Preparation and Preliminary Evaluation of a Promising 99mTc-Labeled Isonitrile-Containing 6-Thia-Fatty Acid Derivative for Myocardial Metabolism Imaging.

For over 40 years, none of the previous 99mTc-labeled fatty acids for myocardial imaging has potential clinical use. 99mTc-(C10-6-thia-CO2H)(MIBI)5 is the first 99mTc-labeled fatty acid to exhibit good myocardial uptake (2.06 ± 0.06%ID/g) at 60 min post injection, high heart-to-liver ratio (6.43 ± 1.85 and 9.68 ± 0.76), high heart-to-lung ratio (9.48 ± 1.39 and 11.02 ± 0.89), and high heart-to-blood ratio (164.01 ± 43.51 and 197.36 ± 32.29) at 60 and 120 min in Sprague-Dawley (SD) rats, respectively. It also demonstrated excellent myocardial imaging quality. The above target-to-nontarget ratios exceeded those of [123I]BMIPP and were higher than or close to those of 99mTc-MIBI at 60 and 120 min. Most of 99mTc-(C10-6-thia-CO2H)(MIBI)5 was partially ß-oxidized to protein-bound metabolites in myocardium. Administration of trimetazidine dihydrochloride (TMZ, a fatty acid ß-oxidation inhibitor) to rats caused 51% reduction in the myocardial uptake of 99mTc-(C10-6-thia-CO2H)(MIBI)5 and 61% reduction in the distribution of 99mTc-radioactivity in a residual tissue pellet at 60 min, indicating its considerable sensitivity to myocardial fatty acid ß-oxidation.

Synthesis and Bioevaluation of Novel Technetium-99m-Labeled Complexes with Norfloxacin HYNIC Derivatives for Bacterial Infection Imaging.

To seek a novel 99mTc-labeled quinolone derivative for bacterial infection SPECT imaging that aims to lower nontarget organ uptake, a novel norfloxacin 6-hydrazinoicotinamide (HYNIC) derivative (HYNICNF) was designed and synthesized. It was radiolabeled with different coligands, such as tricine, trisodium triphenylphosphine-3,3',3″-trisulfonate (TPPTS), sodium triphenylphosphine-3-monosulfonate (TPPMS), and ethylenediamine-N,N'-diacetic acid (EDDA), to obtain three 99mTc-labeled norfloxacin HYNIC complexes, namely, [99mTc]Tc-tricine-TPPTS-HYNICNF, [99mTc]Tc-tricine-TPPMS-HYNICNF, and [99mTc]Tc-EDDA-HYNICNF. These complexes were purified (RCP > 95%) and evaluated in vitro and in vivo for targeting bacteria. All three complexes are hydrophilic, maintain good stability, and specifically bind Staphylococcus aureus in vitro. The biodistribution in mice with bacterial infection demonstrated that [99mTc]Tc-EDDA-HYNICNF showed a higher abscess uptake and lower nontarget organ uptake and was able to distinguish bacterial infection and sterile inflammation. Single photon emission computed tomography (SPECT) image study in bacterial infection mice showed there was a visible accumulation in the infection site, suggesting that [99mTc]Tc-EDDA-HYNICNF is a potential radiotracer for bacterial infection imaging.

Persistent brain damage in reversible cerebral vasoconstriction syndrome on 99mTc-ethyl cysteinate dimer single-photon emission computed tomography: A long-term observational study.

BACKGROUND: Blood-brain barrier (BBB) breakdown is considered a key step in the pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS); however, its temporal course remains unclear. Based on the characteristics and dynamics of 99mTc-ethyl cysteinate dimer (99mTc-ECD) as a tracer, 99mTc-ECD single-photon emission computed tomography (SPECT) can detect not only hypoperfusion but also BBB breakdown and/or brain tissue damage. Therefore, this study aimed to investigate this course using 99mTc-ECD SPECT. METHODS: Between 2011 and 2019, we enrolled seven patients (one male and six female patients) with RCVS without ischemic or hemorrhagic stroke or posterior reversible encephalopathy syndrome. 99mTc-ECD SPECT was performed repeatedly in each patient. SPECT data were statistically analyzed using an easy Z-score imaging system. RESULTS: Thunderclap headache was the initial symptom in all the patients and was most commonly triggered by bathing (three patients). All the patients exhibited vasoconstriction and reduced cerebral uptake of 99mTc-ECD during the acute stage. Follow-up assessment from 3 to 16 months showed that reduced cerebral uptake persisted in all the patients, even after the vasoconstriction had resolved. CONCLUSION: Reduced cerebral uptake of 99mTc-ECD persisted in the late stage of RCVS, even after vasoconstriction and headache subsided. BBB breakdown and/or brain tissue damage may underlie this phenomenon. 99mTc-ECD SPECT is an effective neuroimaging method to detect brain functional abnormalities, reflecting BBB breakdown or tissue damages, throughout the treatment course of RCVS.

Reference Values for Dopamine Transporter Imaging With 99m Tc-TRODAT-1 in Healthy Subjects and Parkinson's Disease Patients.

PURPOSE: The aim of this study was to evaluate different quantitative indexes of striatum dopamine transporter density in healthy subjects and patients with PD. PATIENTS AND METHODS: Sixty-seven patients, 23 healthy (8 male; 59 ± 11 years old) and 44 age-matched patients (29 male; 59 ± 7 years old), with various degrees of severity of idiopathic PD (duration of symptoms, 10 ± 6 years; Hoehn and Yahr Scale, 2.16 ± 0.65; UPDRS-3, 29.74 ± 17.79). All patients performed 99m Tc-TRODAT-1 SPECT. Binding potential indexes (BPIs) of striatum and subregions, asymmetry index (AI), and putamen/caudate ratio (P/C) were calculated. RESULTS: Binding potential index was lower in the PD than in healthy subjects. A BPI cutoff for striatum and putamen ranging from 0.73 to 0.78 showed 95% to 100% sensitivity and 84% to 88% specificity. For the caudate nucleus, a BPI threshold of 0.8 to 0.88 revealed 100% sensitivity and 77% to 84% specificity. The BPI's respective areas under the curve ranged from 0.92 to 0.98. For AI and P/C, the area under the curve was less than 0.70. Binding potential index intraclass correlation coefficient was close to 1.0 in the intraobserver evaluation and 0.76 to 0.87 in the interobserver assessment. Intraclass correlation coefficient for AI and P/C was inferior to 0.75 in the intraobserver and interobserver evaluations. CONCLUSIONS: Different semiquantitative indices differentiated PD and healthy subjects and may help the differential diagnosis of other entities involving the dopaminergic system. Asymmetry index and P/C performances were lower than BPI, including their intraobserver and interobserver reliability, and therefore should be used with caution.

Unexpected Detection of Skeletal Muscle Renal Cell Carcinoma Metastasis With 99m Tc-EDDA/HYNIC-Tyr3-Octreotide (Tektrotyd) Scan.

ABSTRACT: Somatostatin receptor scintigraphy with 99m Tc-Tektrotyd is widely used for the investigation of neuroendocrine tumors. Overexpression of somatostatin receptors has been shown in different tumor types including lymphomas, breast carcinoma, and renal cell carcinoma (RCC). Isolated case reports have shown that RCC metastases can be identified using somatostatin receptor imaging such as Octreoscan scintigraphy and 68 Ga-DOTATATE PET/CT. We report the case of a 70-year-old man with a history of surgically removed RCC who referred to 99m Tc-Tektrotyd scintigraphy for the evaluation of a pancreatic tail lesion. The scan revealed intense tracer uptake in a left splenius cervicis muscle lesion that on biopsy was consistent with metastatic RCC.

Oxorhenium(V) and Oxotechnetium(V) Complexes of N3S Tetradentate Ligands with a Styrylpyridyl Functional Group: Toward Imaging Agents to Assist in the Diagnosis of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-ß (Aß). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aß plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O]3+ and [Re═O]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aß1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [Tc═O]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.

Accumulation of 99m-Tc Phytate in the pyelocalyceal system in a patient with chylous ascites - a pitfall resolved by SPECT/CT.

We reported 99m-Tc phytate accumulation in the pyelocalyceal system of the kidney in the lymphoscintigraphic images of a 3.5 months-old male infant with chylous ascites, which was mistaken with the site of lymph leakage. SPECT/CT localized activity in the para-aortic region to the renal pelvis and on delayed images, this was disappeared. Our case illustrates the added value of SPECT/CT for the differentiation of possible false-positive findings in lymphoscintigraphy.

99mTc-CN7DG: A Highly Expected SPECT Imaging Agent of Cancer with Satisfactory Tumor Uptake and Tumor-to-Nontarget Ratios.

A novel glucose derivative (CN7DG) possessing an isonitrile as a coordinating group was synthesized, and 99mTc-CN7DG, which was expected to be a powerful tumor imaging agent for SPECT, was prepared in a kit by the reaction of CN7DG with SnCl2·2H2O and 99mTcO4-. 99mTc-CN7DG exhibited good stability and was transported via glucose transporters. Biodistribution results in mice bearing A549 tumor models showed that 99mTc-CN7DG had a higher uptake at the tumor sites and better tumor/blood and tumor/muscle ratios than did [18F]FDG and 99mTc-CN5DG. SPECT/CT imaging studies showed obvious accumulation in tumor sites, suggesting that 99mTc-CN7DG is a promising candidate for tumor imaging. Because 99mTc and 188Re stand for a "theranostic pair", 188Re-CN7DG is expected to be prepared as a promising agent for tumor therapy.

Incidental Finding of Bilateral Thalamic Glioma on 99mTc TRODAT-1 SPECT/CT.

ABSTRACT: 99mTc-TRODAT-1 SPECT/CT has been used to evaluate parkinsonian disorders. We present an interesting case of a 63-year-old woman with progressive tremulousness over the left side of the body for 6 months. Bilateral thalamic glioma with reduced uptake was shown on 99mTc-TRODAT-1 SPECT/CT. Secondary parkinsonism was impressed in this case.

Imaging Hydrogen Sulfide in Hypoxic Tissue with [99mTc]Tc-Gluconate.

Hydrogen sulfide (H2S) is the third gasotransmitter and is generated endogenously in hypoxic or inflammatory tissues and various cancers. We have recently demonstrated that endogenous H2S can be imaged with [99mTc]Tc-gluconate. In the present study, we detected H2S generated in hypoxic tissue, both in vitro and in vivo, using [99mTc]Tc-gluconate. In vitro uptake of [99mTc]Tc-gluconate was measured under hypoxic and normoxic conditions, using the colon carcinoma cell line CT26, and was higher in hypoxic cells than that in normoxic cells. An acute hindlimb ischemia-reperfusion model was established in BALB/c mice by exposing the animals to 3 h of ischemia and 3 h of reperfusion prior to in vivo imaging. [99mTc]Tc-gluconate (12.5 MBq) was intravenously injected through the tail vein, and uptake in the lower limb was analyzed by single-photon emission computed tomography/computed tomography (SPECT/CT). SPECT/CT images showed five times higher uptake in the ischemic limb than that in the normal limb. The standard uptake value (SUVmean) of the ischemic limb was 0.39 ± 0.03, while that of the normal limb was 0.07 ± 0.01. [99mTc]Tc-gluconate is a novel imaging agent that can be used both in vitro and in vivo for the detection of endogenous H2S generated in hypoxic tissue.

99mTc-gallic-gold nanoparticles as a new imaging platform for tumor targeting.

Early and accurate detection of tumor assists in identifying more effective therapies. Gold nanoparticles (GNPs) were synthesized by green synthesis method using gallic acid (GA) then characterized and labeled with technetium-99m. This new platform was biologically evaluated in both normal and solid tumor bearing mice. The in-vivo study of [99mTc]Tc-gallic-GNPs via both I.V. and I.T injecton showed a high accumulation in tumor site. As a result, [99mTc]Tc-gallic-GNPs can be afforded as a potential nano-platform for tumor imaging.

99mTc-RBC SPECT/CT for Duodenal Bleeding Point Detection.

This is a case of a 63-year-old man who presented with acute melena and low hemoglobin. Upper and lower gastrointestinal evaluations failed to localize the bleeding focus. Tc-RBC planar scintigraphy identified 2 sites of suspected bleeding in the lower abdomen area. Subsequent SPECT/CT was performed and identified the precise main focus of active bleeding, the second and third parts of the duodenum, and also described the blood accumulation in the jejunum. Esophagogastroduodenoscopy was immediately performed, and results confirmed spurting blood from the small vessel with multiple ulcers in the second part of the duodenum.

Role of [99mTc]Tc-Galacto-RGD2 SPECT/CT in identifying metastatic differentiated thyroid carcinoma after thyroidectomy and radioactive iodine therapy.

PURPOSE: Integrin αvß3, a member of the arginine-glycine-aspartate (RGD)-binding subfamily, is associated with tumor angiogenesis and metastasis. The aim of study is to investigate the clinical role of [99mTc]Tc-Galacto-RGD2 SPECT/CT in high-risk differentiated thyroid carcinoma (DTC) after thyroidectomy and radioactive iodine (RAI) therapy. METHODS: Thirty-six patients with high-risk DTC (20 males, 16 females; mean age: 59.9 ± 16.6 y) who underwent thyroidectomy and RAI therapy were consecutively enrolled in this study. All patients underwent [99mTc]Tc-Galacto-RGD2 SPECT/CT and diagnostic 131I whole-body scan 6 months after the last RAI treatment. A region of interest (ROI) was drawn and the ratio of tumor/non-target (T/NT) was calculated. Per-patient and per-lesion analysis was performed to evaluate the diagnostic efficacy. The final diagnosis was confirmed by histopathology and follow-up. Integrin αvß3, CD31, and Ki-67 expression in the tumor were also analyzed for evaluation of angiogenesis and proliferation. RESULTS: Out of 36 patients, twenty-two had metastatic disease. By per-patient analysis, the area under the curve of [99mTc]Tc-Galacto-RGD2 SPECT/CT was marginally significantly higher than that of 131I whole-body scan and morphological imaging (P = 0.0034 and 0.0006). For per-lesion analysis, [99mTc]Tc-Galacto-RGD2 SPECT/CT identified 67 metastatic lymph nodes in 14 patients, 12 lung metastases in four patients, and 12 bone metastases in six patients; its sensitivity was significantly higher than that of 131I whole-body scan in detection of lymphatic (90.54% vs. 55.41%, P = 0.0124) and bone metastasis (92.31% vs. 30.77%, P = 0.046). The ratio of T/NT in metastatic lesions increased with the DTC upstaging. CONCLUSIONS: [99mTc]Tc-Galacto-RGD2 SPECT/CT has high sensitivity in the detection of metastasis in high-risk DTC and further contributes to evaluation of tumor angiogenesis and radio­iodine refractory status.

Cardiac Scintigraphy With Technetium-99m-Labeled Bone-Seeking Tracers for Suspected Amyloidosis: JACC Review Topic of the Week.

Technetium-labeled cardiac scintigraphy (i.e., Tc-PYP scan) has been repurposed for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Validated in cohorts of patients with heart failure and echocardiographic and/or cardiac magnetic resonance imaging findings suggestive of cardiac amyloidosis, cardiac scintigraphy can confirm the diagnosis of ATTR-CM only when combined with blood and urine testing to exclude a monoclonal protein. Multisocietal guidelines support the nonbiopsy diagnosis of ATTR-CM using cardiac scintigraphy, yet emphasize its use in the appropriate clinical context and the crucial need to rule out light chain amyloid cardiomyopathy. Although increased awareness of ATTR-CM and the advent of effective therapy have led to rapid adoption of diagnostic scintigraphy, there is heterogeneity in adherence to consensus guidelines. This perspective outlines clinical scenarios wherein findings on technetium-labeled cardiac scintigraphy have been misinterpreted, reviews causes of false-negative and false-positive results, and provides strategies to avoid costly and potentially fatal misdiagnoses.

The one-in-all diagnostic value of 99mTc-MDP bone scan combining with single-photon emission tomography (SPECT)/CT imaging in spinal osteoblastoma.

BACKGROUND: Osteoblastoma (OB) is an intermediate lesion, which makes the accurate preoperative diagnosis very important. 99mTc-methylene diphosphonate (99mTc-MDP) bone scan and SPECT/CT imaging were evaluated for their diagnostic value in spinal OB. METHODS: This study was a retrospective analysis of patients with spinal OB lesions confirmed by pathology and diagnosed with bone scan and SPECT/CT for preoperative diagnosis from January 2008 to December 2018. The uptake levels of OB on planar bone scan were divided into low, medium, and high groups by visual assessment referring to the uptake of the normal rib, spine, and bladder. X-ray, CT, MRI, bone scan, and SPECT/CT imaging of the patients were analyzed for characteristics summary. RESULTS: Twenty-five patients were diagnosed for spinal OB (17 males and 8 females with a proportion of 2.1:1), and the average age was 26.8 ± 10.8 years (range 5~59). There were 8 lesions located in the cervical, 6 in the thoracic, and 11 in the lumbar vertebrae. Twenty-four lesions involved posterior elements, especially the pedicles (14/25). Symptoms were predominantly painful with a duration of 18.3 ± 13.9 months (range 0.5~60 months). The lesion size ranged from 9 to 35 mm. All the lesions were low to high uptake in the planar bone scan, and the percentages of low to high levels were 1 (4%), 8 (32%), and 16 (64%) cases. CONCLUSIONS: Spinal OB mainly involved the posterior area, and elderly patients should be considered as well. SPECT/CT combined the characteristics of bone uptake and anatomical features of bone tumors, proving its one-in-all diagnostic value for spinal OB and other osteogenic tumors.

Extrastriatal Peri-infarct Accumulation of 99mTc-TRODAT.

We describe the extrastriatal accumulation of dopamine transporter imaging agent Tc-TRODAT in the peri-infarct area in a 75-year-old man referred for dopamine transporter SPECT imaging with a suspicion of idiopathic Parkinson disease.

Development of 99mTc-SDP-choline SPECT radiopharmaceutical for imaging of cerebrovascular diseases.

Cerebrovascular diseases are known as serious public health problem worldwide, which can be addressed more precisely through molecular imaging of non-functional brain cells. CDP-choline is an active cerebrovascular chemotherapeutic agent that can be used for diagnosis of cerebrovascular diseases post radiolabeling with γ-emitter radioisotopes. In this study we developed 99mTc labeled CDP-choline for imaging of cerebrovascular diseases particularly alzheimer, stroke, and parkinson's diseases. The radiosynthesis reaction resulted 97.47±2.34% radiochemical with promising stability, that is, >95% up to 6 h in blood serum. The biodistribution study in healthy mice revealed non-accumulated uptake of radiochemical in key body organs; in brain it was 8.59±1.11% ID/g at 1h post-injection which washed-out leaving behind 0.87±0.61% ID/g at 24 h post-injection. The over-all data revealed the 99mTc-CDP-choline could be a good candidate for further imaging investigations in diseased animal model.

Synthesis, physicochemical and biological evaluation of tacrine derivative labeled with technetium-99m and gallium-68 as a prospective diagnostic tool for early diagnosis of Alzheimer's disease.

Design, physicochemical and biological studies of novel radioconjugates for the early diagnosis of Alzheimer's disease, based on the newly synthesized tacrine derivatives were performed. Novel tacrine analogues were labeled with technetium-99m and gallium-68. For all obtained radioconjugates ([99mTc]Tc-Hynic-(tricine)2NH(CH2)ntacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine, where n = 2-9 denotes the number of methylene groups CH2) the studies of physicochemical properties (lipophilicity, stability in the presence of an excess of standard amino acids cysteine or histidine, human serum and in cerebrospinal fluid) were performed. For two selected radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9Tac and [68Ga]Ga-DOTA-NH(CH2)9tacrine (characterized with the highest lipophilicity values) the biological tests (inhibition of cholinesterases action, molecular docking and biodistribution studies) have been performed. All novel radioconjugates showed high stability in biological solutions used. Both selected radioconjugates proved to be good inhibitors of cholinesterases and be able to cross the blood-brain barrier. Radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9tacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine fulfil the conditions for application in nuclear medicine. Radiopharmaceutical [68Ga]Ga-DOTA-NH(CH2)9tacrine, due to increased accuracy and improved sensitivity in PET imaging, may be better potential diagnostic tool for early diagnosis of Alzheimer's disease.

Long-acting octreotide treatment has no impact on tumor uptake of 99mTc-HYNIC-TOC in patients with neuroendocrine tumors.

OBJECTIVE: Our purpose is to investigate whether the tumor uptake of Tc-HYNIC-TOC in patients with neuroendocrine tumor would be influenced when the patients were treated with long-acting octreotide. METHODS: Sixty G2 neuroendocrine tumor patients who underwent Tc-HYNIC-TOC single-photon emission computed tomography/computed tomography imaging were retrospectively analyzed. The ratios of target/muscle of normal organs and tumors were compared between the patients with (n = 30) and without octreotide treatment (n = 30). In addition, the octreotide treatment group was divided into two subgroups based on whether the time intervals were more than 14 days between the last time of octreotide administration and the day of imaging. RESULTS: There was no statistical significance in target/muscle of primary tumors (23.86 ± 4.49 vs. 20.72 ± 5.37, P = 0.070), metastases in the liver (20.74 ± 6.14 vs. 19.72 ± 6.54, P = 0.211), lymph nodes (16.29 ± 9.45 vs. 15.52 ± 7.67, P = 0.867), bone (9.18 ± 3.83 vs. 9.07 ± 3.61, P = 0.989) and lung (16.99 ± 6.06 vs. 12.40 ± 5.97, P = 0.133) between octreotide treated and untreated group. However, target/muscle of normal liver and bone were lower in the octreotide treated group than in untreated group (P = 0.003, and 0.0001, respectively). There was also no significant difference in target/muscle of normal organs, primary tumors and metastases between the two subgroups. CONCLUSION: Octreotide treatment had no impact on the results of Tc-HYNIC-TOC single-photon emission computed tomography/computed tomography to detect tumors and metastasis in patients with neuroendocrine tumor. However, the uptake in normal liver and bone can be reduced, which might increase the detection rate of lesions in corresponding organs.