed decreases in perfusion with age only in the ECD group; neither group showed corresponding changes in the grey matter. The present study shows that different effects of age on perfusion are observed depending on whether ^99mTc-HMPAO and ^99mTc-ECD is used. This suggests that the results of perfusion SPET are differently confounded depending on the tracer used, and that perfusion SPET with these tracers has limitations when used in research on subtle perfusion changes.     

Efficacy of <Superscript>99m</Superscript>Tc pertechnetate and <Superscript>131</Superscript>I radioisotope therapy in sodium/iodide symporter (NIS)-expressing neuroendocrine tumors in vivo

Purpose There is growing interest in the human sodium/iodide symporter (NIS) gene both as a molecular imaging reporter gene and as a therapeutic gene. Here, we show the feasibility of radioisotope therapy of neuroendocrine tumors. As a separate application of NIS gene transfer, we image NIS-expressing tumors with pinhole SPECT in living subjects. Methods Biodistribution studies and in vivo therapy experiments were performed in nude mice carrying stably NIS-expressing neuroendocrine tumor xenografts following i.v. injection of ¹³¹I and ^99mTc pertechnetate. To show the usefulness of NIS as an imaging reporter gene, ^99mTc pertechnetate uptake was imaged in vivo using a clinical gamma camera in combination with a custom-made single pinhole collimator, followed by SPECT/small animal MRI data coregistration. Results NIS-expressing neuroendocrine tumors strongly accumulated ¹³¹I and ^99mTc pertechnetate, as did thyroid, stomach, and salivary gland. The volume of NIS-expressing neuroendocrine tumors decreased significantly after therapeutic administration of ¹³¹I or ^99mTc pertechnetate, whereas control tumors continued to grow. NIS-mediated uptake of ^99mTc pertechnetate could be imaged in vivo at high resolution with a clinical gamma camera equipped with a custom-made single pinhole collimator. High-resolution functional and morphologic information could be combined in a single three-dimensional data set by coregistration of SPECT and small animal MRI data. Lastly, we demonstrated a therapeutic effect of ^99mTc pertechnetate on NIS-expressing neuroendocrine tumors in cell culture and, for the first time, in vivo, thought to be due to emitted Auger and conversion electrons. Conclusions NIS-expressing neuroendocrine tumors efficiently concentrate radioisotopes, allowing for in vivo high-resolution small animal SPECT imaging as well as rendering possible successful radioisotope therapy of neuroendocrine tumors.     

[<Superscript>99m</Superscript>Tc]Demotate,a new <Superscript>99m</Superscript>Tc-based [Tyr<Superscript>3</Superscript>]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results

Demotate is a new tetraamine-functionalised [Tyr3]octreotate derivative that binds technetium-99m with a high efficiency under mild conditions. The resulting radioligand, [99mTc]Demotate, forms in a high purity and is stable for at least 6 h after labelling. The affinity of the unlabelled peptide for somatostatin receptors is high (IC(50)=0.13 n M) and comparable to that of [Tyr3]octreotate or [Tyr3]octreotide, as demonstrated by competition binding experiments in rat brain cortex or AR42J cell membrane preparations. An equally very high affinity ( K(d)=0.07 n M) was exhibited by [99mTc/99gTc]Demotate during saturation binding experiments using rat brain cortex membrane homogenates. The radioligand resisted hydrolytic degradation in mouse plasma and was excreted intact in mouse urine. In vivo, [99mTc]Demotate cleared very rapidly from non-target tissues into the bladder via the kidneys, while radioactivity uptake in target organs was very high. In mice bearing the experimental AR42J tumour, [99mTc]Demotate demonstrated a very high tumour uptake at 1 h p.i. (25%ID/g) that remained high (20%ID/g) at 4 h p.i. This uptake could be effectively blocked by co-injection of a high dose of [Tyr3]octreotate together with the radioligand. High-quality planar and single-photon emission tomographic images were acquired 1 h after injection of [99mTc]Demotate in tumour-bearing mice, illustrating the excellent properties of this agent for somatostatin receptor tumour imaging.     

Simultaneous acquisition of <Superscript>99m</Superscript>Tc- and <Superscript>123</Superscript>I-labeled radiotracers using a preclinical SPECT scanner with CZT detectors

Objective

Simultaneous acquisition of ^99mTc and ¹²³I was evaluated using a preclinical SPECT scanner with cadmium zinc telluride (CZT)-based detectors.

Methods

10-ml cylindrical syringes contained about 37 MBq ^99mTc-tetrofosmin (^99mTc-TF) or 37 MBq ¹²³I-15-(p-iodophenyl)-3R,S-methyl pentadecanoic acid (¹²³I-BMIPP) were used to assess the relationship between these SPECT radioactive counts and radioactivity. Two 10-ml syringes contained 100 or 300 MBq ^99mTc-TF and 100 MBq ¹²³I-BMIPP to assess the influence of ^99mTc upscatter and ¹²³I downscatter, respectively. A rat-sized cylindrical phantom also contained both 100 or 300 MBq ^99mTc-TF and 100 MBq ¹²³I-BMIPP. The two 10-ml syringes and phantom were scanned using a pinhole collimator for rats. Myocardial infarction model rats were examined using 300 MBq ^99mTc-TF and 100 MBq ¹²³I-BMIPP. Two 1-ml syringes contained 105 MBq ^99mTc-labeled hexamethylpropyleneamine oxime (^99mTc-HMPAO) and 35 MBq ¹²³I-labeled N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (¹²³I-FP-CIT). The two 1-ml syringes were scanned using a pinhole collimator for mice. Normal mice were examined using 105 MBq ^99mTc-HMPAO and 35 MBq ¹²³I-FP-CIT.

Results

The relationship between SPECT radioactive counts and radioactivity was excellent. Downscatter contamination of ¹²³I-BMIPP exhibited fewer radioactive counts for 300 MBq ^99mTc-TF without scatter correction (SC) in 125–150 keV. There was no upscatter contamination of ^99mTc-TF in 150–175 keV. In the rat-sized phantom, the radioactive count ratio decreased to 4.0 % for 300 MBq ^99mTc-TF without SC in 125–150 keV. In the rats, myocardial images and radioactive counts of ^99mTc-TF with the dual tracer were identical to those of the ^99mTc-TF single injection. Downscatter contamination of ¹²³I-FP-CIT was 4.2 % without SC in 125–150 keV. In the first injection of ^99mTc-HMPAO and second injection of ¹²³I-FP-CIT, brain images and radioactive counts of ^99mTc-HMPAO with the dual tracer in normal mice also were the similar to those of the ^99mTc-HMPAO single injection. In the first injection of ¹²³I-FP-CIT and second injection of ^99mTc-HMPAO, the brain images and radioactive counts with the dual tracer were not much different from those of the ¹²³I-FP-CIT single injection.

Conclusions

Dual-tracer imaging of ^99mTc- and ¹²³I-labeled radiotracers is feasible in a preclinical SPECT scanner with CZT detector. When higher radioactivity of ^99mTc-labeled radiotracers relative to ¹²³I-labeled radiotracers is applied, correction methods are not necessarily required for the quantification of ^99mTc- and ¹²³I-labeled radiotracers when using a preclinical SPECT scanner with CZT detector.

     

Left ventricular function in response to dipyridamole stress: head-to-head comparison between <Superscript>82</Superscript>Rubidium PET and <Superscript>99m</Superscript>Tc-sestamibi SPECT ECG-gated myocardial perfusion imaging

Purpose

Myocardial perfusion imaging (MPI) with ^99mTc-sestamibi (sestamibi) SPECT and rubidium-82 (⁸²Rb) PET both allow for combined assessment of perfusion and left ventricular (LV) function. We sought to compare parameters of LV function obtained with both methods using a single dipyridamole stress dose.

Materials and methods

A group of 221 consecutive patients (65.2?±?10.4 years, 52.9% male) underwent consecutive sestamibi and ⁸²Rb MPI after a single dipyridamole stress dose. Sestamibi and ⁸²Rb summed rest (SRS), stress (SSS) and difference (SDS) scores, and LV end-diastolic (EDV) and end-systolic (ESV) volumes and left ventricular ejection fraction (LVEF) were compared.

Results

Bland-Altman analysis showed that with increasing ESV and EDV the difference between the two perfusion tracers increased both at rest and post-stress. The mean difference in EDV and ESV between the two perfusion tracers at rest could both be independently explained by the ⁸²Rb SDS and the sestamibi SRS. The combined models explained approximately 30% of the variation in these volumes between the two perfusion tracers (R²?=?0.261, p?=?0.005; R²?=?0.296, p?<?0.001, for EDV and ESV respectively). However, the mean difference in LVEF between sestamibi and ⁸²Rb showed no significant trend post-stress (R²?=?0.001, p?=?0.70) and only a modest linear increase with increasing LVEF values at rest (R²?=?0.032, p?=?0.009).

Conclusions

Differences in left ventricular volumes between sestamibi and ⁸²Rb MPI increase with increasing volumes. However, these differences did only marginally affect LVEF between sestamibi and ⁸²Rb. In clinical practice these results should be taken into account when comparing functional derived parameters between sestamibi and ⁸²Rb MPI.

     

Evaluation of <Superscript>99m</Superscript>Tc-3PRGD<Subscript>2</Subscript> integrin receptor imaging in hepatocellular carcinoma tumour-bearing mice: comparison with <Superscript>18</Superscript>F-FDG metabolic imaging

Objective

Our study was designed to explore the utility of ^99mTc-HYNIC-PEG₄-E[PEG₄-c(RGDfK)]₂ (^99mTc-3PRGD₂) for the detection of hepatocellular carcinoma (HCC) and specifically to compare the diagnostic performance of ^99mTc-3PRGD₂ integrin receptor imaging and 2-18-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) metabolic imaging in a nude mouse model.

Methods

^99mTc-3PRGD₂ was synthesized using a HYNIC-3PRGD₂ lyophilized kit with ^99mTcO₄ labelling. The nude mouse animal model was established by subcutaneously injecting 5 × 10⁷/ml HepG2 cells into the shoulder flank of each mouse. Biodistribution studies were performed at 0.5, 1, 2 and 4 h after intravenous administration of 0.37 MBq of ^99mTc-3PRGD₂. Immunohistochemistry was performed to evaluate the expression level of integrin αvβ3 in the HCC tissues. Dynamic imaging was performed using list-mode after the administration of 55.5 MBq of ^99mTc-3PRGD₂, to reconstruct the multiphase images and acquire the best initial scan time. At 8, 12, 16, 20 and 24 days after inoculation with HepG2 cells, 55.5 MBq of ^99mTc-3PRGD₂ and 37 MBq of ¹⁸F-FDG were injected successively into the nude mouse model, subsequently, simultaneous SPECT/PET imaging was performed to calculate the tumour volume and tumour uptake of ^99mTc-3PRGD₂ and ¹⁸F-FDG.

Results

The biodistribution study first validated that the tumour uptake of ^99mTc-3PRGD₂ at the different time points was higher than that of all the other organs tested in the experiment, except for the kidney. Integrin αvβ3 expressed highly in early stage HCC and declined for further necrosis of the tumour tissue. Subcutaneous tumours were visualized clearly with excellent contrast under ^99mTc-3PRGD₂ SPECT/CT imaging, and the multiphase imaging comparison showed the tumours were prominent at 0.5 h, suggesting that the best initial scan time is 0.5 h post-injection. The comparison of the imaging results of the two methods showed that ^99mTc-3PRGD₂ integrin receptor imaging was more sensitive than ¹⁸F-FDG metabolic imaging for the detection of early stage HCC, meanwhile the tumour uptake of ^99mTc-3PRGD₂ was consistently higher than that of ¹⁸F-FDG. However, as tumour necrosis further increased in HCC tissues, the uptake of ¹⁸F-FDG was higher than that of ^99mTc-3PRGD₂.

Conclusion

Our study demonstrated that ^99mTc-3PRGD₂ is a valuable tumour molecular probe for the detection of early stage HCC compared with ¹⁸F-FDG, meriting further investigation of ^99mTc-3PRGD₂ as a novel SPECT tracer for tumour imaging.

     

Targeted functional imaging of estrogen receptors with <Superscript>99m</Superscript>Tc-GAP-EDL

Purpose To evaluate the feasibility of using ^99mTc-glutamate peptide-estradiol in functional imaging of estrogen receptor-positive [ER(+)] diseases. Methods 3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. Cellular uptake studies of ^99mTc-GAP-EDL were conducted in ER(+) cell lines (MCF-7, 13762 and T47D). To demonstrate whether GAP-EDL increases MAP kinase activation, Western blot analysis of GAP-EDL was performed in 13762 cells. Biodistribution was conducted in nine rats with 13762 breast tumors at 0.5–4 h. Each rat was administered ^99mTc-GAP-EDL. Two animal models (rats and rabbits) were created to ascertain whether tumor uptake of ^99mTc-GAP-EDL was via an ER-mediated process. In the tumor model, breast tumor-bearing rats were pretreated with diethylstilbestrol (DES) 1 h prior to receiving ^99mTc-GAP-EDL. In the endometriosis model, part of the rabbit uterine tissue was dissected and grafted to the peritoneal wall. The rabbit was administered with ^99mTc-GAP-EDL. Results There was a 10–40% reduction in uptake of ^99mTc-GAP-EDL in cells treated with DES or tamoxifen compared with untreated cells. Western blot analysis showed an ERK1/2 phosphorylation process with GAP-EDL. Biodistribution studies showed that tumor uptake and tumor-to-muscle count density ratio in ^99mTc-GAP-EDL groups were significantly higher than those in ^99mTc-GAP groups at 4 h. Among ^99mTc-GAP-EDL groups, region of interest analysis of images showed that tumor-to muscle ratios were decreased in blocking groups. In the endometriosis model, the grafted uterine tissue could be visualized by ^99mTc-GAP-EDL. Conclusion Cellular or tumor uptake of ^99mTc-GAP-EDL occurs via an ER-mediated process. ^99mTc-GAP-EDL is a useful agent for imaging functional ER(+) disease.     

Usefulness of<Superscript>201</Superscript>Tl and<Superscript>99m</Superscript>Tc MIBI scintigraphy in a case of oncogenic osteomalacia

A 45-year-old male was admitted with difficulty in walking due to leg pain. At the time of the first visit, a reduced serum phosphorus concentration and an increased serum alkaline phosphatase concentration of unknown etiology were observed. Either a whole body bone scintigraphy or CT of the neck, chest and abdominal region did not reveal any underlying disease. However both the whole body 201Tl scintigraphy and 99mTc MIBI SPECT showed accumulation in the right knee region, and a small tumor was detected by MRI examination. After a diagnosis of oncogenic osteomalacia due to this tumor was determined the tumor was surgically removed, and turned out to be a hemangiopericytoma. By removal of the tumor, either the symptoms or the laboratory data were improved significantly. In this case, both 201Tl scintigraphy and 99mTc scintigraphy MIBI were useful in identifying the location of the tumor which caused oncogenic osteomalacia.     

<Superscript>99m</Superscript>Tc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits

Purpose Apoptosis is commonly observed in advanced atherosclerotic lesions. ^99mTc-annexin A5 (^99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of ^99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. Methods The WHHLMI and control rabbits were injected intravenously with ^99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. Results ^99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of ^99mTc-annexin A5 in WHHLMI rabbits. ^99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2 ± 2.5, %ID × BW/mm² × 10³), followed in decreasing order by neointimal (4.9 ± 1.3), fibroatheromatous (4.5 ± 1.9), and collagen-rich lesions (3.3 ± 1.4). The regional ^99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and “vulnerability index,” an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. Conclusion The present study in WHHLMI rabbits showed higher ^99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. ^99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.