Technetium-99m Radiopharmaceuticals for Ideal Myocardial Perfusion Imaging: Lost and Found Opportunities.

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [99mTc]Tc-Sestamibi, [99mTc]Tc-Tetrofosmin, and [99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [99mTc]Tc-Sestamibi and [99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in 99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies.

Influence of single photon emission computed tomography (SPECT) reconstruction algorithm on diagnostic accuracy of parathyroid scintigraphy: Comparison of iterative reconstruction with filtered backprojection.

BACKGROUND & OBJECTIVES: Preoperative localization of parathyroid lesions is essential for improving the results in patients with primary hyperparathyroidism. The purpose of this study was to evaluate retrospectively the value of technetium-99m (Tc-99m) methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) and to compare the diagnostic accuracy of iterative reconstruction (IR) and filtered backprojection (FBP) reconstruction algorithms about localization of parathyroid lesions. METHODS: Forty four patients with primary hyperparathyroidism, in whom histopathological correlation could be performed, were included in the study. Dual-phase Tc-99m parathyroid scintigraphy was performed 20 and 120 min after injection of 740 MBq Tc-99m MIBI in all patients. Tomographic images were acquired 120 min after the administration of radiopharmaceutical. The SPECT data were evaluated using an IR as well as a FBP algorithm. In 23 of 44 patients, SPECT acquisitions were performed in 64×64 matrix; in the remaining 21 patients, tomographic data were collected in 128×128 matrix. The imaging results were compared with pathological findings and sensitivities of both reconstruction algorithms, and planar views were calculated. RESULTS: Using planar MIBI scans, abnormal parathyroid glands were correctly localized in 75 per cent of the cases. Sensitivity increased to 77 per cent using SPECT with FBP and to 84 per cent with IR. When the sensitivities were calculated according to the acquisition matrix, these were 95 per cent (20/21) and 85 per cent (18/21) for IR and FBP, respectively in patients in whom 128×128 matrix was used. The sensitivities were lower in patients who were imaged with 64×64 matrix; these were calculated as 74 per cent (17/23) and 70 per cent (16/23) with IR and FBP, respectively. INTERPRETATION & CONCLUSIONS: Our findings showed that compared to planar scintigraphy, Tc-99m MIBI SPECT was more sensitive diagnostic modality in the detection of abnormal parathyroid tissues. Image quality and sensitivity may be improved further when larger matrices with IR are used instead of FBP algorithm.

(99m)Tc(CO)(3)-Ibritumomab tiuxetan; a novel radioimmunoimaging (RII) agent of B cell non-Hodgkin's lymphoma (NHL).

To exploit the B-lymphocyte antigen-CD20 binding capacity of the Ibritumomab tiuxetan (IBTN) monoclonal antibody (mAb) for imaging, the over-expression of B cells in non-Hodgkin's lymphoma (NHL) (a myeloproliferative disorder of the lymphatic system) was investigated. In the current investigation, we present the labeling of the IBTN with technetium-99m ((99m)Tc) through [(99m)Tc(CO)(3)](+) precursor for radioimmunoimaging (RII) of the tumor prior to its treatment with (90)Y labeled IBTN. Labeled IBTN was radiobiologically characterized in terms of radiochemical purity, in vitro stability in human plasma, immunoreactivity, binding with Raji and Ramos cells and biodistribution in a female nude mouse (FNM) model. It was observed that the reduced IBTN (rIBTN) showed more promising radiobiologic characteristics than the nonreduced IBTN. Significantly higher transchelation was seen in excess cysteine compared with histidine. The radioconjugate showed higher saturated binding affinity with CD20 antigen. Significantly higher target (tumor) to background ratios were observed 1 h post-injection (p.i.). Based on radiochemical purity, in vitro stability, immunoreactivity, binding and biodistrubtion in the FNM model, we recommend the radiolabeling of the rIBTN using tricarbonyl technique as a potential RII agent.

Technetium-99m-labeled ceftizoxime loaded long-circulating and pH-sensitive liposomes used to identify osteomyelitis.

Osteomyelitis is an infectious disease located in the bone or bone marrow. Long-circulating and pH-sensitive liposomes containing a technetium-99m-labeled antibiotic, ceftizoxime, (SpHL-(99m)Tc-CF) were developed to identify osteomyelitis foci. Biodistribution studies and scintigraphic images of bone infection or non infection-bearing rats that had been treated with these liposomes were performed. A high accumulation in infectious foci and high values in the target-non target ratio could be observed. These results indicate the potential of SpHL-(99m)Tc-CF as a potential agent for the diagnosis of bone infections.

Optimization of newly developed and lead shields thicknesses for protecting taxi drivers from 99mTc injected patients.

Presently, public members are exposed to sources of ionizing radiation, and health risks due to radiation exposures should be a concern. This study aims to calculate the whole-body cumulative radiation exposure of taxi drivers. Also, this study will provide the effect of using a simple lead shield and three types of glass shield AVT6, TZN-D, and SLGC-E5, by calculating the effective annual dose of the taxi drivers that work in medical centers. Two MIRD phantoms as a driver and patient, a sample body of a taxi, pure lead, and glass sheets as a shield, were simulated using the MCNP code. We assumed that the patients had undergone the brain, liver, and kidney SPECT imaging by injecting 99mTC-HMPAO, 99mTC-sulfur colloid, and 99mTC-DMSA with the activity of 740MBq, 185MBq, and 333MBq, respectively. These shields are simulated on two sides of the driver, in the back and right side. The annual effective dose was calculated for 0-3.5 g/cm2 area densities. It was observed that the 0.45, 1.09, 1.28, and 2.11 g/cm2 of Pb, TZN-D, AVT6, and SLGC-E5 respectively decrease the effective dose below the allowed limit. According to the results, using the lead shield, the effective dose was reduced by a factor up to 7.25 times. It is recommended that taxi drivers wear a 0.4 mm lead shield or its equivalent when they have Tc-99 m injected patients.

Preclinical evaluation of DO3P-AME-DO3P: a polyazamacrocyclic methylene phosphonate for diagnosis and therapy of skeletal metastases.

A phosphonate derivative 10'-bis(acetamido)-ethane-bis[1,4,7-tri(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane] (DO3P-AME-DO3P), was synthesized with 90% yield in high purity. It was labeled with (99m)Tc in 97.5% efficiency and specific activity of 112-250 MBq/µmol. The binding affinity of (99m)Tc-DO3P-AME-DO3P towards bone minerals was tested in vitro by using hydroxy apatite as a bone model with absorption of 93% during the first hour of the experiment. Receptor binding assay on human bone cell line SAOS-2 demonstrated K(d) value of 1.07 nM. Cell binding studies of DO3P-AME-DO3P on osteoblasts and osteoclasts cells performed in vitro displayed preferential affinity of the compound towards osteoclast (167.95 ± 3.56% dose/mg protein). The serum stability of (99m)Tc complex was found to be 96.8% after 24 h. Blood kinetics of (99m)Tc-DO3P-AME-DO3P performed on normal rabbits showed fast clearance with t(1/2)(F) = 15 min ± 0.014 min and t(1/2)(S) = 4 h 3 min ± 0.09 min. Biodistribution studies carried out in normal BALB/c mice showed bone-to-blood ratio of 20 and bone-to-muscle ratio of 33. The bone tissue demonstrated highest concentration of bound radioactivity with 10.73% ID/g at 1 h post injection. The protonation and stability constants were determined by pH-potentiometry titrations. The stability constants of DO3P-AME-DO3P with Lu(III), Sm(III), and Ho(III) were 19.7, 21.8, and 20.2 determined by "out of cell" method. The excellent bone seeking properties of DO3P-AME-DO3P make it a candidate of choice for SPECT imaging and preferential uptake of the compound in osteoclasts in comparison to osteoblasts; BMM and BMC can be used to understand the pathway of pathogenesis of osteoporosis and skeletal metastases.

Evaluating 99mTc Auger electrons for targeted tumor radiotherapy by computational methods.

PURPOSE: Technetium-99m (99mTc) has been widely used as an imaging agent but only recently has been considered for therapeutic applications. This study aims to analyze the potential use of 99mTc Auger electrons for targeted tumor radiotherapy by evaluating the DNA damage and its probability of correct repair and by studying the cellular kinetics, following 99mTc Auger electron irradiation in comparison to iodine-131 (131I) beta minus particles and astatine-211 (211At) alpha particle irradiation. METHODS: Computational models were used to estimate the yield of DNA damage (fast Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision repair algorithm), and cell kinetic effects (virtual cell radiobiology algorithm) after irradiation with the selected particles. RESULTS: The results obtained with the algorithms used suggested that 99mTc CKMMX (all M-shell Coster-Kroning--CK--and super-CK transitions) electrons and Auger MXY (all M-shell Auger transitions) have a therapeutic potential comparable to high linear energy transfer 211At alpha particles and higher than 131I beta minus particles. All the other 99mTc electrons had a therapeutic potential similar to 131I beta minus particles. CONCLUSIONS: 99mTc CKMMX electrons and Auger MXY presented a higher probability to induce apoptosis than 131I beta minus particles and a probability similar to 211At alpha particles. Based on the results here, 99mTc CKMMX electrons and Auger MXY are useful electrons for targeted tumor radiotherapy.

Olmesartan, an angiotensin II receptor blocker, restores cerebral hypoperfusion in elderly patients with hypertension.

We evaluated the effects of olmesartan, an angiotensin II receptor blocker (ARB), on cerebral blood flow (CBF) in elderly and hypertensive subjects. Ten subjects with first- or second-degree essential hypertension (mean age, 70.5 years) underwent brain single-photon emission tomography (SPECT) scanning with (99m)Tc-ethyl cysteinate dimer before and after a 24-week course of olmesartan. Mean systolic blood pressure (SBP) was 156.2+/-9.9 mm Hg, and mean diastolic blood pressure (DBP) was 89.1+/-5.5mm Hg. No subject had any abnormalities on neurologic examination or previous history of stroke or cardiovascular disease. Before olmesartan administration, the hypertensive subjects had approximately 15% less whole brain CBF compared with age-matched normotensive controls. Regional CBF was decreased by 11%-20% in the frontal, parietal, temporal, and posterior lobes. Olmesartan treatment significantly decreased SBP to 130.4+/-4.2mm Hg (P < .001) and DBP to 78.2+/-7.0mm Hg (P < .001). After 24 weeks of olmesartan treatment, CBF of whole brain and regional CBF of the frontal, parietal, and temporal lobe were similar to those of control subjects. Our brain SPECT data indicate that olmesartan restores brain hypoperfusion in elderly and hypertensive patients without organic damage. This ARB may have a favorable potential for cerebrovascular circulation, in addition to a blood pressure-lowering effect.

Studies on the development of 99mTc-labeled biphosphonate alginate beads.

The preparation of alginate-dextran pyrophosphate/biphosphonate loaded beads, were labeled with technetium-99m ((99m)Tc) and rhenium-188 ((188)Re). The radiolabelled phosphonic acid derivatives,are well-known bone imaging agents and have also been used for bone pain palliation treatment. The alginates have been used extensively as an excipient in drug products due to their thickening, gel forming and stabilizing behavior. The aim of this study was the preparation of alginate polymeric beads with and without dextran coating, to be used for imaging and possible treatment. We studied (99m)Tc-labelled biphosphonate alginates. We reported our results on the basis of size, swelling capacity and the coating material. The size effect of loading, decreases size and increases loading capacity of alginate beads. Pyrophosphate (PYP) loaded beads had 95% swelling, while ethylene diamine tetramethylene phosphonic acid (EDTMP) loaded beads had 90% (swelling). However combination of both (PYP+EDTMP) loaded beads had 95% swelling. Sustained drug release study indicated different ratios of EDTMP, PYP and EDTMP+PYP loaded beads on different days. Total drug extracted from 30 g beads was 1365.45 µg, 5352.86 µg and 711.8 µg, from EDTMP, PYP and EDTMP+PYP respectively during 15 days of studies. Binding with PYP and EDTMP was 98% and 99% respectively. In conclusion, (chemical and physical characteristics of (99m)Tc-biphosphonate and other alginate beads that we have prepared suggest that the alginate beads could be used for diagnostic and therapeutic purposes.).

The use of technetium-99m radiolabeled human antimicrobial peptides for infection specific imaging.

Bacterial resistance to conventional antibiotics poses a challenge medicine to search for alternatives. Cationic antimicrobial peptides (AMPs) are promising for the development of a new class of antibiotics. This review focuses on the use of technetium-99m labeled synthetic AMPs, derived from human natural cationic AMPs, for target-delivery to and in vivo detection of infection sites caused by (drug-resistant) micro-organisms. The scintigraphic approach has proven to be a reliable method for evaluating AMPs in pharmacological studies and for optimizing target-delivery of radiolabeled AMPs to pathological sites in animals and humans. In addition, the effect of alterations in amphipathicity, amino acid substitution, and dimerization on the biological performance of AMPs is reported. Radiolabeled AMPs offer good perspectives for diagnosis of infections, for monitoring therapy, and, most importantly, for the ability to discriminate between infections and sterile inflammatory processes.

The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer.

The prostate-specific membrane antigen (PSMA) has received increased consideration during the past few years as an excellent target for both imaging and therapy of prostate cancer. After many years of outstanding preclinical research, the first significant step forward in clinical use was achieved in 2008 with the first human experience with the small-molecule PSMA inhibitors 123I-MIP-1972 and 123I-MIP-1095. A clinical breakthrough followed in 2011 with 68Ga-PSMA-11 for PET imaging and 131I-MIP-1095 for endoradiotherapy of metastatic prostate cancer. Since then, PET/CT with 68Ga-PSMA-11 has rapidly spread worldwide, and endoradiotherapy with PSMA ligands has been conducted at increasing numbers of centers. 68Ga-PSMA-11 is currently the subject of multicenter studies in different countries. Since 2013, 131I-related PSMA therapy has been replaced by 177Lu-labeled ligands, such as PSMA-617, which is also the subject of multicenter studies. Alternative PSMA ligands for both imaging and therapy are available. Among them is 99mTc-MIP-1404, which has recently entered a phase 3 clinical trial. This article focuses on the highlights of the development and clinical application of PSMA ligands.

Myocardial salvage in patients with non-ST-elevation myocardial infarction determined by myocardial perfusion imaging.

We compared acute and late myocardial perfusion imaging using technetium-99m isotopes in 69 patients who had non-ST-elevation myocardial infarction. Among these patients, we found that the ischemic risk area was often large (19% of the left ventricle), and that 67% had significant myocardial salvage, defined as a >25% decrease in risk area, which was associated with an improved ejection fraction.

Comparison of the biodistribution and the efficacy of monoclonal antibody 323/A3 labeled with either 131I or 186Re in human ovarian cancer xenografts.

PURPOSE: The radionuclide 186Re has favorable physical characteristics for use in radioimmunotherapy, including the emission of beta-particles of a high-energy and a low-abundance of gamma-emission. The gamma-emission, in particular, is ideal for tumor imaging and poses less hazards to the patient and the medical personnel when compared with the gamma-emission of the widely used radionuclide 131I. In the present study, we determined whether 186Re-labeled monoclonal antibody 323/A3 may be better suited for the treatment of ovarian cancer than 131I-323/A3. METHODS AND MATERIALS: We compared the biodistribution and the efficacy of 186Re- and 131I-labeled 323/A3 in nude mice bearing s.c. the human ovarian cancer xenografts FMa, OVCAR-3 and Ov.Pe. 186Re was conjugated to 323/A3 with the use of the S-benzoylmercaptoacetyltriglycine (S-benzoyl-MAG3) chelate. RESULTS: A molar ratio of Re-MAG3:323/A3 of 3:1 did not affect the integrity and the pharmacokinetic behaviour of the MAb. The tumor uptake and the retention of 186Re- and 131I-labeled 323/A3 were comparable, but the cumulative absorbed radiation dose in the tumor delivered by 186Re-323/A3 was 1.3-fold higher than that of 131I-323/A3. When mice were treated with equivalent radionuclide doses, the tumor growth inhibition induced by 186Re-323/A3 was similar or slightly better when compared with the efficacy of 131I-323/A3. When mice were treated with radionuclide doses that were adjusted to obtain equal cumulative absorbed radiation doses in the tumor for both conjugates, 131I-323/A3 was slightly more effective in the inhibition of the growth of FMa and OVCAR-3 xenografts. CONCLUSIONS: The favorable physical characteristics of 186Re as well as its efficacy when conjugated to a MAb indicate 186Re as an attractive radionuclide in radioimmunotherapy of ovarian cancer patients.

Clinical value of endoscopy and histology in the diagnosis of duodenogastric reflux disease.

BACKGROUND: The endoscopic observation of a bile lake in the stomach, antral gastritis, or ulcerations and the histologic finding of foveolar hyperplasia or chronic gastritis have been implicated as indicators of excessive duodenogastric reflux. The accuracy of these criteria was evaluated in 135 patients with nonspecific symptoms in the foregut suggestive of duodenogastric reflux and no evidence for alcohol- or drug-induced gastric mucosal injury. METHODS: The presence of excessive duodenogastric reflux was objectively determined by means of both gastric pH monitoring and cholescintigraphy with cholecystokinin stimulation. RESULTS: Endoscopy showed antral gastritis in 67 patients, gastric ulcers in 19, and a bile lake in the stomach in 39 (total of 135 patients). Of 90 patients who underwent biopsy, histologic findings showed foveolar hyperplasia in 26, chronic gastritis in 19, and active gastritis in 28 patients. The latter condition was associated with Helicobacter pylori in 20 patients. When gastric pH monitoring, cholescintigraphy, or both were used as "gold standard," the sensitivity, specificity, accuracy, and positive predictive value of endoscopic and histologic criteria to diagnose the presence of excessive duodenogastric reflux were poor except in the rare case of active gastritis but no Helicobacter pylori. CONCLUSIONS: The presence of duodenogastric reflux disease cannot be accurately diagnosed with endoscopic or histologic criteria. The diagnosis should be made with objective techniques, particularly when surgical therapy is considered.

[(186/188)Re] rhenium-ethylene dicysteine (Re-Ec): preparation and evaluation for possible use in endovascular brachytherapy.

188ReO(4)(-), (188)Re-MAG(3), and (188)Re-DTPA are currently under investigation as radiation sources in liquid-filled balloons for prevention of restenosis following coronary angioplasty. Because (99m)Tc-labeled ethylene dicysteine (EC) is a well-established agent for renal tubular function imaging, the use of [(188)Re] rhenium-labeled EC as a potential agent for prevention of restenosis after angioplasty is worth evaluation. In this article, the preparation and pharmacological behavior of [(188/186)Re]Re complex of EC are reported. The yield of the Re complex was optimized by varying the parameters of complexation. The complex prepared under the optimized conditions was found to be stable over a period of 7 days when stored at pH 2 and at 4 degrees C. The pharmacological behavior of [(188/186)Re]Re-EC confirms its similarity to (188)Re-MAG(3) and its superiority over (188)ReO(4)(-) for use in endovascular brachytherapy.

Stress MIBI scintigraphy in multiple coronary-pulmonary fistula: failure to demonstrate "steal" phenomenon.

Stress radionuclide studies were performed in a patient with angiographically proven multiple coronary-pulmonary fistulas, in the presence of atypical chest pain. MIBI scintigraphy showed no myocardial perfusion defects. Multigated ventriculography showed an ejection fraction of 68% and 80% at rest and following exercise, respectively. Three separate fistulas were present between each coronary artery and the pulmonary trunk. The Qp:Qs ratio was 1.3. In the presence of atypical chest pain, stress MIBI scintigraphy and multigated ventriculography both failed to reveal myocardial ischemia in a 49-year-old patient with multiple coronary-pulmonary fistulas. She is using no medication, but advice concerning endocarditis prophylaxis was given.

99mTc-EDDA/HYNIC-TOC in the management of medullary thyroid carcinoma.

An early diagnosis of distant metastases or local recurrences of medullary thyroid carcinoma (MTC) can be achieved by several conventional radiological modalities (e.g., ultrasonography, computed tomography [CT], and magnetic resonance imaging [MRI] as well as by radioisotopic procedures, such as positron emission tomography (PET), scintigraphy with different types of radiopharmaceuticals, and radiolabeled receptor-ligands in particular. The aim of this study was to evaluate the clinical utility of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative, to detect recurrences of disease or distant metastases in MTC. Images obtained of 5 patients with high levels of serum calcitonin were compared to findings obtained with other diagnostic procedures: 111In-octreotide, 99mTc-DMSA-V, 18F-flouro-D-deoxyglucose-PET, and CT/MRI. 99mTc-EDDA/HYNIC-TOC was positive in all patients and showed 15 areas of pathological uptake in the cervical and mediastinal regions. 111In-octreotide was positive in 3 of 3 patients and showed 4 areas, compared to 8 of 99mTc-EDDA/HYNIC-TOC. 99mTc-V-DMSA was positive in 3 of 4 patients but showed 6 pathological areas, compared to 13 of 99mTc-EDDA/HYNIC-TOC. 18F-FDG-PET was positive in 5 of 5 patients but showed only 11 areas, compared to 15 of 99mTc-EDDA/HYNIC-TOC. The CT scan was positive in only 2 patients. In conclusion, 99mTc-EDDA/HYNIC-TOC detected more sites of pathological uptake than other modalities, showed better imaging properties than 111In-octreotide, and might be the radiopharmaceutical of choice for providing a rationale for radioisotopic therapy.