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Introduction: Lipophilic cations such as phosphonium cations penetrate the hydrophobic barriers of the plasma and mitochondrial membranes and accumulate in the mitochondria in response to negative inner-transmembrane potentials. The present study reports the radiosynthesis and evaluation of (18)F-labeled aliphatic triphenylphosphonium cations as a potential agent for myocardial imaging by using PET., Materials and Methods: (7-[(18)F]fluoroheptyl)triphenylphosphonium salt ([(18)F]3) and (8-[(18)F]fluorooctyl)triphenylphosphonium salt ([(18)F]6) were radiolabeled by means of two-step nucleophilic substitution reactions. We measured the log P value of [(18)F]3 and [F]6 to assess the appropriate range of lipophilicity for their suitability as PET myocardial imaging agents. Normal rats were imaged with microPET after intravenous injection of 37 MBq of [(18)F]3 and [(18)F]6. To determine the pharmacokinetics, a region of interest was drawn around the heart, and time-activity curves of [(18)F]3 and [(18)F]6 were generated to obtain the counts per pixel per second., Results: The radiolabeled compounds [(18)F]3 and [(18)F]6 were synthesized with 18-25% yield. The radiochemical purity was greater than 98% on the basis of the analytical high-performance liquid chromatography system, and the specific activity was greater than 160-170 Ci/mmol. The log P value of the tracers was 2.52 ± 0.01 ([(18)F]3) and 2.91 ± 0.02 ([(18)F]6). Myocardium-to-liver ratios of [(18)F]3 and [(18)F]6 were 2.59 and 1.07, respectively, 10 min after injection, whereas the myocardium-to-lung ratios were 5.57 and 3.35, respectively. In addition, [(18)F]3 and [(18)F]6 showed intense, homogenous uptake in the myocardium., Conclusion: (18)F-labeled aliphatic phosphonium cations [(18)F]3 and [(18)F]6 might have potential as novel myocardial agents for PET and could prove useful in clinical cardiac PET/computed tomography applications.

Objective: A lack of response to cardiac resynchronization therapy (CRT) has been reported in 20-40% of heart failure patients with left ventricular (LV) dyssynchrony who underwent treatment based on the established guidelines. The study aimed to investigate the relationship between (99m)Tc-tetrofosmin ((99m)Tc-TF) myocardial scintigraphy and the response to CRT., Patients and Methods: Twenty-one patients with drug-refractory heart failure who underwent CRT were evaluated. All patients underwent (99m)Tc-TF myocardial scintigraphy before and after CRT. Single-photon emission computed tomography images of (99m)Tc-TF were acquired at 30 min and 3 h after injection and were used to determine the total defect score (TDS) and washout score (WOS). The change in the LV volume and ejection fraction (ΔLVEF) and relative reduction in left ventricular end-systolic volume (%ΔLVESV) were calculated as an index of LV functional recovery after CRT. Response to CRT was considered to have occurred when ΔLVEF was greater than 15% or when ΔLVEF was greater than 5% and %ΔLVESV was greater than 15%., Results: Significant differences were observed between the patients who responded to CRT (the responder group, 13 patients) and the nonresponder group (eight patients) for both early and delayed TDS and WOS (P<0.05). Moreover, there was a good correlation between early TDS before CRT and both ΔLVEF and %ΔLVESV (P<0.01) and an excellent correlation between WOS before CRT and both ΔLVEF and %ΔLVESV (P<0.01)., Conclusion: Evaluating the washout of (99m)Tc-TF in addition to myocardial perfusion before CRT using (99m)Tc-TF myocardial scintigraphy might be useful in drug-refractory heart failure patients.

Objective: The clearance rate of inhaled 99mTc-sestamibi from the lungs of healthy nonsmoking individuals is much slower than would be expected from its physical properties. The clearance rate is even slower in healthy cigarette smokers. As 99mTc-sestamibi is a substrate for P-glycoprotein (P-gp), pulmonary P-gp may be influential in 99mTc-sestamibi clearance and may be upregulated in smokers. 99mTc-tetrofosmin is also a substrate for P-gp, therefore we hypothesized that it would display similar kinetics to 99mTc-sestamibi and support a role for P-gp. We also hypothesized that administration of P-gp modulators would accelerate clearance of 99mTc-sestamibi., Methods: We measured clearance rates of 99mTc-tetrofosmin in four healthy smokers and four healthy nonsmokers and of 99mTc-sestamibi in six otherwise healthy patients with psoriasis before and after 2 weeks of therapy with cyclosporine A (2.5-5 mg/kg/day) and two healthy women taking the oral contraceptive pill, as both cyclosporine and steroids are known to be P-gp modulators., Results: The clearance rate of 99mTc-tetrofosmin in nonsmokers ranged from 0.38 to 0.63%/min, similar to the previously recorded rate for 99mTc-sestamibi [0.43 (SD 0.083)%/min], but it was not delayed in smokers (range 0.42-0.97%/min). Cyclosporine had no significant effect on 99mTc-sestamibi clearance, although clearance rates in the two women taking the oral contraceptive pill were both fast (0.58 and 0.62%/min)., Conclusion: Although the role of P-gp expression in the clearance of 99mTc-sestamibi remains unproven, we conclude that 99mTc-tetrofosmin is not as P-gp-avid as 99mTc-sestamibi. A role for P-gp expression in the clearance of 99mTc-sestamibi remains unproven. Higher doses of P-gp inhibitors will be required and clearance rates correlated with immunohistochemical expression of P-gp.

Aim: Digestive activity can interfere with the interpretation of myocardial perfusion single photon emission computed tomography using sestamibi or tetrofosmin. Compared with sestamibi, the liver clearance of tetrofosmin is more rapid, but its absolute cardiac uptake is lower. In this study, the activity of sestamibi and tetrofosmin was quantified after exercise or pharmacological stress and at rest to objectify the biokinetic differences and to evaluate whether there is a correlation between quantitative measurements and the visual assessment of image quality., Methods: Left ventricular activity and five ratios (R1-R5) of cardiac to adjacent extra-cardiac activity were quantified in 204 sestamibi (68 exercise stress/56 pharmacological stress/80 rest) and 221 tetrofosmin (67 exercise stress/59 pharmacological stress/95 rest) studies. Image quality was assessed by a three-point score (1, good; 2, moderate; 3, poor) and correlated with the heart to left supra-diaphragmatic region (R1) and heart to right supra-diaphragmatic region (R2) ratios., Results: The mean left ventricular activity was higher for sestamibi, especially at rest (sestamibi, 0.21+/-0.05 counts/pixel/injected MBq; tetrofosmin, 0.16+/-0.042 counts/pixel/injected MBq; P<0.001). By contrast, most ratios were higher with tetrofosmin, particularly for the exercise stress and rest studies. Using the three-point quality scoring, more sestamibi than tetrofosmin studies were scored as 3 (12.2% versus 6.3%), also particularly for the exercise stress and rest studies. A highly significant relationship was found between decreasing R1 and R2 and an increasing quality score, regardless of the radiopharmaceutical used (P values between 0.02 and <0.001)., Conclusions: Despite a lower cardiac uptake, the more rapid liver clearance of tetrofosmin than sestamibi significantly improves the ratios of cardiac to digestive activity, especially after exercise or at rest. These quantitative differences in biokinetics result in less poor scans with tetrofosmin in daily practice.

Background: We sought to determine whether drinking lemon juice reduces extra-cardiac activity and improves image quality on (99m)Tc-tetrafosmin myocardial single photon emission computed tomography (SPECT)., Methods: Eighty male patients were enrolled in this study and divided into four groups with 20 patients in each group. Each patient received 259-333 MBq tetrofosmin. Ten minutes after injection no action was taken for group 1 (G1), patients in group 2 (G2) each drank 250 ml of water, patients in group 3 (G3) each drank 250 ml of whole milk, and patients in group 4 (G4) each drank 250 ml diluted lemon juice. Myocardial perfusion imaging without attenuation correction was performed after a 1 day rest-stress protocol. Both rest and stress images were aligned at corresponding slices for comparison. Interfering activity was determined visually on reconstructed images, and the heart-to-liver (H/L) ratios were calculated with planar images at 25-30 min and at 45-50 min., Results: Interfering activity was seen in 80% of G1, 70% of G2, 60% of G3, and 35% of G4 (G4 vs. G1, P=0.006) on rest images, and in 70% of G1, 60% of G2, 55% of G3, and 30% of G4 (G4 vs. G1, P=0.014) on stress images at 25-30 min. It was also observed in 60% of G1, 50% of G2, 45% of G3, and 15% of G4 (G4 vs. G1, P=0.006) on rest images, and in 50% of G1, 45% of G2, 40% of G3, and 10% of G4 (G4 vs. G1, P=0.011) on stress images at 45-50 min. The mean H/L ratios of rest images were 0.47+/-0.13 for G1, 0.71+/-0.17 for G2, 0.65+/-0.12 for G3, and 0.93+/-0.23 for G4 at 25-30 min, and 0.63+/-0.14 for G1, 0.73+/-0.14 for G2, 0.85+/-0.25 for G3, and 1.15+/-0.25 for G4 at 45-50 min. On stress images, they were 0.49+/-0.11 for G1, 0.74+/-0.16 for G2, 0.69+/-0.11 for G3, and 0.98+/-0.22 for G4 at 25-30 min, and 0.66+/-0.15 for G1, 0.77+/-0.11 for G2, 0.89+/-0.26 for G3, and 1.21+/-0.19 for G4 at 45-50 min., Conclusion: Drinking 250 ml of diluted lemon juice accelerates the transit of tetrofosmin through the liver parenchyma and improves image quality on (99m)Tc-tetrafosmin myocardial SPECT.

Objective: To test the association of early post-stress lung/heart ratio (LHR) of 99mTc tetrofosmin radioactivity with gated-SPECT findings and angiographic results., Methods: We studied 158 consecutive patients, with stress/rest 99mTc tetrofosmin myocardial SPECT and coronary angiography. Rest scans were obtained as gated SPECT and the left ventricular ejection fraction and end diastolic volume were calculated. To evaluate myocardial ischaemia, we calculated the summed stress score, summed rest score and summed difference score indices. For the LHR calculation, we acquired an anterior image, 4-6 min after radiotracer injection at stress; LHR was defined as mean counts/pixel in the lung region of interest divided by the mean counts/pixel in the myocardial region of interest., Results: An early post-stress LHR value of 0.500 was defined as the upper normal limit. The most significant correlation (P<0.001) was observed among early post-stress LHR, summed stress score and the number of stenosed vessels. The incidence of multi-vessel coronary artery disease in the subgroup of patients with increased values of early post-stress LHR, was significantly higher than in the normal group (81% vs. 42%, P<0.001). There was a significant difference (P<0.001) of the early post-stress LHR value between patients with normal coronary arteries or one-vessel disease and patients with multi-vessel disease. Early post-stress LHR was an independent predictor of multi-vessel coronary artery disease (coefficient 1.85, SD 0.16, P<0.001), with an incremental value for its identification., Conclusions: Our results suggest that early post-stress 99mTc tetrofosmin LHR appears to be a useful index of extensive myocardial ischaemia dysfunction and multi-vessel coronary artery disease.

Background: Coronary artery disease impairs cardiac vasodilatory reserve. A low ratio of cardiac to hepatic vasodilatory reserve may be diagnostic for coronary artery disease., Aim: To compare the ratio of cardiac to hepatic uptake of 99mTc-tetrofosmin during adenosine infusion and at rest in patients with and without coronary artery disease in order to determine whether the ratio was significantly different between the two groups., Methods: Fifty-one patients who underwent coronary angiography and adenosine stress myocardial perfusion imaging using 99mTc-tetrofosmin were studied retrospectively. Anterior planar images from the single photon emission computed tomography (SPECT) raw data were used to draw regions of interest around the heart and liver. The counts per pixel in each region were used to calculate the stress ratio (SR) and the rest ratio (RR) as follows: SR = (cardiac counts per pixel)at stress/(hepatic counts per pixel)at stress; RR = (cardiac counts per pixel)at rest/(hepatic counts per pixel)at rest. The SR and SR/RR ratios were compared in patients with and without significant coronary artery disease. Receiver operating characteristic curves were drawn for SR and SR/RR., Results: The SR and SR/RR ratios were significantly lower in patients with significant coronary artery disease than in patients without (P<0.001). A cut-off ratio of SR/RR = 1.00 yielded 87% sensitivity and 74% specificity for the detection of significant coronary artery disease. Combining SR/RR with standard SPECT image interpretation increased the sensitivity without substantially changing the specificity in comparison with standard SPECT image interpretation only., Conclusion: Comparison of cardiac to hepatic 99mTc-tetrofosmin concentration at rest and under adenosine stress provides useful diagnostic information for the assessment of the presence of significant coronary artery disease.

Background and Aim: Bone-seeking radiopharmaceuticals have been proposed for delivering ablative radiation doses to marrow in multiple myeloma and other haematological malignancies. The aim of this research was to examine the feasibility of labelling ethylenediaminetetramethylenephosphonate (EDTMP) with Dy/Ho as an in vivo generator system and to evaluate whether the in vitro and in vivo stability of Dy-EDTMP and Ho-EDTMP complexes is maintained when the daughter Ho is formed., Methods: Dy was obtained by neutron irradiation of enriched Dy2O3 in a TRIGA Mark III reactor. Labelling was carried out in an aqueous phosphate medium at pH 8.0 by addition of DyCl3 to EDTMP at a molar ratio 1:1.75. Dy/Ho labelled EDTMP was obtained with a 99.3+/-0.6% radiochemical purity determined by thin-layer chromatography and high-performance liquid chromatography., Results: In vitro studies demonstrated that Dy/Ho-EDTMP is unstable after dilution in saline and stable in human serum and no translocation of the daughter nucleus occurring subsequent to beta decay of Dy which could produce release of Ho. Biodistribution in mice shows a fast blood clearance after administration of Dy/Ho-EDTMP with a skeletal uptake of 22.32+/-1.86% ID/g at 2 h and 20.12+/-1.94% ID/g after 10 d, a rapid renal elimination and no accumulation in other organs. Theoretical bone marrow absorbed dose calculations indicate that the Dy/Ho-EDTMP in vivo generator system would produce 7.80 times more radiation dose to marrow than that produced by Sm-EDTMP and 3.47 times more than Ho-DOTMP per unit of initial activity retained in the skeleton., Conclusion: The prepared radiolabelled EDTMP has adequate properties as a stable in vivo generator system for bone marrow ablation.

Background: Previous reports have demonstrated the feasibility of scintigraphic assessment of the multi-drug resistance (MDR) of tumours caused by ATP binding cassette (ABC) transporters by using Tc cationic tracers such as Tc tetrofosmin (TF). Furthermore, the potential of these tracers for evaluating the effects of reversal agents for MDR has been documented. However, most reversal agents simultaneously affect cationic ion transporters related to tracer accumulation in tumours., Methods: The uptake of Tc-TF was examined in the MCF7/WT cell line, a wild-type breast cancer cell line that does not exhibit MDR, and its subclonal etoposide resistant cell line MCF7/VP, which expresses high levels of MRP1, one of the multi-drug resistance associated proteins (MRPs), in the presence of increasing concentrations of verapamil, a classical MDR modulator. In the absence of verapamil, MCF7/VP cells showed significantly lower Tc-TF uptake than did MCF7/WT cells, indicating that Tc-TF is a substrate for MRP1. The presence of verapamil enhanced the uptake of Tc-TF in MCF7/VP cells. On the other hand, verapamil also increased tracer uptake in MCF7/WT cells, which was readily appreciated when the uptake values were corrected by viable cell numbers: an approximately 100% increase of Tc-TF uptake was observed in comparison with that in the absence of verapamil in viable MCF7/WT cells whereas a 100-200% increase occurred in viable MCF7/VP cells. In addition, verapamil prolonged the retention of radioactivity in both MCF7/WT cells and MCF7/VP cells., Conclusion: These results suggest that cellular functions other than MRP1 function, probably cationic ion transporters, are simultaneously and significantly involved in the verapamil induced changes of cellular uptake of Tc-TF. Tc-TF scintigraphy may overestimate the reversal effects of modulators on chemoresistance caused by MRP1 when the modulators simultaneously affect ion transporters.

Tc-tetrofosmin seems to show a prolonged thyroid retention when compared with Tc-sestamibi; this may explain its poorer performance in the dual-phase parathyroid scintigraphy. In order to verify objectively whether and to what extent Tc-sestamibi and Tc-tetrofosmin uptake and retention differ in the thyroid gland, we performed a head-to-head comparison between the tracers in 86 euthyroid subjects enrolled in five centres. Data were compared with those of Tc-pertechnetate obtained from the same subjects. For comparison purposes, quantitative data from the salivary glands were also obtained. Tc-sestamibi showed a higher early thyroid uptake (2.26+/-0.52 vs. 2.01+/-0.49, respectively; P<0.002) and a lower retention (1.4+/-0.37 vs. 1.65+/-0.58, respectively; P<0.002) when compared with Tc-tetrofosmin. This finding provides an objective basis for the poorer results of Tc-tetrofosmin in dual-phase parathyroid scintigraphy. Delayed Tc-tetrofosmin salivary gland uptake was unexpectedly high and approached the Tc-pertechnetate value (2.29+/-0.56 vs. 2.46+/-0.75, respectively; P =not significant). This finding should be kept in mind in order to avoid interpretation pitfalls in thyroid and parathyroid imaging with Tc-tetrofosmin, as well as in other oncological imaging of the neck region. This study definitely establishes that Tc-tetrofosmin and Tc-sestamibi are not twin but rather sibling tracers.

Our aim was to determine whether the Ca2+ ion or cell membrane Ca2+ and Na+/Ca2+ ion transport systems are involved in maintaining the cell-associated activity of technetium-99m-hexakis-methoxy-isobutyl-isonitrile (99mTc-MIBI) and technetium-99m-ethylene-bis[bis(2-ethoxyethyl)phosphin] (99mTc-tetrofosmin) in tumour cell lines. The cell-associated activities of 99mTc-MIBI and 99mTc-tetrofosmin were assessed in various buffers, with or without Na+ and/or with different concentrations of Ca2+, in Lewi's murine lung cell carcinoma and human glioma cell lines. Different Ca2+ channel modulators, such as verapamil, flunarizine and 3,4-dichlorobenzamil (DCB), were used to assess the effect of Ca2+ channels on the cell-associated activity of 99mTc-MIBI and 99mTc-tetrofosmin. Despite significant differences between cell lines, the cell-associated activity of 99mTc-MIBI was higher in buffers without extracellular Ca2+ and Na+. The cell-associated activity of 99mTc-MIBI was significantly lower in all buffers containing high concentrations of Ca2+ in both cell lines. The cell-associated activity of Tc-tetrofosmin was also significantly higher in buffers without Ca2+, and was significantly decreased in buffers with high concentrations of Ca2+. All modulators significantly increased the cell-associated activity of 99mTc-MIBI in both cell lines in all buffers. All modulators increased the cell-associated activity of 99mTc-tetrofosmin, particularly in buffers containing Ca2+. The cell-associated activities of both 99mTc-MIBI and 99mTc-tetrofosmin may be dependent on verapamil-, flunarizine- and DCB-sensitive Ca2+ channels.

It is generally accepted that the quality of myocardial images deteriorates with increasing patient weight. This is attributed to a reduction of counts detected from the myocardium. In this paper we have looked at the count reduction in obese patients and suggest a workable algorithm to increase the injected activity to compensate for this loss of count. In this prospective study, 64 consecutive patients with normal myocardial images were selected to include a weight range of 50-120 kg. The height, weight and gender of patients were noted. Each patient had two studies (total of 128 studies), one at rest and one following stress with adenosine and 20-40 W bicycle exercise. Total myocardial counts were calculated from the back-projected views. The total myocardial counts per MBq of the injected activity were calculated. There was no significant difference in the injected activity and the size of the heart (pixel length of heart) between stress and rest, or gender of the patient. The normalized myocardial counts were not different between men and women, but the counts were slightly, although not significantly, higher ( P=NS) with adenosine and exercise (mean of 243 x 10(3) counts) compared to rest images (229 x 10(3) counts). There was a significant progressive loss of counts in patients with increasing weight, body mass index or body surface area ( P<0.001). There was no significant difference in the changes in counts with weight between male and female, or rest and stress studies. The combined data from all the studies were used to calculate the correlation coefficient and the slope of the line for reduction of cardiac counts with a patient's weight, body mass index, and body surface area. The best correlation was with patient weight ( r=0.58, P<0.001). This was used to calculate the increase in injection activity with increasing weight to maintain the same average counts as achieved in a 70 kg patient with a 400 MBq injection. We suggest that the injection activity should increase from 100% for a 70 kg patient to 140% for 110 kg, 200% for 140 kg, and 250% for a 150 kg patient.

The aims of this study were to assess the role of (99m)Tc-tetrofosmin scintigraphy in the diagnosis of malignant vs. benign musculoskeletal tumours and to determine the relationship between P-glycoprotein expression and tetrofosmin uptake in malignant lesions. Forty-six patients (32 malignant, 14 benign) with various musculoskeletal lesions were studied. Each patient underwent (99m)Tc-methylene diphosphonate three-phase bone scanning initially. At least 2 days later, dynamic and static (99m)Tc-tetrofosmin scans were obtained. The tetrofosmin scans were evaluated by visual and quantitative analysis. The count ratio of the lesion to the contralateral normal area (uptake ratio, UR) was calculated from the region of interest drawn on the tetrofosmin scan. The lesions were then resected by open biopsy to obtain a histopathological diagnosis. P-glycoprotein levels were determined immunohistochemically in 22 of 32 malignant lesions. A significant difference between the mean UR values of benign and malignant lesions was found (1.36 +/- 0.47 vs. 3.35 +/- 2.08, P = 0.000). Visual analysis showed an accuracy of 85%, and the accuracy of the quantitative analysis was 87% with the threshold level of UR as 1.76. When perfusion findings were added to the evaluation criteria, the accuracies of visual and quantitative analysis were increased to 87% and 89%, respectively. The relationship between the levels of P-glycoprotein and the UR values of tetrofosmin was not statistically significant (r = -0.235, P = 0.2). In addition, the mean UR value of the patients with P-glycoprotein expression was not statistically different from that of the patients without P-glycoprotein expression (3.01 +/- 1.48 vs. 4.27 +/- 2.90, P = 0.297). In conclusion, visually significant tetrofosmin uptake and increased perfusion in a musculoskeletal lesion strongly suggest that the lesion is malignant (positive predictive value, 96%). P-glycoprotein expression was not found to be a major factor interfering with 30 min tetrofosmin uptake in a malignant musculoskeletal lesion. However, the relatively high false-negative rate among negative results (28%) limits the value of (99m)Tc-tetrofosmin scintigraphy as a single diagnostic tool in differentiating between benign and malignant musculoskeletal tumours., (Copyright 2002 Lippincott Williams & Wilkins)

Left ventricular function is an important prognostic indicator in patients with coronary artery disease. The electrocardiogram gated, myocardial, single photon emission tomography (SPECT) program is coming into wide use. This program permits measurement of end diastolic volume, end systolic volume, and ejection fraction. This study was designed to show whether the measurement of ejection fraction by using (99c)Tc tetrofosmin gated SPECT at rest could give additional information to the interpretation of perfusion. Exercise 99mTc tetrofosmin SPECT and gated (99c)Tc tetrofosmin SPECT at rest were performed in 33 patients with or suspected of having coronary artery disease. Left ventricular ejection fraction was calculated from reconstructed gated SPECT at rest with a software quantitative gated SPECT. The results showed a poor correlation between segmental ejection fraction and segmental perfusion in stress and rest. There was an increasing probability of reversibility as the ejection fraction increased, while there was a greater chance of a fixed defect as the ejection fraction decreased. It is concluded that gated SPECT using (99c)Tc tetrofosmin provides clinically satisfactory functional data that, in combination with the perfusion information, will improve diagnostic and prognostic accuracy without an increase in cost or radiation dose to patients.

Historically, patients for radionuclide therapy have received fixed activities, sometimes normalized to body weight or body surface area. As radionuclide therapy develops, however, practitioners are becoming interested in individualized doses. This requires individual estimates of uptake to be routinely available. Such estimates need not necessarily be highly accurate but the magnitude of associated errors must be known. This paper looks specifically at simple methods for estimating relative (tumour to organ) uptake and also absolute (organ) uptake, for abdominal tumours and the liver. For relative uptake, the ratio of geometric mean counts gives a rough estimate, to within a factor of 2. Absolute liver uptake can be estimated from the geometric mean of liver counts but a correction must be applied for patient attenuation. Such a correction can be calculated solely from the patient's height and weight. The patient weight alone gives a correlation coefficient of 0.86, when plotted against the measured attenuation. However, this correction does not work well for patients heavier than 100 kg. The attenuation index, which is calculated from a patient's weight and height, gives a correlation coefficient of 0.90, for patients ranging in weight from 41 kg to 120 kg.

Breast cancer remains one of the most common cancers in the developed world. New treatments are proving effective against both limited disease and metastases. Nuclear medicine is in a unique position as it is one of the only methods used to image the breast which is linked to cell cycle changes, the receptors on the cell surface and the cells' response to chemotherapy. Nuclear medicine is unaffected by the anatomical changes seen post-chemotherapy and radiotherapy and is uniquely placed to become a major methodology in the continued assessment of the breast cancer patient. However, before this can happen the utility of nuclear medicine techniques must be proved in multi-centre trials.

The purpose of this investigation was to compare the efficiency of two different imaging protocols using two different clinically available 99mTc labelled myocardial perfusion tracers. One thousand one hundred and thirty-four imaging studies were performed prospectively, using either 99mTc-tetrofosmin or 99mTc-sestamibi, alternating the use of each tracer for a total period of 8 months. 99mTc-tetrofosmin rest studies were performed with injections of 259MBq-370MBq and imaging 30 min later. Exercise studies were performed with injections of 777MBq-1.11GBq and imaging 20 min later. 99mTc-sestamibi studies used doses similar to those in the 99mTc-tetrofosmin studies. Imaging followed a standard procedure, at 60 min after rest injection, and 30 min after exercise. For patients undergoing pharmacological stress testing99mTc-sestamibi was imaged 45 min after injection and 99mTc-tetrofosmin was imaged 30 min after injection. Variables analysed were (1) injection-to-imaging time for the procedure, and (2) the number of repeated scans because of extra cardiac activity. The completion time for the rest study was significantly shorter for 99mTc-tetrofosmin compared to 99mTc-sestamibi (47.7+/-21.7 min vs 74.3+/-25.8 min P<0.0001). Likewise, the total study time was shorter for 99mTc-tetrofosmin compared to 99mTc-sestamibi (90+/-32.7 min vs 124+/-37 min, P<0.0001). More importantly, the number of repeated scans was higher with 99mTc-sestamibi compared to 99mTc-tetrofosmin, 21.4% vs 10%, P=0.001 for rest studies and 16.4% vs 7.9% P=0.001 [corrected] for rest and stress. It was concluded that, using a same day rest/stress protocol, 99mTc-tetrofosmin provided higher patient throughput with fewer repeat scans. These factors may be considered for efficiency improvement in nuclear cardiology laboratories using 99mTc perfusion tracers.

Resting (99m)Tc-tetrofosmin (TF) uptake was compared with thallium ((201)Tl) rest-redistribution (R-RD) uptake in patients with previous myocardial infarction (MI) and significant coronary artery disease (CAD) to assess the ability of TF to detect viable myocardium. We studied 30 patients (21 males and nine females, mean age 53.9+/-12.5 years) with prior MI and left ventricular dysfunction who had been referred for coronary revascularization procedures. Myocardial single photon emission computed tomography (SPECT) images were obtained 1 h after injection of 750 MBq of TF. Within 1 week of the TF study, R-RD (201)Tl SPECT imaging was performed after injection of 111 MBq of (201)Tl . Quantitative analysis was performed in 21 segments. Viability was defined as the presence of tracer uptake greater than 50% of the peak activity on baseline studies or after reversibility. There was significant correlation between the quantitative regional R-RD (201)Tl activity and the resting TF activity (r=0.88, P<0.001). Quantitative analysis showed that the uptake of the two tracers was comparable in normal segments as well as in segments with fixed (201)Tl defects. In contrast, in segments with reversible (201)Tl defects, TF uptake was significantly greater than resting (201)Tl uptake, but lower than R-RD (201)Tl uptake. There were 52 segments (47% of the severely reduced segments on TF images) that showed no viability with TF, but were viable on the redistribution (201)Tl studies. We conclude that quantitative resting TF SPECT underestimates the presence of viable myocardium compared with R-RD (201)Tl imaging on the basis of using 50% of the peak activity as the viability threshold.

99Tcm-methoxyisobutylisonitrile (99Tcm-MIBI) and 99Tcm-tetrofosmin are cationic tracers recognized by the efflux pump P-glycoprotein (Pgp). Verapamil has been shown to be a competitive inhibitor of Pgp, and was one of the first multidrug-resistant reversing agents identified. The aim of this preclinical in vitro study was to evaluate the effects of verapamil on the accumulation of 99Tcm-MIBI and 99Tcm-tetrofosmin in the human breast cancer cell lines MCF-7 and SK-BR-3 and in the human soft tissue sarcoma cell lines SW 982 and SW 1353, in comparison with respective control cells, i.e. without preincubation with verapamil. After preincubation with 10 or 100 microM of verapamil for 15 or 30 min, the 99Tcm-MIBI and 99Tcm-tetrofosmin accumulation in cells was assessed at 10, 30 and 60 min after incubation with these tracers. Addition of verapamil caused a decline in the accumulation of the two tracers at all incubation times, as compared with control cells. These effects of verapamil were neither dose- nor preincubation time-dependent in most cells. Our data indicate that verapamil is not a promising agent for increasing the sensitivity of scintigraphy with 99Tcm-MIBI or 99Tcm-tetrofosmin, or for evaluating Pgp tumour status in these types of tumours.

The aim of this study was to determine the diagnostic value of 99Tcm-tetrofosmin whole-body imaging in comparison to 201Tl scintigraphy in patients with metastatic melanoma. In 27 patients with known or suspected melanoma metastases we performed 201Tl scintigraphy and 99Tcm-tetrofosmin scintigraphy using a 1-day protocol. In five patients with known locoregional metastasis the in vivo uptake kinetics of both radiotracers were compared. The final diagnosis was confirmed by surgical histology in 39 lesions (group I) and computed tomography (CT) and clinical course in 14 lesions (group II). In group I, containing mainly locoregional metastases, 201Tl scintigraphy correctly identified 36 of 39 metastases and 99Tcm-tetrofosmin 35 of 39 resulting in a sensitivity of 92% and 90% respectively. The T/B ratios of 201Tl (1.4-4.0, mean 2.15) were statistically significantly higher in comparison to tetrofosmin (1.3-3.0, mean 1.88). However, both radiotracers showed similar uptake and washout kinetics with a maximum of tracer uptake between 1 and 5 min p.i. In group II, containing mainly cerebral and pulmonary metastases, both methods correctly identified six of 14 metastases resulting in a sensitivity of only 43%. We conclude that the uptake of 99Tcm-tetrofosmin and 201Tl in melanoma metastases is very similar. The T/B ratios with 99Tcm-tetrofosmin are significantly lower than with 201Tl. In locoregional melanoma metastases the sensitivity of tetrofosmin scintigraphy is identical with 201Tl imaging and amounts to 90%. In cerebral and lung metastases the sensitivity of both methods is limited when using whole-body scintigraphy.

The fractionation of Myoview into 1:5 was followed by storage at -80 degrees C for 3 months. The kits were reconstituted with 3.5 GBq 99Tcm-pertechnetate and the average radiochemical purity (RCP) was maintained at 96.5 +/- 1.6% (n = 24) for 24 h. There was no difference in biodistribution between the 1:5 fraction and the full kit, especially with respect to myocardial uptake. These observations show that it is possible to fractionate and store Myoview kits at -80 degrees C and produce a product that is stable over 3 months. This provides a cost-effective method for using 99Tcm-tetrofosmin. Two new methods of determining RCP were also examined and found to give results that were not significantly different from the recommended manufacturer's method. A mini paper chromatography (MPC) method using Whatman 17 paper and a solvent mixture of ethyl acetate: acetone (1:9) and an Amprep SAX cartridge method using absolute ethanol as the solvent were found to be more rapid and reliable methods of quality control for this product.

Myocardial uptake of 99Tcm-tetrofosmin in vivo is determined by a combination of flow and metabolic status of myocytes. The accumulation of tetrofosmin in the mitochondria is related to their ability to transduce metabolic energy into electronegative membrane potential. Trimetazidine (TMZ), an anti-ischaemic drug, appears to have a metabolic cytoprotective effect related to mitochondrial function, since it does not induce systemic or coronary haemodynamic changes. In this study, we evaluated the effects of TMZ on tetrofosmin uptake in hypoperfused myocardial regions in patients with coronary artery disease (CAD). Twenty-two patients, 14 with previous myocardial infarction (group A) and eight with a history of angina (group B), with angiographically documented CAD were studied. All patients underwent two tetrofosmin SPET studies at rest, before (baseline) and 1 week after TMZ administration (post-TMZ). On quantitative analysis, 131 segments showed less tetrofosmin uptake at baseline. In these segments, tetrofosmin uptake was 51 +/- 13% at baseline and 55 +/- 15% post-TMZ (P < 0.001 vs control). In the 86 hypoperfused segments of group A, tetrofosmin uptake was 48 +/- 14% at baseline and 52 +/- 17% post-TMZ (P < 0.001 vs control). In the 45 hypoperfused segments of group B, tetrofosmin uptake was 56 +/- 9% at baseline and 60 +/- 10% post-TMZ (P < 0.001 vs control). In the remaining 309 segments, no significant difference in tetrofosmin uptake before and after TMZ was observed. In conclusion, our results suggest that TMZ administration may increase myocardial uptake of tetrofosmin in hypoperfused regions at rest in patients with CAD, based on its metabolic effect.

Many quantitative analysis methods for myocardial perfusion studies require as a central step a comparison with a 'normal' or average density distribution map or reference image. It has been recognized, however, that the normal distribution can be affected by patient attributes, including sex and weight or body habitus, and by acquisition attributes, including the choice of tracer and the position of the patient during imaging. Some authors have proposed separate reference images for the sexes and the tracer. This approach fails if a large number of binary attributes have to be considered, since one would need 2" reference images for each attribute. The problem is compounded when continuous attributes (e.g. age and weight) are included, especially if the approach is to average separate homogeneous groups for each attribute. We propose to create case-specific reference images for the interpretation of myocardial perfusion studies by creating a model based on the influence of each attribute. From a non-homogeneous population of normal cases, or cases presumed to be normal on the basis of the Diamond and Forrester stratification, the effect of patient and study attributes on the density distribution in the stress image and the density differences between rest and stress images were computed. The effects are computed by multi-linear regression, to account for cross-correlation. Significance is assigned on the basis of a partial Fisher test. The data are myocardial perfusion images matched in 3D to a template by an elastic transformation. Even though there was some cross-correlation in the data, we were able to show independent effects of sex, position (prone or supine), age, weight, tracer combination and stress method (exercise, persantine and adenosine). Taken as a whole, the multi-linear regression demonstrated a significant effect in 72% of the pixels within the myocardial volume. In addition, the distribution predicted by the model was equivalent to average images from homogeneous matched groups. In conclusion, our approach makes it possible to produce case-specific reference images without the need for multiple homogeneous large groups to produce averages for each possible patient or study attribute.

99Tcm-labelled myocardial perfusion tracers allow simultaneous assessment of myocardial perfusion and left ventricular function using ECG-gated SPET. The aim of this study was to evaluate left ventricular performance during exercise by means of ECG-gated myocardial perfusion SPET. After the administration of 99Tcm-tetrofosmin (555-740 MBq), eight healthy volunteers aged 27-49 years underwent ECG-gated myocardial perfusion SPET at rest and during supine submaximal exercise (75 and 125 W), for 3 min each. Using ECG-gated SPET data, left ventricular end-diastolic volume (LVEDV) demonstrated a biphasic response during exercise (from 106.4 +/- 17.5 to 119.9 +/- 19.9 to 108.1 +/- 19.2 ml). In contrast, left ventricular end-systolic volume decreased gradually and significantly during exercise (from 47.1 +/- 11.9 to 41.5 +/- 8.9 to 36.1 +/- 10.1 ml; P < 0.05), and left ventricular ejection fraction continued to increase at higher workloads (from 56.1 +/- 6.0 to 63.0 +/- 2.7 to 67.0 +/- 4.3; P < 0.01) despite a fall in LVEDV. There was a progressive increase in cardiac output during exercise, which reached a peak of 7.2 +/- 0.9 l.min-1. We conclude that ECG-gated myocardial perfusion SPET can assess left ventricular function during exercise and may provide useful information for the evaluation of patients with ischaemic heart disease.

Evaluation of lung uptake during routine 99Tcm-tetrofosmin myocardial SPET (single photon emission tomography) studies may be hindered by substantial chest muscle uptake, particularly post-exercise. This study investigated this proposal and analysed the various components of chest activity that may add to the real lung uptake. Exercise SPET studies were performed on normal subjects using 99Tcm-tetrofosmin and compared with the results of 99Tcm-sestamibi and 201Tl studies. The chest to heart count ratio (CHR) was calculated from the anterior SPET projection and further subclassified into lung, anterior chest and posterior chest to heart ratios (LHR, AHR, PHR) from the left anterior oblique (LAO) projection. On post-exercise images, the 99Tcm-tetrofosmin CHR was significantly higher than that of 201Tl and 99Tcm-sestamibi. Both the 99Tcm-tetrofosmin AHR and PHR were higher than those of 201Tl and 99Tcm-sestamibi. However, the LHR was similar for all three radiopharmaceuticals. In contrast, the rest 99Tcm-tetrofosmin images differed little from the 201Tl and 99Tcm-sestamibi ones. Thus, 99Tcm-tetrofosmin lung uptake post-exercise should be interpreted with caution, as chest muscle uptake is higher than normal. A more accurate evaluation of 99Tcm-tetrofosmin lung uptake is achieved from the LAO projection, where the contribution from chest muscle counts is much less than in the routinely used anterior projection.

Lutetium-177 (177Lu) has both beta particle emissions for a therapeutic effect and gamma emissions for imaging. This study was undertaken to synthesize and evaluate 177Lu-EDTMP (ethylenediaminetetramethylene phosphonic acid) as a therapeutic radiopharmaceutical for the palliation of pain from bone metastases. Chelation of 177Lu to EDTMP was obtained by heating for 30 min in boiling water at pH 8.8, resulting in a radiochemical yield of over 99%. The compound was stable for 20 days without any appreciable dissociation. Biodistribution studies in normal rats indicated selective bone accumulation, showing faster blood clearance, higher bone uptake and higher bone-to-soft tissue ratios than 99Tcm-MDP. In conclusion, 177Lu-EDTMP has favourable biological and physical characteristics for the palliative treatment of painful bone metastases.

We performed measurements of the sensitivity in water of the radioguided surgery system, Neoprobe 1000. Point sources of 125I, 153Sm and 165Er were measured to a geometric accuracy of 0.1 mm. These measurements were performed with the detector uncollimated and with two different collimators; the results were used to construct three-dimensional sensitivity matrices from which isosensitivity curves could be derived. The matrices were used to simulate the reliability of detecting tumours of various sizes, at various depths, and with variable uptake ratios and activity levels of the three radionuclides investigated. Simulations showed improved tumour detection with a conical collimator, demonstrating that collimator design is important. To minimize the radiation dose during diagnostic work-up, a novel bone-seeking radiopharmaceutical, 165Er-EDTMP, was developed and tested. It showed rapid bone localization, especially in growth zones, and rapid clearance from blood and non-osseous tissues. Its biodistribution was similar to that of 153Sm-EDTMP. Based on these results and previous clinical data, the simulations predicted that lung metastases with a radius of 1 mm might be reliably detected with the Neoprobe 1000 system, if equipped with a suitable collimator.

Comparative studies of thallium-201 (201Tl) and 99Tcm-tetrofosmin for the detection of ischaemic heart disease (IHD) have previously been reported. These 201Tl and 99Tcm-tetrofosmin studies were usually performed separately with different exercise loads at an interval of several days. Here, we used a dual-isotope technique with exercise myocardial SPET (single photon emission tomography) in 17 patients with IHD and 10 patients with normal coronary arteries. The triple-energy window (TEW) method was applied for cross-talk correction. SPET imaging was performed at 10 and 70 min (S1 and S2) after the injection of 99Tcm-tetrofosmin (222 MBq) and 201Tl (74 MBq) at peak exercise to determine the optimal imaging time of 99Tcm-tetrofosmin. The S2 value was obtained 35 min after the subject drank a glass of milk to accelerate hepatobiliary clearance. Twenty-five minutes after S2, 37 MBq of 201Tl were reinjected at rest and SPET imaging (S3) was performed. Immediately after S3, 666 MBq of 99Tcm-tetrofosmin were reinjected and SPET imaging (S4) was performed 50 min later. Representative short and vertical long axis tomograms were divided into 17 segments. Each segment was assessed using a 4-point scoring system. The defect score was defined as the sum of each segmental score. The defect scores for imaging at exercise were 14.3 +/- 11.4 for 201Tl at S1, 11.4 +/- 8 for 99Tcm-tetrofosmin at S1 and 9.7 +/-9.8 for 99Tcm-tetrofosmin at S2 (P < 0.01), respectively. The washout rate of 99Tcm-tetrofosmin for the first hour was 15.5 +/- 7.3% and 11.8 +/- 7.7% (P < 0.01), respectively, for the normal and ischaemic segments. The image quality of 201Tl at S1 was almost equivalent to that of 99Tcm-tetrofosmin at S1/S2. The overall sensitivity and specificity for the detection of ischaemia was 94% and 82% for 201Tl at S1, 89% and 86% for 99Tcm-tetrofosmin at S1, and 88% and 95% for 99Tcm-tetrofosmin at S2, respectively. The overall accuracy was 86%, 88% and 92%, respectively. The myocardial viability score was 7.4 +/- 7.1 for 201Tl at S3 and 5.8 +/- 7.0 for 99Tcm-tetrofosmin at S4 (P < 0.01). The results indicate that the diagnostic accuracy of 99Tcm-tetrofosmin for myocardial ischaemia is almost equivalent to that of 201Tl as assessed by dual SPET imaging, and that the optimal imaging time for 99Tcm-tetrofosmin is within 10-35 min (S1) after exercise.

The aim of this exploratory study was to assess the potential of discriminating malignant from non-malignant lesions using 99Tcm-tetrofosmin scintimammography in the detection of palpable breast tumours. Nine patients with palpable masses were studied; seven had malignant lesions and two had non-malignant lesions. All diagnoses were established by fine-needle aspiration (FNA) biopsy cytology. Each patient received 925 MBq (25 mCi) 99Tcm-tetrosfosmin intravenously. Planar prone views were acquired in the right lateral, left lateral and anterior positions, and the axillary regions were included in the field of view. Scintimammography showed focally increased tracer uptake in seven patients with a positive FNA result. The two patients with a negative FNA result showed no increased uptake. We suggest that 99Tcm-tetrosfosmin shows promise as a radiopharmaceutical in the detection and discrimination of the nature of palpable breast tumours. Larger studies are required to confirm these findings.

The kinetics, intracellular distribution and effects of ion transport inhibitors on the uptake of 99Tcm-tetrofosmin, 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) and 201Tl were investigated in a tumour cell line. Both uptake and washout of the tracers were measured at specific intervals. Cells were treated with ouabain, dimethyl amiloride (DMA) and bumetanide to observe the effects on uptake, while carbonyl cyanide m-chlorophenylhydrazone (CCCP) was used to study the release of the tracers. The tracers showed similar uptake and washout kinetics. Ouabain inhibited 55-67% of 201Tl, 16-22% of 99Tcm-tetrofosmin and 8-14% of 99Tcm-MIBI. DMA inhibited the uptake of both 99Tcm-tetrofosmin (30%) and 99Tcm-MIBI (21%). Bumetanide stimulated the uptake of 99Tcm-tetrofosmin and 99Tcm-MIBI but inhibited that of 201Tl (37%). When cells were pretreated with various combinations of these ion transport inhibitors, the uptake of 201Tl was related to Na+,K+ pump, Na+,K+, 2Cl- co-transport systems, whereas the uptake of both 99Tcm-tetrofosmin and 99Tcm-MIBI was related to the Na+,K+ pump, Na+/H+ antiport systems. Addition of CCCP released 55% and 90% of accumulated 99Tcm-tetrofosmin and 99Tcm-MIBI respectively, indicating that the percentage released was related to mitochondrial uptake.

99Tcm-tetrofosmin is a new myocardial perfusion agent with the advantage that it can be reconstituted at room temperature. Because two separate injections are required for rest and stress images, a separate-day imaging protocol with one injection each day would be optimal in terms of image quality. From the logistical point of view, a 1 day protocol may be more convenient for the majority of those referred as outpatients. The main aim of this study was to determine whether the detection of myocardial ischaemia would be impeded by the use of a 1 day protocol instead of a 2 day protocol. A secondary aim was to establish the relative diagnostic accuracy of the two imaging strategies. 99Tcm-tetrofosmin SPET imaging was performed in 157 patients. Sixty-nine (44%) patients were administered 250 MBq (7 mCi) 99Tcm-tetrofosmin at rest followed 4 h later by 750 MBq (21 mCi) during stress (the 1 day protocol), whereas 88 (56%) patients had rest and stress imaging studies on two separate days, receiving a 500 MBq (14 mCi) dose of 99Tcm-tetrofosmin on each occasion (the 2 day protocol). With the 1 day protocol, 135 of 621 (22%) abnormal segments (i.e. both reversible and persistent defects) were observed, compared with 195 of 792 (25%) segments with the 2 day protocol. Also, the occurrence of reversible defects only did not differ between the two protocols (both 9%). The sensitivity for the detection of coronary artery disease was 83 and 90% for the 1 and 2 day protocols respectively. We conclude that the 1 and 2 day protocols provide similar scintigraphic information and are equally sensitive and specific for the detection of coronary artery disease. Therefore, the imaging protocol can be adjusted as appropriate for the patient in question.

The distribution and elimination of 99Tcm-complexes with methylene-diphosphonate (MDP) and with the calcium salt of diethylene-triamine-penta(methylene phosphonate) (DTPMP) were compared in rats. Both compounds exhibited high bone uptake and long-term retention of radioactivity in the skeleton. No significant accumulation of the complexes in non-osseous tissues was found. The pharmacokinetics of both chelates were similar, small differences in their distribution and elimination probably being due to different binding to plasma proteins. Two processes, namely bone uptake and kidney elimination, contributed to the disappearance of the complexes from the blood. The higher protein binding of 99Tcm-MDP probably caused its slower rate of urine elimination and insignificantly higher bone uptake compared with 99Tcm-DTPMP. On the other hand, the more rapid reduction in blood and muscle radioactivity with 99Tcm-DTPMP resulted in accelerated non-osseous tissue clearance compared with 99Tcm-MDP. This suggests that the time between administration and imaging may be shorter for 99Tcm-DTPMP than for 99Tcm-MDP. Furthermore, the much greater stability of 99Tcm-DTPMP may also reduce degradation of the complex and 99Tcm liberation in the body. For a general evaluation of both compounds, it will be necessary to determine lesion-to-bone ratios.

To investigate the role of sublingual nitrate plus 99Tcm-tetrofosmin infusion in the detection of severely ischaemic but viable myocardium, we selected 25 patients with coronary artery disease who had at least one fixed segmental defect during conventional stress-redistribution (ST-RD) 201Tl single photon emission tomographic (SPET) imaging. Reinjection (RI) and 24 h late redistribution (LRD) imaging were also performed. Within a week of 201Tl imaging, one-day rest-stress (R-ST) 99Tcm-tetrofosmin SPET was performed with the same stress levels. The following day, 99Tcm-tetrofosmin was infused over 1 h immediately after sublingual nitrate administration and SPET images (N + Inf) were acquired. Of 100 fixed defects on R-ST 99Tcm-tetrofosmin imaging, 15 were reversible on N + Inf 99Tcm-tetrofosmin imaging. There was 91% concordance between ST-RD/RI/LRD 201Tl and R-ST/N + Inf 99Tcm-tetrofosmin imaging regarding reversibility. We conclude that N + Inf 99Tcm-tetrofosmin imaging may be clinically useful in the detection of severely ischaemic but viable myocardium.