99mTc-labeled Agents Research Articles

The Role of Myocardial Perfusion Imaging in Patients with Diabetes Mellitus

Abstract Diabetes mellitus is a complex pathology with increasing incidence, associated with an increased risk of coronary heart disease. Myocardial perfusion imaging (MPI) is an important diagnostic tool for the evaluation of coronary artery disease (CAD), with a high prognostic value. Objective. The aim of this study was to evaluate the role of stress-rest MPI in the assessment of patients with DM and suspected or confirmed CAD. Method. We performed a retrospective analysis of 128 patients who underwent stress-rest MPI in our department, all of them with coronary angiography (CA) available. All patients underwent stress rest myocardial perfusion SPECT using a 1-day or 2-day protocol. The radiopharmaceuticals used were 99m-Tc-MIBI or tetrofosmin. The study was performed with a gated protocol SPECT, synchronous with the ECG, using a dual-head gamma camera. Patients were divided in 4 subgroups based on the presence of DM and of significant CA changes. Results. In the group of patients with significant coronary disease on CA and previously diagnosed DM, number of perfusion defects on the stress-rest MPI were higher and also the presence of systolic disfunction and the severity of defects. Our results support the idea that the severity and extent of myocardial perfusion defects are greater in diabetic patients than in non-diabetic patients. Conclusions. We can consider myocardial perfusion SPECT with 99mTc-labeled agents as a feasible method for the diagnosis and evaluation of CAD and for the management of diabetic patients.

Pattern of myocardial 99mTc-HMDP uptake and impact on myocardial function in patients with transthyretin cardiac amyloidosis

AimsThe purpose of the study was to describe the pattern of 99mTc-labeled phosphate agents myocardial uptake by scintigraphy and explore its impact on left ventricular (LV) functions in transthyretin cardiac amyloidosis (TTR-CA). MethodsFifty patients with TTR-CA underwent 99mTc- hydroxymethylene-diphosphonate (99mTc-HMDP) scintigraphy and echocardiography with measure of LV thickness, longitudinal strain (LS), systolic and diastolic functions. Cardiac retention by scintigraphy was assessed by visual scoring and the heart/whole body (H/WB) ratio was calculated by dividing counts in the heart by counts in late whole-body images. ResultsThe mean population age was 79 ± 10 years. Mean H/WB ratio was 12 ± 7. Myocardial 99mTc-HMDP uptake on segments 5, 6, 7, 8, 11, 12, 13, 14, 16, and 17 was correlated with H/WB ratio. Mean LVEF and global LS were 51 ± 10% and − 10 ± 3%, respectively. H/WB ratio was correlated with global LS (R = 0.408, P = .003), Ea (R = − 0.566, P < .001) and mean left ventricular wall thickness (R = 0.476, P < .001) but not with LVEF (R = − 0.109, P = .453). Segmental myocardial uptake was slightly correlated with segmental LS (R = 0.152, P < .001). H/WB ratio was not correlated with NT-proBNP levels (R = 0.219, P = .148) neither E/Ea ratio (R = 0.204, P = .184). ConclusionThese findings show the relationship between bone tracer myocardial uptake and LV functions in patients with TTR cardiac amyloidosis.

Impact of cardiac 99mTc-HMDP uptake on myocardial function and left ventricular filling pressure in patients with transthyretin amyloidosis

Background Pathophysiology of 99mTc-labeled phosphate agents cardiac uptake by scintigraphy in transthyretin-related (TTR) amyloidosis remains unclear. The impact of cardiac uptake on cardiac function is unknown. The aim of this study was to explore the pattern of 99mTc-labeled phosphate agents cardiac uptake by scintigraphy and its impact on left ventricular (LV) functions assessed by echocardiography. Methods Fifty patients with TTR cardiac amyloidosis underwent 99mTc- hydroxymethylene-diphosphonate (99mTc-HMDP) scintigraphy and echocardiography with measure of LV morphology, longitudinal strain (LS), systolic and diastolic functions. Cardiac retention by scintigraphy was assessed by visual scoring and the heart/whole body (H/B) ratio was calculated by dividing counts in the heart by counts in late whole body images. Results The mean population age was 79 ± 10 years. Most of the patients (88%) were male. Visual score was 2 and 3 for 6 (12%) and 44 (88%) patients, respectively. Mean H/WB ratio was 12 ± 7. Mean LV ejection fraction and global LS were 51 ± 10% and -10 ± 3%, respectively. H/WB ratio was correlated with global LS (R = 0.408, P = 0.003), Ea (R = -0.566, P < 0.001) and mean left ventricular wall thickness (R = 0.476, P < 0.001) but not with LV ejection fraction (R = -0.109, P = 0.453). Segmental myocardial uptake normalized by H/WB ratio was correlated with segmental LS (n = 850 segments, R = 0.162, P < 0.001). H/WB ratio was not correlated with NT-proBNP levels (R = 0.219, P = 0.148) neither E/Ea ratio (R = 0.204, P = 0.184). Conclusion In patients with TTR cardiac amyloidosis, myocardial uptake by 99mTc-HMDP scintigraphy is correlated with decrease of myocardial LS.

Bone scintigraphy for cardiac amyloidosis imaging: Past, present and future

The aim of the article was to review the history of the emergence of 99mTc-labeled phosphate agents in the exploration of cardiac amyloidosis and the give an overview of the technique, its accuracy and its application in clinical practice. Potential future directions are mentioned.

Preparation and Biodistribution of Technetium-99m-Labeled Bis- Misonidazole (MISO) as an Imaging Agent for Tumour Hypoxia.

Diagnosis of tumour hypoxia is an important aspect in determining the course of tumour therapy. In this study, we developed a novel imaging agent, (99m)Tc-ethylenedicysteine-bis-misonidazole ((99m)Tc-EC-MISO), for diagnosing tumour hypoxia. We used 2-nitroimidazole as a reactant to synthesize the amino derivative of misonidazole (MISO) in the first step and then conjugated the di-amino derivative of MISO to the chelating agent ethylenedicysteine (EC) for labelling (99m)Tc in the second step. (99m)Tc-pertechnetate ((99m)TcO4-) was reduced by tin chloride (SnCl2) for radiolabeling. The radiochemical purity was up to 94%. Tissue biodistribution and SPECT/CT imaging studies were conducted on subcutaneous gliomal tumour-bearing mice. The tumour-to-muscle ratio in the (99m)Tc-EC-MISO group increased with time, up to 4.6 at 4 h after injection. SPECT/CT imaging confirmed that the tumours could be visualized clearly with (99m)Tc-EC-MISO at 2 h. By introducing a second 2-nitroimidazole redox centre, an apparent hypoxic accumulation of this novel (99m)Tc-labeled imaging agent in the tumour was observed.

Radiolabeling and biological evaluation of the GX1 and RGD-GX1 peptide sequence for angiogenesis targeting

IntroductionAiming to develop a novel 99mTc-labeled imaging agent, for angiogenesis and tumor receptors, two peptides obtained from phage display library, namely GX1 and the heterodimer RGD-GX1, were synthesized in a cyclic conformation. They were radiolabeled with 99mTc, employing the HYNIC chelator, for radiochemical evaluation and biological properties. MethodsRadiolabeling, radiochemical control, plasma protein binding, and partition coefficient were assessed for both radioconjugates. Biodistribution in healthy Balb/c mice was carried out, in order to evaluate the biological behaviour of the radiocomplexes. ResultsThe conjugates displayed a rather similar pharmacokinetic profile. They were prepared with high radiochemical purity (>96%), and both were hydrophilic (log P of −2.25 and −2.51 respectively). Preferential renal excretion was observed. Kidney uptake (42.31±5.35 %ID/g) for 99mTc-HYNIC-E-[c(RGDfk)-c(GX1)], 1h post-injection was about three times higher than the uptake of 99mTc-HYNIC-PEG4-c(GX1) (11.92±4.77%ID/g). Total blood, bone and muscle values revealed a slightly slower clearance for the RGD-GX1 radiocomplex. ConclusionThe high radiochemical purity achieved, and the similar in vivo profile observed for both radioconjugates, make them potential candidates for radiopharmaceuticals for tumor imaging. Further investigations of binding affinity, and uptake of GX1 and RGD-GX1 peptides in tumor models, are warranted.

Synthesis and evaluation of a 99mTc-labeled tubulin-binding agent for tumor imaging.

Cholchicine and its derivatives are very potent tubulin-binding compounds and can be used as a potential tumor targeting agents. In this study, colchicine was labeled with (99m) Tc via hydrazinonicotinic acid (HYNIC) and was investigated further. HYNIC/cholchicine was synthesized and labeling with (99m)Tc was performed at 95 °C for 15 min and radiochemical analysis included HPLC method. The stability of radiconjugate was checked in the presence of human serum at 37 °C up to 24 h. Biodistribution was studied in breast tumor-bearing mice. Labeling yield of 95.8 ± 0.54% was obtained corresponding to a specific activity of 54 MBq/µmol. Radioconjugate showed good stability in the presence of human serum. Biodistribution studies in tumor-bearing mice showed that (99m) Tc/HYNIC/colchicine conjugate accumulated in tumor with good uptake (3.17 ± 0.14% g/g at 1 h post-injection). The radioconjugate was cleared fast from normal organs and showed clearance through urinary and hepatobiliary systems with accumulation of activity in kidneys and intestine. This radioconjugate may be useful to assess the presence of tumor by imaging.

Spatially resolved assessment of hepatic function using 99mTc‐IDA SPECT

99mTc-iminodiacetic acid (IDA) hepatobiliary imaging is usually quantified for hepatic function on the entire liver or regions of interest (ROIs) in the liver. The authors presented a method to estimate the hepatic extraction fraction (HEF) voxel-by-voxel from single-photon emission computed tomography (SPECT)∕CT with a 99mTc-labeled IDA agent of mebrofenin and evaluated the spatially resolved HEF measurements with an independent physiological measurement. Fourteen patients with intrahepatic cancers were treated with radiation therapy (RT) and imaged by 99mTc-mebrofenin SPECT before and 1 month after RT. The dynamic SPECT volumes were with a resolution of 3.9 × 3.9 × 2.5 mm(3). Throughout the whole liver with approximate 50 000 voxels, voxelwise HEF quantifications were estimated and compared between using arterial input function (AIF) from the heart and using vascular input function (VIF) from the spleen. The correlation between mean of the HEFs over the nontumor liver tissue and the overall liver function measured by Indocyanine green clearance half-time (T1∕2) was assessed. Variation of the voxelwise estimation was evaluated in ROIs drawn in relatively homogeneous regions of the livers. The authors also examined effects of the time range parameter on the voxelwise HEF quantification. Mean of the HEFs over the liver estimated using AIF significantly correlated with the physiological measurement T1∕2 (r = 0.52, p = 0.0004), and the correlation was greatly improved by using VIF (r = 0.79, p < 0.0001). The parameter of time range for the retention phase did not lead to a significant difference in the means of the HEFs in the ROIs. Using VIF and a retention phase time range of 7-30 min, the relative variation of the voxelwise HEF in the ROIs was 10% ± 6% of respective mean HEF. The voxelwise HEF derived from 99mTc-IDA SPECT by the deconvolution analysis is feasible to assess the spatial distribution of hepatic function in the liver.

Tc-99m-HL91 imaging in the early detection of neuronal injury in a neonatal rat model of hypoxic ischemia*

Hypoxic-ischemic insult in newborns results in progressive neuronal loss. For neuroprotective therapy to be effective, it is important to identify high-risk neonates soon after birth. 99mTc-labeled imaging agent, Tc-99m-HL91, developed as a putative hypoxic reagent, has been reported to demonstrate increased uptake in ischemic myocardium. We hypothesized that Tc-99m-HL91 is sensitive for the early identification of hypoxic-ischemic injury in neonatal rat brains. Laboratory investigation. University research laboratory. Sprague-Dawley rat pups. Postnatal day-7 pups were divided into four groups: hypoxic-ischemia, hypoxia-only, ischemia-only, and controls. In the early (2 hrs), intermediate (20 hrs), and late (44 hrs) reoxygenation phases, Tc-99m-HL91 in vivo and ex vivo imaging and quantitative autoradiography were performed. Regions of interest were drawn to calculate the contrast ratio of Tc-99m-HL91 uptake between the ipsilateral and contralateral hemispheres. Pathology, cerebral blood flow, and blood-brain barrier damage were determined. After hypoxic-ischemia, there were very few pyknotic neurons in the early phase, many pyknotic neurons in the intermediate phase, and extensive neuronal loss in the late phase postreoxygenation. Blood-brain barrier damage occurred in the early phase, progressed in the intermediate phase, and became extensive in the late phase. The hypoxia-only and ischemia-only pups showed no neuronal or blood-brain barrier damage and had higher cerebral blood flow postreoxygenation compared with the hypoxia-ischemia pups. Regions of interest analysis of in vivo and ex vivo images and autoradiography revealed significantly higher Tc-99m-HL91 contrast ratio at early and intermediate phases, not late phase of hypoxic-ischemic group. Hypoxic-ischemia group had significantly higher contrast ratio values in the early and intermediate phases than the hypoxia-only and ischemia-only groups. A contrast ratio value of 0.15 in the early phase on postnatal day 7 had a sensitivity of 0.95 and specificity of 0.89 in detecting significant hypoxic-ischemic lesions on postnatal day 21. Tc-99m-HL91 uptake is sensitive for the early detection of hypoxic-ischemic injury in neonatal brains.

Abstract 5231: Tilmaocept: A novel biotargeted agent for enhanced intraoperative discrimination of sentinel lymph nodes in breast cancer, melanoma, and head &amp; neck SCC

Abstract Sentinel lymph node (SLN) mapping and identification is a primary component of surgical therapies for breast cancers, melanomas, pediatric soft tissue sarcomas, and certain other cancers. The current standard of care for identifying SLNs to inject into a tumor (or near a tumor) a blue dye (often called “vital blue dye”), of which several are available, in conjunction with a radiolabeled (99mTc) tracer, available as either a technetium sulfur colloid or as a technetium labeled albumin formulation. The exact formulations used vary, especially between those used in the United States and Europe. All such compounds are effectively agents of passive transport in the lymphatic ducts and are “inert” with regard to any biomarker recognition specificity. Allegedly, such agents move passively from the tumor/tumor basin into lymph nodes with a presumptive tumor-node anatomic nexus and the nodes are elucidated as blue and/or radioactive, the former based on excision line-of-sight, the latter based on intraoperative evaluation with a gamma-detecting probe. But because such components do not bear any specificity, that is, bind or accumulate lymph nodes bearing targets, they either remain static at the injection site and/or quickly drain away, reducing their real-time clinical effectiveness. A novel 99mTc-labeled, prospectively designed, low Mr molecule (99mTc DTPA Mannosyl Dextran; Tilmanocept) targeted as a ligand for the mannose binding receptor (MBR) of lymphatic reticuloendothelial cells and intended for real-time intraoperative gamma mapping of tumor-lymphatic nexuses has been synthesized and clinically tested in Phase 3 clinical studies in breast cancer and melanoma. The results of the development process and clinical testing indicate: 1) The prospective molecular designs resulted in safety and clinical performance characteristics that provided times from agent injection to patient evaluation that were significantly reduced compared to currently applied 99mTc-labeled agents; and 2) The specificity, sensitivity, and performance with regard to anatomic localization, false negative rates, and receptor retention exceed those of other colorimetric and 99mTc-labeled agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5231. doi:10.1158/1538-7445.AM2011-5231

A Phase 2 Study of 99mTc-Tilmanocept in the Detection of Sentinel Lymph Nodes in Melanoma and Breast Cancer

Several (99m)Tc-labeled agents that are not approved by the U.S. Food and Drug Administration are used for lymphatic mapping. A new low-molecular-weight mannose receptor-based, reticuloendothelial cell-directed, (99m)Tc-labeled lymphatic imaging agent, (99m)Tc-tilmanocept, was used for lymphatic mapping of sentinel lymph nodes (SLNs) from patients with primary breast cancer or melanoma malignancies. This novel molecular species provides the basis for potentially enhanced SLN mapping reliability. In a prospectively planned, open-label phase 2 clinical study, (99m)Tc-tilmanocept was injected into breast cancer and cutaneous melanoma patients before intraoperative lymphatic mapping. Injection technique, preoperative lymphoscintigraphy (LS), and intraoperative lymphatic mapping with a handheld gamma detection probe were performed by investigators per standard practice. Seventy-eight patients underwent (99m)Tc-tilmanocept injection and were evaluated (47 melanoma, 31 breast cancer). For those whom LS was performed (55 patients, 70.5%), a (99m)Tc-tilmanocept hot spot was identified in 94.5% of LS patients before surgery. Intraoperatively, (99m)Tc-tilmanocept identified at least one regional SLN in 75 (96.2%) of 78 patients: 46 (97.9%) of 47 in melanoma and 29 (93.5%) of 31 in breast cancer cases. Tissue specificity of (99m)Tc-tilmanocept for lymph nodes was 100%, displaying 95.1% mapping sensitivity by localizing in 173 of 182 nodes removed during surgery. The overall proportion of (99m)Tc-tilmanocept-identified nodes that contained metastatic disease was 13.7%. Five procedure-related serious adverse events occurred, none related to (99m)Tc-tilmanocept. Our results demonstrate the safety and efficacy of (99m)Tc-tilmanocept for use in intraoperative lymphatic mapping. The high intraoperative localization and lymph node specificity of (99m)Tc-tilmanocept and the identification of metastatic disease within the nodes suggest SLNs are effectively identified by this novel mannose receptor-targeted molecule.

Three-Dimensional Ordered-Subset Expectation Maximization Iterative Protocol for Evaluation of Left Ventricular Volumes and Function by Quantitative Gated SPECT: A Dynamic Phantom Study

The purposes of this study were to characterize the performance of a 3-dimensional (3D) ordered-subset expectation maximization (OSEM) algorithm in the quantification of left ventricular (LV) function with (99m)Tc-labeled agent gated SPECT (G-SPECT), the QGS program, and a beating-heart phantom and to optimize the reconstruction parameters for clinical applications. A G-SPECT image of a dynamic heart phantom simulating the beating left ventricle was acquired. The exact volumes of the phantom were known and were as follows: end-diastolic volume (EDV) of 112 mL, end-systolic volume (ESV) of 37 mL, and stroke volume (SV) of 75 mL; these volumes produced an LV ejection fraction (LVEF) of 67%. Tomographic reconstructions were obtained after 10-20 iterations (I) with 4, 8, and 16 subsets (S) at full width at half maximum (FWHM) gaussian postprocessing filter cutoff values of 8-15 mm. The QGS program was used for quantitative measurements. Measured values ranged from 72 to 92 mL for EDV, from 18 to 32 mL for ESV, and from 54 to 63 mL for SV, and the calculated LVEF ranged from 65% to 76%. Overall, the combination of 10 I, 8 S, and a cutoff filter value of 10 mm produced the most accurate results. The plot of the measures with respect to the expectation maximization-equivalent iterations (I x S product) revealed a bell-shaped curve for the LV volumes and a reverse distribution for the LVEF, with the best results in the intermediate range. In particular, FWHM cutoff values exceeding 10 mm affected the estimation of the LV volumes. The QGS program is able to correctly calculate the LVEF when used in association with an optimized 3D OSEM algorithm (8 S, 10 I, and FWHM of 10 mm) but underestimates the LV volumes. However, various combinations of technical parameters, including a limited range of I and S (80-160 expectation maximization-equivalent iterations) and low cutoff values (< or =10 mm) for the gaussian postprocessing filter, produced results with similar accuracies and without clinically relevant differences in the LV volumes and the estimated LVEF.

Unconventional Nuclides for Radiopharmaceuticals

Rapid and widespread growth in the use of nuclear medicine for both diagnosis and therapy of disease has been the driving force behind burgeoning research interests in the design of novel radiopharmaceuticals. Until recently, the majority of clinical and basic science research has focused on the development of 11C-, 13N-, 15O-, and 18F-radiopharmaceuticals for use with positron emission tomography (PET) and 99mTc-labeled agents for use with single-photon emission computed tomography (SPECT). With the increased availability of small, low-energy cyclotrons and improvements in both cyclotron targetry and purification chemistries, the use of "nonstandard" radionuclides is becoming more prevalent. This brief review describes the physical characteristics of 60 radionuclides, including beta+, beta-, gamma-ray, and alpha-particle emitters, which have the potential for use in the design and synthesis of the next generation of diagnostic and/or radiotherapeutic drugs. As the decay processes of many of the radionuclides described herein involve emission of high-energy gamma-rays, relevant shielding and radiation safety issues are also considered. In particular, the properties and safety considerations associated with the increasingly prevalent PET nuclides 64Cu, 68Ga, 86Y, 89Zr, and 124I are discussed.

Radiopharmaceutical Agents for Myocardial Perfusion Imaging

Myocardial perfusion imaging (MPI) is a well-established noninvasive method of assessing coronary blood flow.1–5 MPI is capable of identifying regional abnormalities in coronary artery blood flow and determining their physiological relevance to myocardial function and viability. MPI requires the intravenous injection of a radioactive blood flow marker followed by imaging of regional myocardial uptake.6–10 Imaging is most frequently performed by tomographic techniques (ie, SPECT [single-photon emission computerized tomography]) with electrocardiographically synchronized image gating. Used frequently in conjunction with either physical exercise or pharmacological stress, MPI is useful in unmasking myocardial perfusion deficits not evident at rest. A thorough discussion of clinical indications for MPI is beyond the scope of this review, but the reader is referred to recently published consensus committee documents.11,12 Three radioactive blood flow markers (RBFMs) are clinically available and in widespread use: (1) thallium Tl 201 chloride, (2) technetium Tc-99m sestamibi (Cardiolite; Lantheus Medical Imaging, North Billerica, Mass), and (3) technetium Tc-99m tetrofosmin (Myoview; GE Healthcare, Princeton, NJ). In the present review, these agents will be referred to by their nonproprietary names. The oldest of the 3 RBFMs, thallium 201, has been in use since approximately 1980, and the original experimental and clinical validation studies of MPI were performed with this agent.1,13–16 More recently, 99mTc-labeled sestamibi, approved in 1990, and tetrofosmin, approved in 1995, have been developed and validated clinically.6–8,17,18 In comparative imaging studies analyzed for accuracy (sensitivity, specificity, and normalcy rates), no obvious differences have been found among these 3 agents. Each RBFM has unique properties that determine the logistics of its use and its test performance characteristics. The purpose of the present review is to compare and contrast these 3 RBFMs. It is hoped this detailed overview will assist clinicians in choosing which agent(s) to use and in understanding …

Diastolic Filling Parameters Derived from Myocardial Perfusion Imaging Can Predict Left Ventricular End-Diastolic Pressure at Subsequent Cardiac Catheterization

Morbidity and mortality increase when diastolic dysfunction accompanies coronary artery disease (CAD). An elevated stress (201)Tl lung-to-heart ratio (LHR) is a traditional marker of elevated left ventricular end-diastolic pressure (LVEDP), which adds prognostic value in CAD. Since the introduction of (99m)Tc-labeled agents, this valuable marker has been lost. Hence, there is only a limited ability to assess diastolic dysfunction by myocardial perfusion imaging (MPI). Fifty-two consecutive patients with an ejection fraction of >or=45% underwent MPI and cardiac catheterization within 15 d. Peak filling rate (PFR), time to PFR (TPFR), and filling rate during the first third of diastole (1/3FR) were obtained from MPI with SPECT software. Resting (201)Tl LHR was calculated manually, and LVEDP was obtained at catheterization. PFR, TPFR, and 1/3FR correlated significantly with LVEDP (r= -0.53, 0.45, and -0.45, respectively; P=0.00005, 0.0009, and 0.0009, respectively), whereas resting (201)Tl LHR did not (r=0.10, P=0.49). Receiver-operating-characteristic curve analysis of PFR, TPFR, and 1/3FR for detecting LVEDPs of >or=18 mm Hg showed areas under the curve of 0.83, 0.75, and 0.80, respectively. The combination of PFR and 1/3FR showed a negative predictive value of 84%, a positive predictive value of 86%, and a specificity of 94%. Diastolic filling variables obtained with the SPECT software showed a significant correlation with LVEDP. PFR, TPFR, and 1/3FR were superior to resting (201)Tl LHR and showed good sensitivity, specificity, and predictive power for detecting LVEDPs of >or=18 mm Hg. Hence, combining data on the presence of perfusion defects with data on diastolic impairments can be achieved by adding these variables to MPI results.

Absolute quantitation of myocardial blood flow with 201Tl and dynamic SPECT in canine: optimisation and validation of kinetic modelling

201Tl has been extensively used for myocardial perfusion and viability assessment. Unlike 99mTc-labelled agents, such as 99mTc-sestamibi and 99mTc-tetrofosmine, the regional concentration of 201Tl varies with time. This study is intended to validate a kinetic modelling approach for in vivo quantitative estimation of regional myocardial blood flow (MBF) and volume of distribution of 201Tl using dynamic SPECT. Dynamic SPECT was carried out on 20 normal canines after the intravenous administration of 201Tl using a commercial SPECT system. Seven animals were studied at rest, nine during adenosine infusion, and four after beta-blocker administration. Quantitative images were reconstructed with a previously validated technique, employing OS-EM with attenuation-correction, and transmission-dependent convolution subtraction scatter correction. Measured regional time-activity curves in myocardial segments were fitted to two- and three-compartment models. Regional MBF was defined as the influx rate constant (K(1)) with corrections for the partial volume effect, haematocrit and limited first-pass extraction fraction, and was compared with that determined from radio-labelled microspheres experiments. Regional time-activity curves responded well to pharmacological stress. Quantitative MBF values were higher with adenosine and decreased after beta-blocker compared to a resting condition. MBFs obtained with SPECT (MBF(SPECT)) correlated well with the MBF values obtained by the radio-labelled microspheres (MBF(MS)) (MBF(SPECT) = -0.067 + 1.042 x MBF(MS), p < 0.001). The three-compartment model provided better fit than the two-compartment model, but the difference in MBF values between the two methods was small and could be accounted for with a simple linear regression. Absolute quantitation of regional MBF, for a wide physiological flow range, appears to be feasible using 201Tl and dynamic SPECT.

Biphenyls labeled with technetium 99m for imaging β-amyloid plaques in the brain

Formation and accumulation of excess aggregates of β-amyloid (Aβ) plaques in the brain are critical factors contributing to the development and progression of Alzheimer's disease (AD). There is an urgent need for in vivo imaging agents that can specifically demonstrate the location and density of Aβ plaques in the brain. The aim of this study was to develop potential technetium 99m ( 99mTc)-labeled diagnostic imaging agents specific for the detection of Aβ plaques. Based on previously obtained Aβ plaque-specific biphenyls containing a p- N, N-dimethylaminophenyl group, a series of 99mTc and Re–N 2S 2–biphenyl derivatives was prepared. The stable neutral and lipophilic 99mTc complexes, [ 99mTc] 19 and [ 99mTc] 23, A+B, were successfully obtained. As surrogates for the 99mTc complexes, the corresponding surrogates, Re complexes of 23, were also prepared. Surprisingly, it was found that the Re complexes showed distinctively different retention profiles as compared with the corresponding 99mTc complexes. Biodistribution studies indicated that [ 99mTc] 23A readily passed through the blood–brain barrier (1.18% dose/brain at 2 min) in contrast to the low brain penetration of [ 99mTc] 19 (0.29% dose/brain at 2 min). Initial results suggested that [ 99mTc] 23A showed selective binding to the Aβ plaque-like structures in the brain sections from transgenic mice but not in the postmortem human brain tissue of patients with confirmed AD. The results provide encouraging evidence that development of a 99mTc-labeled agent for imaging Aβ plaques in the brain may be feasible. Caution should be taken when comparing these 99mTc complexes with the corresponding surrogates — the Re complexes.

Image improvement in pinhole SPECT using complete data acquisition combined with statistical image reconstruction

Pinhole single-photon emission computed tomography (SPECT) with high spatial-resolution is suitable for small-animal imaging, but has limitations associated with spatial-resolution inhomogeneity or axial blurring. We have hypothesized that this blurring is due to incompleteness of projection data acquired by a single circular pinhole orbit. And we have developed a pinhole SPECT system with two circular orbits which satisfy Tuy's condition so as to provide complete data for 3D pinhole SPECT reconstruction within the whole field-of-view (FOV); a dedicated 3D ordered subsets expectation maximization (3D-OSEM) reconstruction method for two-orbit data. This study is aimed at evaluating accuracy and impact of this system. In this system, not the camera but the object rotates and the two orbits are 90° and 45° relative to object's axis. Experiments using a multiple-disk phantom filled with 99mTc solution and a mouse bone scan using 99mTc-labeled HMDP agent were carried out. The Feldkamp's filtered back-projection (FBP) method and the 3D-OSEM method were applied to these data sets. The axial blurring was apparent on images reconstructed by FBP for single-orbit data, while the 3D-OSEM using two-orbit data dramatically improved the resolution homogeneity and statistical noise property, and also demonstrated considerably better image quality in the mouse scan.

Synthesis of stereoisomers of 6β- and 7β-(benzylthio)-3-(p-tolyl) tropane-2-carboxylic acid methyl ester

To develop new 99mTc-labelled agents to evaluate dopamine transporters (DAT) involved in Parkinson's disease, by in vivo SPECT imaging, we have synthesized six new sulfur-containing ligands with the tropane skeleton. We have introduced the complexing sulfur atom far from the three sites of recognition by DAT of these tropane derivatives. The 6β-substituted tropinone has been obtained by a double Mannich condensation followed by the introduction of the moieties for molecular interactions at the binding site on C2 and C3, leading to the six stereoisomers.

Imaging recognition of multidrug resistance in human breast tumors using 99mTc-labeled monocationic agents and a high-resolution stationary SPECT system

Imaging recognition of multidrug-resistance by 99mTc-labeled sestamibi, tetrofosmin and furifosmin in mice bearing human breast tumors was evaluated using a high-resolution SPECT, FASTSPECT. Imaging results showed that the washout rates in drug-resistant MCF7/D40 tumors were significantly greater than that in drug-sensitive MCF7/S tumors. Furifosmin exhibited greater washout from both MCF7/S and MCF7/D40 than sestamibi, while tetrofosmin washout was greater than sestamibi in MCF7/D40 only. Feasibility of the monocationic agents for characterizing MDR expression was well clarified with FASTSPECT imaging.