[188Re]rhenium sulfide suspension: a potential radiopharmaceutical for tumor treatment following intra-tumor injection

Intralesional therapy has been shown to be an effective treatment for tumors. In this study, the suitability of [¹⁸⁸Re]rhenium sulfide suspension for tumor treatment following intra-tumor injection was evaluated. The [¹⁸⁸Re]rhenium sulfide suspension was radiolabeled with ¹⁸⁸Re with a radiochemical yield of more than 96%. In vitro stability studies revealed that more than 99% of the ¹⁸⁸Re remained in sulfide form over a 3-day period. After ultrasonication for 5 or 10 min, the main particle size was 1–5 μm. Two [¹⁸⁸Re]rhenium sulfide suspensions ultrasonicated for 5 and 10 min, respectively, were injected into separate group of tumor-bearing mice that were killed after specified times to compare the retention of ¹⁸⁸Re in tumors and the leakage to different organs by periods and organs removed to gamma counting. The mean retention percentages of ¹⁸⁸Re in tumors injected with suspension ultrasonicated for 5 (or 10) min were as follows: 1 h, 90.5 ± 7.7% (83.1 ± 13.7%); 24 h, 92.2 ± 8.6% (83.9 ± 9.8%); 48 h, 88.3 ± 10.9% (80.2 ± 3.8%); and 72 h, 91.5 ± 7.6% (78.8 ± 3.0%). Tumor-inhibiting ratio was 96.5%. These results demonstrated that [¹⁸⁸Re]rhenium sulfide suspension is an effective radiopharmaceutical for tumor treatment by intralesional therapy.     

In vivo imaging of tumour angiogenesis in mice with the α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin-targeted tracer <Superscript>99m</Superscript>Tc-RAFT-RGD

Purpose The molecular imaging of tumour neoangiogenesis currently represents a major field of research for the diagnostic and treatment strategy of solid tumours. Endothelial cells from tumour neovessels overexpress the α_vβ₃ integrin, which selectively binds to Arg-Gly-Asp (RGD)-containing peptides. We evaluated the potential of the novel radiotracer ^99mTc-RAFT-RGD for the non-invasive molecular imaging of α_vβ₃ integrin expression in mice models of tumour development. Methods ^99mTc-RAFT-RGD, ^99mTc-cRGD (specific control) and ^99mTc-RAFT-RAD (non-specific control) were injected intravenously to mice bearing B16F0 or TS/A-pc tumours. In vivo whole-body tomographic imaging and post-mortem biodistribution studies were performed 60 min following tracer injection. Adjacent tumour slices were used to compare the localisation of neovessels from immunostaining and the pattern of ^99mTc-RAFT-RGD uptake from autoradiographic ex vivo imaging. Results Biodistribution studies indicated that ^99mTc-RAFT-RGD tumour uptake was significantly higher than that of ^99mTc-RAFT-RAD in B16F0 (2.4±0.5 vs 1.0±0.1%ID/g, respectively) and in TS/A-pc tumours (2.7±0.8 vs 0.7±0.1%ID/g, respectively). Immunohistochemical and autoradiographic studies indicated that ^99mTc-RAFT-RGD intratumoural uptake preferentially occurred in angiogenic areas. Tomographic imaging allowed tumour visualisation following injection of ^99mTc-RAFT-RGD and ^99mTc-cRGD with similar tumour-to-contralateral muscle (T/CM) ratios in B16F0 and in TS/A-pc tumours whereas ^99mTc-RAFT-RAD T/CM ratios did not allow tumour imaging. In accordance with the higher level of α_vβ₃ integrin expression on TS/A-pc tumours than on B16F0 tumours as determined from western blot and immunoprecipitation analyses, the ^99mTc-RAFT-RGD T/CM ratio was significantly higher in TS/A-pc than in B16F0 tumours. Conclusion ^99mTc-RAFT-RGD allowed the in vivo imaging of α_vβ₃ integrin tumour expression.     

Assessment of split renal function with99mTc-aprotinin

The aim of this work is to correlate the net kidney uptake of^99mTc-aprotinin (TcA) in 103 subjects with separate effective renal plasma flow (ERPF) and some blood chemistry parameters at 90, 180, and 360 min postinjection both in the normal and diseased kidney. Correlations found with separate ERPFs are highly significant at any time (P < 0.001). However, although the slope of the regression line is steeper at 180 min,r tends to deteriorate slightly with time postinjection and a higher intercept on they axis: this pattern is more pronounced if diseased kidneys are considered separately. The following are probably related to the renal handling of TcA: (1) Early scans better reflect blood flow to the kidney, while later scans are more related to the metabolism/excretion tubular mechanisms; (2) correlations found with urea, creatinine, urea clearance, and creatinine clearance are highly significant at any time; (3) in 20 additional patients with diseased kidneys, renal uptake measurements done 360 min postinjection first with TcA and then with DMSA showed better correlations with ERPF employing TcA. Our results indicate that TcA is a feasible indicator of split renal function even at 90 min postinjection when a scan is easily carried out on an outpatient basis.This paper was in part presented at the European Nuclear Medicine Congress, August 14–17, 1984, Helsinki, Finland     

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.     

99mTc-sestamibi kinetics predict myocardial viability in a perfused rat heart model

Introduction ^99mTc-sestamibi has been proposed as a viability imaging agent. The purposes of this study were: (1) to determine the relationship between myocardial viability and ^99mTc-sestamibi kinetics using perfused rat heart models across a full spectrum of viability, (2) to do so under conditions where myocardial flow was controlled and held constant, and (3) to do so using multiple quantitative methods to assess myocardial viability. Methods Twenty-three isolated rat hearts were perfused retrogradely with a modified Krebs-Henseleit (KH) solution. Four groups were studied: controls (C, n = 6), stunned (S, n = 6), ischemic-reperfused (IR, n = 6), and calcium injured (CAL, n = 5). Following a 20-min baseline and subsequent treatment phase, ^99mTc-sestamibi was infused over 60 min (uptake) followed by 60 min clearance. Treatment phases consisted of 20 min no flow for S, 60 min no flow followed by 60 min reflow for IR, and 10 min infusion of KH solution without calcium followed by 20 min infusion of KH solution with 2 times normal calcium for CAL hearts. Creatine kinase (CK) assay, triphenyltetrazolium chloride (TTC) staining, and transmission electron microscopic (TEM) analysis were used to determine tissue viability. Results Myocardial peak ^99mTc-sestamibi uptake (%id) was significantly decreased in IR (4.11 ± 0.22 SEM; p < 0.05) and CAL (1.07 ± 0.13; p < 0.05), but not in S (4.88 ± 0.17) as compared with C (5.99 ± 0.50). One hour fractional retention was 79.3 ± 1.9% for C, 80.3 ± 1.3% for S (p = n.s.), 79.1 ± 1.8% for IR (p = n.s.), and 14.9 ± 4.3% for CAL (p < 0.05 compared to all other groups). ^99mTc-sestamibi absolute retention (%id) 1 h after the end of tracer administration was significantly decreased in IR (3.26 ± 0.23) and CAL (0.15 ± 0.02) as compared with both S (3.92 ± 0.16) and C (4.52 ± 0.32) (p < 0.05). CK increased significantly from baseline in the IR and CAL hearts. TTC determined percent viability was 100 ± 0% for C, 98.3 ± 1.1% for S, 82.8 ± 2.6% for IR, and 0.0 ± 0% for CAL. TEM analysis supported these findings. End tracer activity was significantly correlated with TTC determined percentage viable myocardium (r = 0.93, p < 0.05) and CK leak (r = −0.90, p < 0.05). Conclusion ^99mTc-sestamibi myocardial activity is significantly reduced in areas of nonviability after 1 h of tracer uptake and 1 h of tracer clearance. There is a linear correlation between myocardial viability, as determined by three independent methods, and tracer activity. This work was supported by the American Heart Association, the Anne and Henry Zarrow Foundation, and the William K. Warren Medical Research Foundation.     

Technetium-99m pyrophosphate/thallium-201 dual-isotope SPECT imaging predicts reperfusion injury in patients with acute myocardial infarction after reperfusion

Purpose  Microcirculatory failure after reperfusion is clinically indicated to cause reperfusion injury whereas excessive intracellular calcium ion overload is experimentally proved as a key mechanism of reperfusion injury. We hypothesized that technetium-99m (^99mTc) pyrophosphate (Tc-PYP) uptake in injured but viable infarct-related myocardium with preserved myocardial perfusion after reperfusion estimated by thallium-201 (²⁰¹Tl) uptake would be associated with final functional recovery. Methods  Dual-isotope Tc-PYP/²⁰¹Tl single-photon emission computed tomography (SPECT) was performed 2 days after successful reperfusion therapy in patients with first acute myocardial infarction, and 50 patients (63 ± 13 years old, female 22%) with preserved ²⁰¹Tl uptakes of ≥50% in reperfused myocardium was followed for 1 month. Tc-PYP uptake was assessed as the heart-to-sternum (H/S) ratio. Two-dimensional echocardiography was also performed 2 days and 1 month after reperfusion to evaluate functional recovery. Results  High Tc-PYP uptake, defined as the H/S ratio ≥0.81, was predictive of chronic phase no functional recovery (73.7% in 14 of 19 patients with high uptake vs 16.1% in five of 31 patients without those, p < 0.0001). After adjustment for potential confounding variables, including electrocardiographic persistent ST segment elevation at 1 h after reperfusion, high Tc-PYP uptake remained independently predictive of no functional recovery with odds ratio of 8.7 (95% confidential interval = 2 to 38.7; p = 0.005). Conclusion  High Tc-PYP uptake in reperfused but viable infarct-related myocardium was a powerful predictor of no functional recovery, which may reflect excessive intracellular calcium ion overload caused by reperfusion injury. Tc-PYP/²⁰¹Tl dual-isotope SPECT imaging can provide prognostic information after reperfusion.     

Regional alterations in myocardial sympathetic innervation in patients with transient left-ventricular apical ballooning (Tako-Tsubo cardiomyopathy)

Background  Excess sympathetic nervous activity was proposed to play a crucial role in the pathogenesis of transient left-ventricular apical ballooning (TLVAB, also known as Tako-Tsubo cardiomyopathy). This study was conducted to assess presynaptic adrenergic alterations in the dysfunctional myocardium of patients with TLVAB. Methods and Results  Ten consecutive patients undergoing coronary angiography for acute coronary syndrome who fulfilled the proposed Mayo Clinic criteria for the diagnosis of TLVAB were investigated. Myocardial iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) studies (planar and single-photon emission computed tomography [SPECT]) were performed to evaluate adrenergic innervation. Concomitantly, myocardial perfusion was assessed by means of technetium-99m methoxyisobutylisonitrile (^99mTc-MIBI) SPECT. In all patients, angiography revealed typical ballooning of the left-ventricular (LV) apex and hyperkinesis of the basal LV segments (overall ejection fraction, 41%±5% [mean±SEM]). Planar ¹²³I-MIBG scans revealed decreased heart-to-mediastinum ratios at early (20 minutes) and delayed (4 hours) images (2.1±0.1 and 1.9±0.1, respectively). The cardiac washout rate of ¹²³I-MIBG on the late images was increased to 34%±3%. The ¹²³I-MIBG uptake on SPECT scans was obviously reduced in the akinetic LV apex (defect score, 3.30±0.34), whereas ^99mTc-MIBI SPECT indicated normal or only mildly reduced perfusion within this region (defect score, 0.89±0.35). Conclusions  Our study indicates a functional alteration in presynaptic sympathetic neurotransmission in patients with TLVAB, and suggests a pathophysiologic explanation of the impairment of LV function.     

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.     

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.     

Reduction of <Superscript>99m</Superscript>Tc-sestamibi and <Superscript>99m</Superscript>Tc-tetrofosmin uptake in MRP-expressing breast cancer cells under hypoxic conditions is independent of MRP function

Hypoxia reduces the uptake of technetium-99m sestamibi (MIBI) in human cancer cell lines. In the current investigation, we attempted to identify the relationship between hypoxia-induced alteration of ^99mTc-MIBI accumulation and expression of multi-drug resistance-associated protein (MRP) in the MCF7/WT breast cancer cell line and its subclonal cell line, MCF7/VP, which expresses high levels of MRP1. A second cationic compound, ^99mTc-tetrofosmin (TF), was also examined. Cellular uptake of ^99mTc-MIBI and ^99mTc-TF was significantly higher in parental MCF7/WT cells than in MCF7/VP cells. Hypoxic conditions generated with a mixture of 95% N₂ and 5% CO₂ reduced cellular uptake of the two tracers in both parental MCF7/WT cells and MRP1-expressing MCF7/VP cells. Cell binding assay with iodine-125-labelled anti-MRP1 antibody demonstrated its specific binding to MCF7/VP cells. Hypoxia did not affect the amount of antibody bound to MCF7/VP cells. These results indicate that hypoxia-induced reduction of tracer uptake in tumour cells is a phenomenon independent of MRP function.     

Prospective dosimetry with <Superscript>99m</Superscript>Tc-MDP in metabolic radiotherapy of bone metastases with <Superscript>153</Superscript>Sm-EDTMP

Purpose

On the basis of the encouraging results achieved in several clinical trials and its proven therapeutic efficacy, ¹⁵³Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP) has become widely used to palliate pain from bone metastases. The results reported in the literature have led the product suppliers (QUADRAMET®, Schering) to suggest administering a fixed activity per kilogram (37 MBq/kg). However, considering the observed extreme inter-patient variability of skeletal uptake of ¹⁵³Sm-EDTMP, a real therapy optimization would require the individualization of the activity to be administered on a dosimetric basis. This should be planned taking into account the generally accepted 2-Gy dose constraint to the haematopoietic red marrow, the critical organ in palliative treatments with beta-emitting, bone-seeking radiopharmaceuticals.

Methods

Seven to 14 days before treatment with ¹⁵³Sm-EDTMP, 44 patients underwent ^99mTc-methylene diphosphonate (MDP) total-body bone scan with two scans (the first within 10 min of injection, the second after 6 h). The percentage bone uptake (Tc_%) was evaluated as the ratio between total counts at 6 h, adjusted for decay, and total counts at the first scan. Tc_% was then compared to Sm_% similarly derived from 10-min and 24-h whole-body scans. Tc_% and Sm_% were compared both with and without Brenner’s method for soft tissue uptake.

Results

The correlation between Tc_% and Sm_% was R ²?=?0.81 and R ²?=?0.88 with and without soft tissue correction, respectively. The difference between their average values was statistically significant (Sm_%?=?64.3?±?15.2, Tc_%?=?56.2?±?16.0; p?=?0.017) with soft tissue correction, while was not statistically significant (Sm_%?=?68.2?±?15.5, Tc_%?=?66.9?±?14.0; p?=?0.670) without soft tissue correction.

Conclusions

The rate of retention of ^99mTc-MDP in bone provides a reliable estimate of the ¹⁵³Sm-EDTMP rate of retention. The proposed method can be usefully adopted for prospective dosimetry seeing its extreme simplicity, and it requires no special investment in terms of human or instrumental resources. This allows an optimization of administered ¹⁵³Sm-EDTMP activity.

     

Myocardial 99mTc-sestamibi extraction and washout in hypertensive heart failure using an isolated rat heart

PurposeMyocardial mitochondria are the primary part of energy production for healthy cardiac contraction. And mitochondrial dysfunction would play an important role in progressive heart failure. In the recent years, myocardial washout of ^99mTc-sestamibi [(^99mTc-hexakis-2-methoxy-2-methylpropyl isonitrile (MIBI)] has been introduced to be a potential marker in patients with heart failure. The objective of this study was to clarify MIBI extraction and washout kinetics using isolated perfusion system in hypertension induced model of myocardial dysfunction.MethodsSix-week-old Dahl-salt sensitive rats, allotted to 4 groups; a 5-week high-salt group (5wk-HS), 12-week high-salt group (12wk-HS) and two age-matched, low-salt diet control groups (5wk-LS and 12wk-LS). The rats in 5wk-HS and 12wk-HS groups were fed a high-salt diet (containing 8% NaCl). Cardiac function was examined by echocardiography before removing heart. Hearts were perfused according to the Langendorff method at a constant flow rate, in which 20-min MIBI washin was conducted followed by 25-min MIBI washout. Whole heart radioactivity was collected every sec by an external gamma detector. The myocardial extraction, K₁ (ml/min) and washout rate, k₂ (min^?1) were generated.ResultsHigh-salt diet groups showed significant high-blood pressure. Echocardiography revealed thickened LV walls in 5wk-HS, and reduced cardiac function in 12wk-HS, compared to each age-matched control group. K₁ showed no significant difference among all groups (5wk-HS: 2.36±1.07, 5wk-control: 2.59±0.28, 12wk-HS: 1.91±0.90, and 12wk-control: 2.84±0.57). k₂ in 5wk-HS was comparable to that in the age matched control group (0.00030±0.00039 vs ?0.000010±0.00044), but it was increased remarkably in 18wk-HS compared to the age matched control group (0.0025±0.0011 vs 0.000025±0.000041, P<.01), and 5wk-HS (P<.01).ConclusionIn the course of hypertensive heart disease, MIBI washout was increased in the transitional state from hypertrophied to dilated and failing heart, while MIBI extraction remained intact.     

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

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

Kinetics of Tc-99m hexakis t-butyl isonitrile in normal and ischemic canine myocardium

Hexakis ^99mTc-tertiary butyl isonitrile (^99mTc-TBI) was studied as a cardiac perfusion imaging agent in nine dogs with partial occlusion of the LAD. Thirty min after applying the stenosis, ^99mTc-TBI was injected into the right atrium (RA) in five dogs and left atrium (LA) in four dogs. Normal and ischemic zone regional myocardial ^99mTc-TBI activites were monitored continuously for 4 h. Dogs with LA injections had minimal and equivalent 4 h fractional clearance from the normal and ischemic zones. Dogs with RA injections had minimal, but significantly lower 4 h fractional ^99mTc clearances in the ischemic zone (0.08±0.08) compared to the normal zone (0.16±0.07, P<0.05). The delayed ischemic zone clearance is probably due to the high initial lung uptake observed after RA injection. Despite the differences in clearance, this minimal amount of redistribution could not be detected on gamma camera images. The minimal myocardial washout and redistribution, and the 140 keV gamma make ^99mTc-TBI a promising cardiac perfusion imaging agent.Dr. Okada is an Established Investigator of the American Heart Association     

Influence of whole-body vibration on biodistribution of the radiopharmaceutical [99mTc]methylene diphosphonate in Wistar rats

Abstract

Purpose: The radionuclide bone scan is the basis of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive method for indicating disease in bone. Mechanical stimulation in the manner of whole-body vibration (WBV) appears beneficial to the maintenance and/or enhancement of skeletal mass in individuals. The aim of this work was to evaluate the effect of WBV on the biodistribution of the radiopharmaceutical [^99mTc]methylene diphosphonate (^99mTc-MDP ) in Wistar rats.

Materials and methods: In the biodistribution analysis, animals were anesthetized with sodium thiopental, the radiopharmaceutical ^99mTc-MDP was administered via ocular plexus and after 10 min the animals were submitted to vibration of 20 Hz (1 min) in an oscillatory platform. Following, the animals were sacrificed, the organs were isolated, the radioactivity determined in a well counter, and the percentages of radioactivity per gram (%ATI/g) in the organs were calculated. An unpaired t-test following Welch test (p < 0.05) was done for statistical analysis of the results.

Results: The biodistribution was significantly (p < 0.05) decreased in kidney, bone, lung, stomach, prostate and bowel.

Conclusion: The analysis of the results indicates that the vibration could produce metabolic alterations with influence in the uptake of the radiopharmaceutical ^99mTc-MDP in bone, stomach, bowel, prostate, kidney and bladder.     

HER-2受体放射性配体99Tcm-TP1623的制备及其在正常动物体内的分布

目的 探讨HER-2受体放射性配体 ⁹⁹Tc^m-B2-S22-AFA(⁹⁹Tc^m-TP1623)在健康小鼠体内的生物分布和健康家兔体内的动态显像分布.方法 采用氯化亚锡间接法 ⁹⁹Tc^m标记TP1623,3MM色谱纸层析测定 ⁹⁹Tc^m-TP1623标记率,计算其比活度;通过体外稳定性实验、血清蛋白结合实验和油/水分配实验,鉴定标记产品理化性质;研究 ⁹⁹Tc^m-TP1623于1、5、10、30、60和120 min在健康小鼠体内的生物分布特性;通过SPECT显像,结合感兴趣区(ROI)时间-放射性曲线分析,观察 ⁹⁹Tc^m-TP1623在健康家兔体内的动态分布变化.结果 ⁹⁹Tc^m-TP1623标记率为(96.4±0.1)%,比活度为(24.35±0.06)TBq/mmol,室温下放置6 h后放化纯度为(95.03±0.97)%.油/水分配系数P为－(2.51±0.15).小鼠血液放射性清除快,通过肾脏排泄较快,心、肺、肝、肌肉、骨骼等放射性随时间延长逐渐减低,60 min后放射性呈明显低水平,肠道放射性则随时间缓慢增加.脑放射性始终呈最低水平.健康家兔体内 ⁹⁹Tc^m-TP1623血池影消退迅速,主要通过肾脏排泄,见胆囊、肠道排泄影,胃区和颈部未见放射性浓聚,脑组织始终呈低本底.结论 ⁹⁹Tc^m-TP1623制备方法简便,标记率及产品比活度高,体内、外稳定性好,具有优良的动物体内动力学特性.     

125I-脱氧尿嘧啶核苷-壳聚糖载药纳米微粒的研制和鉴定

目的 研制直径100～200 nm的¹²⁵I-脱氧尿嘧啶核苷-壳聚糖载药纳米微粒( ¹²⁵I-UdR-CS-DLN),并进一步分析其药物缓释性能和肿瘤靶向性。方法 采用离子交联法制备CS纳米微粒,以单因素分析和正交试验优化制备条件和工艺;用动态透析法分析其释放特性;激光共聚焦显微镜观察其肿瘤靶向性。结果 按照CS浓度1 g/L,搅拌速度600 r/min,TPP浓度2 g/L,相对分子质量为3×10³的条件下得到平均粒径(70.39±5.12) nm的纳米微粒(PDI为0.16±0.012)。透射电镜观察其外观为规整的球形,大小均匀,分散度较好。在投药量为2.96 MBq/ml、pH值为5的条件下, ¹²⁵I-UdR-CS-DLN的载药量1253.55 MBq/g,包封率42.35%,具有明显的缓释作用。激光共聚焦显微镜观察结果证明肿瘤细胞在2 h内摄入的纳米粒子明显多于正常细胞。结论 成功制备了直径为(127.81±15.25) nm (PDI 为0.240±0.035)的 ¹²⁵I-UdR-CS-DLN,确定了最佳工艺条件。所制备的纳米粒子具有典型的长效缓释制剂特性,并具有肿瘤细胞被动靶向性,为 ¹²⁵I-UdR应用于肿瘤内照射治疗提供了更有效的途径。     

131I标记纳米脂质体靶向治疗结肠癌的实验研究

目的 研究¹³¹I-antiEGFR-BSA-PCL对LS180细胞结肠癌裸鼠移植瘤内照射的治疗效果。方法 构建抗表皮生长因子受体(EGFR)标记的纳米脂质体及EGFR靶向性。通过荧光共聚焦显微镜、细胞摄碘实验观察纳米载体的靶向性及LS180细胞对其摄取情况。将裸鼠40只按随机数字表法分为4组,通过瘤体内注射的方式向移植瘤内分别注射74 MBq (740 MBq/ml) ¹³¹I-antiEGFR-BSA-PCL、¹³¹I-BSA-PCL、¹³¹I及相同体积的生理盐水。通过研究裸鼠体重、肿瘤体积、SPECT显像及组织病理学方法,观察纳米脂质体的抑瘤效果。结果 共聚焦实验显示,与BSA-PCL组相比,antiEGFR-BSA-PCL组细胞内绿色荧光较明显,其介导的胞吞效应显著。摄碘率实验中,LS180细胞对¹³¹I-antiEGFR-BSA-PCL的摄取率明显高于¹³¹I-BSA-PCL(t=2.77~5.40,P<0.01)。¹³¹I-antiEGFR-BSA-PCL组与¹³¹I-BSA-PCL组裸鼠肿瘤增殖均较慢,二者差异无统计学意义(P>0.05)。给药后72 h,¹³¹I-antiEGFR-BSA-PCL与¹³¹I-BSA-PCL的肿瘤摄取率分别为(21.61±1.01)和(20.58±0.65)% ID/g,均明显高于¹³¹I组(t=9.36、8.69,P<0.01)。SPECT显像显示纳米脂质体主要特异性积聚在肿瘤区。结论 ¹³¹I-antiEGFR-BSA-PCL对LS180结肠癌裸鼠移植瘤有明显的抑制作用。     

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.     

Comparative assessment of18F-fluorodeoxyglucose PET and99mTc-tetrofosmin SPECT for the prediction of functional recovery in patients with reperfused acute myocardial infarction

Purpose: Although preserved glucose metabolism is considered to be a marker of myocardial viability in the chronic stage, it has not been fully elucidated whether this is also true with regard to reperfused acute myocardial infarction (AMI). The aim of this study was to compare the diagnostic performance of^99mTc-tetrofosmin SPECT and¹⁸F-fluorodeoxyglucose (FDG) PET for the prediction of functional recovery in reperfused AMI.Methods: The study population comprised 28 patients. Both tetrofosmin SPECT and FDG PET were performed in all 28 patients at ca. 2 weeks and in 23 at 6 months. The tetrofosmin and FDG findings in infarct-related segments were compared with the regional wall motion score assessed by left ventriculography over 6 months to determine the predictive value for functional recovery.Results: Of 120 infarct-related segments, 83 had preserved flow (tetrofosmin uptake ≥50%) and 81 had preserved glucose metabolism (FDG uptake ≥40%). The sensitivity and specificity of tetrofosmin SPECT for the prediction of functional recovery tended to be superior to those of FDG PET (90.0% and 72.5% vs 85.0% and 67.5%, respectively). Thirteen segments with preserved flow and decreased glucose metabolism demonstrated marked recovery of contractile function from 2.5±1.0 to 1.4±1.4 (p<0.01), with restoration of glucose metabolism at 6 months. In contrast, 11 segments with decreased flow and preserved glucose metabolism demonstrated incomplete functional improvement from 3.0±0.8 to 2.2±1.2.Conclusion: In the subacute phase, preserved myocardial blood flow is more reliable than glucose metabolism in predicting functional recovery in reperfused myocardium.