99mTc-MIBI Uptake Research Articles

Synthesis, cytotoxicity and 99mTc-MIBI tumor cell uptake evaluation of 2-phenylbenzothiazole tagged triazole derivatives.

Aim: The extensive utilization of 2-phenylbenzothiazole due to their wide array of biological activities, particularly in cancer therapy, has caused great attention to explore more potent derivatives.Materials & methods: We report the synthesis of 2-phenylbenzothiazole tagged 1,2,3-triaozle (8) through Cu(I)-catalyzed cycloaddition of alkyne side chain with aryl-substituted azides.Results: The in vitro experiments, using MTT and 99mTc-MIBI cell uptake methods, demonstrated the remarkable anticancer activity of these compounds against A549, SKOV3 and MCF7 cell lines.Conclusion: Compounds 8b, 8f and 8i possessed high cytotoxic activity as compared with doxorubicin. Compound 8g has a similar inhibitory effect on the proliferation of breast cancer cells as doxorubicin. In silico study indicated that compound 8 would be a good lead for the development of new potent anticancer agents.

Enhanced Differentiation of Amiodarone-Induced Thyrotoxicosis Types Using Semi-Quantitative 99mTc-MIBI Uptake Analysis: A Pilot Study.

BACKGROUND Technetium (99mTc)-labelled Methoxy-2-Isobutylisonitrile (MIBI) is a diagnostic lipophilic cationic radiotracer used to evaluate the cardiac, breast, thyroid, and parathyroid pathology. This study aimed to evaluate the role of MIBI combined with Tc-99m pertechnetate thyroid scintigraphy, thyroid ultrasonography, and measurement of thyrotropin, thyroid hormones, and autoantibodies to subtype amiodarone-induced thyrotoxicosis (AIT) and the contribution of semi-quantitative analysis of MIBI uptake. MATERIAL AND METHODS This cross-sectional study included 36 patients with AIT who underwent thyrotropin, thyroid hormone, and autoantibody analysis using chemiluminescent method, ultrasonography, pertechnetate, and MIBI thyroid scintigraphy with semi-quantitative uptake, including calculation of the target-to-background ratio (TBR) with 2 different background regions. The MIBI washout rate (WR) was analyzed in all groups. Statistical analysis was performed using descriptive statistics, correlations, and the receiver operating characteristic curve - area under the curve (ROC-AUC). The results were compared with the control group. RESULTS Based on visual and semi-quantitative analyses, patients were successfully categorized into AIT groups (AIT-1, AIT-2 and AIT-3) but the latter method enabled better differentiation of MIBI uptake between all groups. Additionally, ROC-AUC analysis determined cutoff values which enabled discerning between AIT-1 and AIT-2 groups, and AIT-1 and AIT-3 groups. WR showed no significant difference between all AIT groups and controls (P>0.05). CONCLUSIONS Visual MIBI analysis enabled differentiation between AIT-1 and 2 groups, but the method was substantially improved with semi-quantitative analysis, especially in defining AIT-3 group. However, multicenter collaboration with larger studies is needed to standardize the method and obtain more accurate and consistent results.

In Vivo Detection of Multidrug-Resistance Related Proteins in Locally Advanced Breast Cancer Using 99mTc-MIBI SPECT/CT Imaging: Correlation with Clinical Outcomes.

Neoadjuvant chemotherapy (NACT) is widely used for treating locally advanced Breast cancer (LABC). However, development of multidrug resistance (MDR) is the main underlying factor for chemoresistance. Technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) is a substrate for MDR. This study aimed to analyze the relationship between expression of MDR-related proteins (P-gp and Bcl-2) and 99mTc-MIBI uptake and retention in BC tumor cells, pathologic response to NACT, disease free survival (DFS) and overall survival (OS). prospective analysis recruited 31 patients with LABC who received NACT between January 2019 and March 2020. 99mTc-MIBI planar and SPECT/CT imaging was conducted before and after NACT. Qualitative and quantitative analyses were performed, pre and post-NACT early and delayed lesion to non-lesion (LNL) ratios, and retention index (RI) of 99mTc-MIBI were calculated. Expression of P-gp and Bcl-2 in tumor cells was determined by immunohistochemistry. Quantitively, inter-reader ICC for SPECT/CT based quantification was consistently higher than that of planar images. Post-NACT LNL ratios were significantly higher in patients with pathologic persistent disease (PPD). A change in RI between pre- and post-NACT scans demonstrated a significant association with DFS with a hazard ratio of 0.7 (95%CI: 06-1.0). Qualitatively, SPECT/CT was significantly more accurate compared to planar imaging in identifying residual viable tumor (81% compared to 57%). Her2neu positivity and high post-operative Bcl-2 and P-gp were associated with worse DFS. A significant association was found between increased expression of post-NACT Bcl-2 and PPD, advanced tumor stage and poor OS. 99mTc-MIBI SPECT/CT based qualitative evaluation of BC response to NACT is more accurate than planar imaging. Post-NACT MIBI retention is positively correlated with P-gp and Bcl-2 expression. 99mTc-MIBI SPECT/CT may predict MDR development. High post-NACT Bcl-2 expression is significantly associated with advanced tumor stage and OS. High post-NACT P-gp expression has a worse impact on pathologic response and DFS.

Incidental Tc-99m MIBI Lung Uptake in Parathyroid Scintigraphy.

Diffuse Tc-99m MIBI uptake in the lungs during parathyroid scintigraphy is exceptional, and only a few cases have described this unusual aspect. The differential diagnostic of this funding is a challenge when interpreting the examination, since it can be a sign of serious pathology. We report the case of unexpected diffusely increased Tc-99m MIBI uptake in bilateral lung fields in a patient with left cardiac dysfunction.

KÜÇÜK HÜCRELİ DIŞI AKCİĞER TÜMÖRLERİNİN DEĞERLENDİRİLMESİNDE Tc-99m MIBI SPECT’İN YERİ

Objective: In this study, it was aimed to investigate the role of Tc-99m MIBI scintigraphy in the diagnosis and evaluation of non-small cell lung cancers and also to evaluate the use of MIBI scintigraphy and MDP bone scintigraphy together in the detection of metastases. Methods: For this purpose, 30 patients with non-small cell lung cancer and 15 patients with benign lesions other than lung cancer (as a control group) were included in the study. By applying Tc-99m MIBI and Tc99m MDP scintigraphy to whole patients with benign and malign lung lesions, anterior-posterior planar and SPECT MIBI images were obtained. Bone scintigraphy was performed as whole-body images. Scintigraphic findings were compared with the histopathological diagnosis of patients. Data were analyzed statistically. Results: According to the result of the findings, the sensitivity, specificity, positive, predictive value, negative predictive value, and accuracy rate of Tc-99m MIBI scintigraphy in the detection of non-small cell lung tumors were determined as 87%, 93.5%, 96%, 77.7%, and 88.8%, respectively. Scintigraphic findings were evaluated quantitatively and visually. While there was no statistically significant difference between the early uptake rates of non-small cell lung tumors and benign lesions in the quantitative evaluation using planar MIBI images, late Tc-99m MIBI uptake rates were significantly higher in lesions with non-small cell lung tumors than that of benign lesions. However, it was detected that both the early and late uptake ratios were significantly higher in malign lesions than in benign lesions in the quantitative evaluation of SPECT images. It was observed that MIBI washout in benign lesions was higher than in malignant lesions in visual washout analysis. Additionally, multiple bone metastases were observed in 14 patients on the visual evaluation of bone scan of the patients with non-small cell lung cancer. Tc-99m MDP uptake was not observed in the malignant lung lesion region or in the soft tissue except the lesion. Conclusion: In light of the findings, it was concluded that Tc-99m MIBI scintigraphy is a noninvasive method with high sensitivity and specificity that can be used to differentiate non-small cell lung tumors from benign lesions.

Hyperfunctioning Intrathyroidal Parathyroid: a Misleading Preoperative Diagnosis.

Hyperfunctioning parathyroid glands may be rarely located in the thyroidal parenchyma and not identified by imaging or during surgical procedures. We present three patients with primary hyperparathyroidism related to hyperfunctioning intrathyroidal parathyroid retrospectively selected among 732 cases from own Institutional parathyroid PET/CT registry from 2018 to 2022. Intrathyroidal parathyroids showed intense 18F-fluorocholine uptake but a variable echographic pattern, inconstant 99mTc-MIBI uptake, and atypic iodine-contrast enhancement. Although rare, the possibility of an intrathyroidal parathyroid should be considered when no hyperfunctioning gland is found on preoperative imaging and thorough bilateral neck exploration.

Semiquantitative assessment of 99mTc-MIBI uptake in parathyroids of secondary hyperparathyroidism patients with chronic renal failure.

ObjectiveTo explore the valuably influential factors and improve the diagnostic accuracy and efficiency of 99mTc-methoxyisobutylisonitrile (MIBI) uptake in parathyroids of secondary hyperparathyroidism (SHPT) patients with chronic renal failure (CRF).MethodsThe correlation analysis was performed between clinical indices related to CRF and 99mTc-MIBI uptake intensity TBR (the gray value mean ratio between the parathyroid target and the bilateral neck background, semiquantitatively calculated with ImageJ software). All clinical indices and TBRs were compared by a three- or two-level grouping method of MIBI uptake, which was visually qualitatively assessed. The three-level grouping method comprised slight, medium, and high groups with little, faint, and distinct MIBI concentration in parathyroids, respectively. The two-level grouping method comprised insignificant and significant groups with TBR greater than or less than 0.49–0.71, respectively.ResultsMIBI uptake was significantly positively related to patient age, CRF course, hemodialysis vintage, serum parathyroid hormone (PTH), and alkaline phosphatase (AKP) but was significantly negatively related to serum uric acid (UA). MIBI washout was significantly positively related to patient age but was significantly negatively related to serum phosphorus (P) and calcium (Ca) × P. Oral administration of calcitriol and calcium could significantly reduce the MIBI uptake. MIBI uptake tendency might alter. Such seven indices, namely the MIBI uptake, CRF course, hemodialysis vintage, serum AKP, calcium, cysteine proteinase inhibitor C, and PTH, were comparable between the slight and medium groups but were significantly different between the slight and high groups or between the medium and high groups. The above seven indices plus blood urea nitrogen/creatinine were all significantly different between the insignificant and significant groups. All above significances were with P < 0.05.ConclusionsPatient age, CRF course, hemodialysis vintage, serum PTH, AKP, UA, phosphorus, Ca × P, oral administration of calcitriol and calcium, and parathyroids themselves can significantly influence MIBI uptake in parathyroids of SHPT patients with CRF. The two-level grouping method of MIBI intensity should be adopted to qualitatively diagnose the MIBI uptake.

The Utility of a Combination of 99mTc-MIBI Washout Imaging and Cardiac Magnetic Resonance Imaging in the Evaluation of Cardiomyopathy.

Background: In cardiomyopathy, 99mTc-MIBI washout can reflect mitochondrial dysfunction and late gadolinium enhancement (LGE) on cardiac magnetic imaging (MRI) is associated with tissue fibrosis. We sought to determine the relationship between 99mTc-MIBI uptake, 99mTc-MIBI washout, and LGE on MRI in patients with cardiomyopathy. Methods: Twenty-one patients underwent rest myocardial perfusion scintigraphy at 45 minutes (early) and 4 hours (delayed) after intravenous 99mTc-MIBI administration and cardiac MRI. We assessed myocardial perfusion, 99mTc-MIBI washout, and LGE. We divided the left ventricle (LV) wall into 16 segments using a polar map. Then, we classified each segment into 5 groups according to 99mTc-MIBI uptake in early-rest images and washout. Additionally, we created a contingency table based on LGE presence/absence in the groups. Results: We evaluated 336 segments in 21 patients. 99mTc-MIBI uptake was decreased in 168 segments in the early-rest 99mTc-MIBI images. 99mTc-MIBI washout was observed in 108 segments with either normal perfusion or reduced perfusion in the early-rest 99mTc-MIBI images. LGE was positive in 104 segments. A contingency table analysis with Fisher's exact test showed that LGE was observed significantly more frequently in the segments with decreased 99mTc-MIBI uptake (p<0.001). In segments without a decreased 99mTc-MIBI uptake, there was a significant correlation between increased 99mTc-MIBI washout and the presence of LGE (p=0.033). Conclusions: In cardiomyopathy, the mitochondrial dysfunction in the early stage is shown as 99mTc-MIBI washout, and fibrotic changes in the myocardium in advanced stages are shown as LGE on cardiac MRI. The severity of myocardial damage and the clinical stage of cardiomyopathy can be evaluated using multimodal imaging.

Focal severe decrease in myocardial technetium-99 m sestamibi uptake indicates ventricular irreversibility in patients with dilated cardiomyopathy.

Technetium-99 m sestamibi (99mTc-MIBI) scintigraphy can identify non-viable left ventricular (LV) myocardium. However, the optimal cut-off value and the details of decreased 99mTc-MIBI uptake of the non-viable LV myocardium in patients with dilated cardiomyopathy (DCM) have not been well established. This study aimed to evaluate the decrease in 99mTc-MIBI uptake in each segment and in the whole LV myocardium, and to determine cut-off values for identifying non-viable LV myocardium in DCM patients. Overall, 53 DCM patients with reduced LV ejection fraction (LVEF ≤ 40%) who underwent 99mTc-MIBI scintigraphy and any optimization of heart failure treatments were evaluated. LV myocardium was classified as viable or non-viable based on the absolute increase in LVEF of ≥ 10% unit leading to an LVEF of > 40% at follow-up, respectively. The decrease in myocardial 99mTc-MIBI uptake in each of the 17 segments was evaluated using three indices determined by different thresholds or standard references: segmental %uptake, rest score, and defect extent. Changes in the whole LV myocardium were evaluated by the minimum %uptake, and the summed rest score (SRS) and extent of LV defect were obtained using summed data of 17 segments. Segmental evaluation indicated a mild decrease in 99mTc-MIBI uptake in 18 patients with viable LV myocardium, whereas focal severe decrease in uptake was observed in patients with non-viable LV myocardium. In the receiver-operating characteristic curve analysis, the cut-off values of minimum %uptake, SRS, and LV defect extent for predicting non-viable LV were 39% (p < 0.01, area under the curve [AUC]: 0.87), 10 (p < 0.01, AUC: 0.91), and 23% (p < 0.01, AUC: 0.92), respectively. In DCM patients, myocardial 99mTc-MIBI %uptake of < 40% indicated non-viable myocardium. The focal and severe decrease in uptake in approximately more than a quarter of the LV myocardium may indicate non-viable LV.

Value of 99mTc-MIBI SPECT/CT in distinguishing between parathyroid lesions and nodular goiter.

Hyperfunctioning parathyroid lesions require surgical resection. 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) single-photon emission computed tomography/computed tomography (SPECT/CT) plays an important role in the diagnosis of parathyroid lesions. Some nodular goiters have a higher uptake of 99mTc-MIBI, which is difficult to distinguish from hyperfunctioning parathyroid lesions. This study aims to explore the value of 99mTc-MIBI SPECT/CT in the differential diagnosis of parathyroid lesions and nodular goiter. This study was a retrospective analysis. A total of 68 patients who were diagnosed as parathyroid lesions by 99mTc-MIBI SPECT/CT were enrolled, with a total of 81 lesions. According to the results of pathological examination after surgical resection, the lesions were divided into a parathyroid lesion group (n=69) and a nodular goiter group (n=12). The target maximum radioactivity count (Tmax) of all lesions was measured. The mean radioactivity count of the aortic arch was used as the background mean radioactivity count (Bmean), and the ratio of the Tmax to Bmean was calculated. The difference in Tmax/Bmean between the 2 groups was compared. The minimum, mean, and maximum of CT density in the lesion were measured. The difference of CT density between the 2 groups was compared. The receiver operating characteristic (ROC) curve of patients with parathyroid lesions and patients with nodular goiter was drawn, and the diagnostic efficacy of each CT density value was evaluated. The 99mTc-MIBI radioactive uptake in parathyroid lesions and nodular goiter lesions was significantly concentrated. The CT density values of the 2 lesions were lower than normal thyroid tissue, and the boundary between the 2 lesions and the thyroid was clear or blurred. There was no significant difference in Tmax/Bmean between the 2 groups (P=0.221). The differences in the minimum, mean and maximum of CT density between the 2 groups were statistically significant (all P<0.05). The diagnostic efficiency of maximum of CT density was the best, area under the ROC curve was 0.894 (P<0.001), the cut-off was 91 HU, the sensitivity was 83.3%, and the specificity was 94.2%. The degree of 99mTc-MIBI radiation uptake in the focus has limited value in differentiating parathyroid lesions from nodular goiter, and the maximum density of CT possesses high diagnostic efficiency.

Assessment of Organ Doses for Patients undergoing 99mTc-MIBI Myocardial Perfusion Imaging.

Radiation absorbed doses associated with myocardial perfusion imaging (MPI) using 99mTc-MIBI has been determined at the Radioisotopes Institute of the Abdou Moumouni University. Thirty patients undergoing MPI were scanned and image quantification was done using Mediso Inter View XP® software. The average administrated activities of 99mTc-Sestamibi were 370 MBq (10 mCi) in stress condition and 1110 MBq (30 mCi) in rest condition with one day protocol. The radionuclide activities in the heart, liver, kidneys and urinary bladder were determined using the conjugate view method. The uptake of 99mTc-MIBI in the heart, liver and kidneys were respectively about 2.17% ±0.64, 6.53% ±1.47 and 5% ±0.52, 10 minutes after injection. The cumulative activities for the heart, liver, kidneys and urinary bladder were respectively 21.97 MBq.h, 63.11 MBq.h, 36.61 MBq.h, 79.48 MBq.h for the stress and 68.23 MBq.h, 239.79 MBq.h, 101.69 MBq.h and 223.1 MBq.hin the rest conditions. The organs absorbed doses in this study were 3.06 mGy for kidneys, 0.75 mGy for liver, 0.75 mGy for the heart, and 20.46mGy for bladder.

99mTc-MIBI uptake as a marker of mitochondrial membrane potential in cancer cells and effects of MDR1 and verapamil.

We investigated the relation of 99mTc-MIBI uptake to mitochondrial membrane potential (MMP) in cancer cell lines and patient-derived tumor cells (PDCs). In T47D and HT29 cells with low MDR1 expression, FCCP dose-dependently reduced MMP and 99mTc-MIBI accumulation in similar patterns with nearly perfect linear relationships. T47D and HT29 cells with high MDR1 expression had low 99mTc-MIBI accumulation that was minimally affected by FCCP dose. In these cells, verapamil markedly increased 99mTc-MIBI accumulation to magnitudes that were excessive compared to MMP increase. Decreased plasma membrane potential by verapamil and its recovery by FCCP suggested that enhanced 99mTc-MIBI transport through modified plasma membranes contributed to the excess accumulation. Evaluation of three different colon cancer PDCs with low to modest MDR1 expression verified that FCCP significantly suppressed MMP and similarly reduced 99mTc-MIBI accumulation. Verapamil partially recovered both MMP and 99mTc-MIBI accumulation that was lowered by FCCP. Importantly, a high linear correlation was found (r = 0.865) between 99mTc-MIBI accumulation and MMP in these cells. These findings indicate that low baseline 99mTc-MIBI uptake that is markedly increased by verapamil represents cancer cells with high levels of MDR1 expression. However, in cancer cells with low or modest levels of MDR1 expression that do not markedly increase 99mTc-MIBI uptake by verapamil, the magnitude of uptake is largely dependent on cellular MMP.

SUN-496 A Perioperative Risk For Exacerbation of Hypercalcemia in Primary Hyperparathyroidism

[Introduction] Primary hyperparathyroidism (PHPT) occasionally presents a hyperparathyroid crisis which provides a pivotal cue for its diagnosis. However, the perioperative risk for exacerbation of hypercalcemia has been unknown in PHPT. We herein report 2 cases of PHPT which presented a hyperparathyroid crisis during the perioperative period for other complications. [Case presentaion] Case 1; A 81-year-old man was referred to our center due to urinary stone and hypercalcemia. Baseline laboratory data were as follows; corrected serum Ca 11.2 mg/dl; serum P 2.0 mg/dl; whole PTH 89.6 pg/ml, eGFR 49 ml/min/1.73m2. CT revealed a neck tumor of 10 mm with 99mTc-MIBI uptake, which was considered as a cause of PHPT. Simultaneously, CT also pointed out thoracic aortic aneurysm of 70 mm. Therefore, he underwent endovascular stent graft therapy prior to tumorectomy of PHPT. The procedure of stent graft was successfully performed but also caused subarachnoid hemorrhage and acute kidney injury (AKI). Corrected Ca level was subsequently elevated to 12.4 mg/dl, implying an exacerbation of PHPT. He received 60 mg denosumab administration in order to control Ca level complicated with AKI, resulted in improvement of hypercalcemia. However, PTH level was not significantly changed (57.4 pg/ml) during the period, indicated that lower urinary excretion of calcium due to AKI was the main cause of Ca level elevation. Case 2; A 57-year-old woman was admitted to our center due to incidental hypercalcemia. Baseline laboratory data were as follows; corrected serum Ca 12.5 mg/dl; serum P 2.1 mg/dl; whole PTH 140 pg/ml, eGFR 74 ml/min/1.73m2. CT revealed a neck tumor of 17 mm with 99mTc-MIBI uptake, considered as a cause of PHPT. Unexpectedly, MR imaging revealed meningioma of 48 mm on the Turkish saddle. She underwent embolization and removal of meningioma prior to tumorectomy of PHPT. After surgery, she had a persistent disturbance of consciousness because of hypernatremia (over 160 mM) and hypercalcemia (17.2 mg/dl) complicated with AKI. As a hyperparathyroid crisis, we administered 60 mg denosumab and continued fluid replacement therapy, leading to gradual improvement of electrolyte imbalances. PTH level was significantly elevated to 443 pg/ml compatible with a hyperparathyroid crisis. Her serum Ca level was kept lower than 12 mg/dl by denosumab for more than 3 months. [Conclusion] Our cases suggested that serum Ca level in PHPT could be influenced by perioperative conditions, although the trigger for exacerbation of PHPT remains unclear. Management of PHPT should be considered before surgery for other complications. Denosumab is useful for management of PHPT regardless of renal function.

Relationship between parathyroid gland scintigraphy and its histopathology, oxyphil cell content and volume: a retrospective study.

Mechanisms that are responsible for positive 99mTc-MIBI uptake in parathyroid glands are not clearly understood, some authors suggest there is a correlation between 99mTc MIBI accumulation and oxyphil cell content or parathyroid gland volume. The aim of our work was to assess the relationship between the pathological structure of parathyroids, their volume, oxyphil cell content and parathyroid 99mTc-MIBI retention. A total of 62 hyperfunctioning parathyroid glands in 46 patients were retrospectively analyzed. Preoperative 99mTc-MIBI scintigraphy was performed according to the double-phase and subtraction protocol. After surgery all glands were evaluated histologically, oxyphil cell content was assessed and volume of each excised gland was calculated. Scintigraphy was positive in 41 of 62 parathyroid glands (66%). The median volume of positive glands was larger than that of negative glands (1.33 ml vs 0.7 ml, p = 0.015). Of the parathyroid lesions, there were 14 (22.6%) cases of nodular hyperplasia, 23 (37.1%) cases of diffuse hyperplasia, and 25 (40.3%) cases of adenomas. A high (≥ 25%) oxyphil cell content was found in 16 glands (25.8%) and a low ( < 25%) oxyphil cell content in 46 (74.2%) glands. Histopathology of parathyroid glands was related to the scintigraphy result (p = 0.002), but not to the 99mTc-MIBI uptake pattern (p = 0.868). The overall result of scintigraphy was not related to the oxyphil cell content (p = 0.797). 99mTc-MIBI uptake pattern wasn't related to the oxyphil cell content (p = 0.833). In general, parathyroid lesions with low oxyphil cell content were larger than parathyroid glands with high oxyphil cell content (1.33 ml vs 0.5 ml, respectively; p = 0.01). The median volume of parathyroids containing a high number of oxyphil cells and having a prolonged 99mTc-MIBI retention was larger than those without prolonged 99mTc-MIBI retention (1.62 ml vs 0.3 ml, respectively; p = 0.008). The median volume of parathyroids with low oxyphil cells content and showing prolonged 99mTc-MIBI retention was larger than those without prolonged 99mTc-MIBI retention (1.95 ml vs 1.07 ml, respectively; p = 0.014). Our findings suggest that a positive scintigraphy result depends on parathyroid histopathology and gland volume and does not depend on the presence of oxyphil cells. Prolonged 99mTc-retention is not related to the parathyroid gland histopathology and the presence of oxyphil cells but to the gland volume.

Different Efflux Transporter Affinity and Metabolism of 99mTc-2-Methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer.

Little is known about the affinity and stability of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability. 99mTc-MIBI and 99mTc-TF were incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability was evaluated. In vesicles, 99mTc-labeled compounds had affinity for MDR1 and MRP1. 99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99mTc-labeled compounds. 99mTc-MIBI uptake with inhibitors was higher than 99mTc-TF uptake with inhibitors. 99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99mTc-MIBI was metabolized, whereas 99mTc-TF had high stability. 99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Because 99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.

In vitro and in silico evaluation of P-glycoprotein inhibition through 99m Tc-methoxyisobutylisonitrile uptake.

P-glycoprotein (P-gp) is a multidrug resistance (MDR) transporter with unknown structural details. This macromolecule is normally responsible for extruding xenobiotics from normal cells. Overexpression of P-gp in tumor cells is a major obstacle in cancer chemotherapy. In this study, human 3D model of P-gp was built by homology modeling based on mouse P-gp crystallographic structure and stabilized through 1ns molecular dynamics (MD) simulation. Stabilized human P-gp structure was used for flexible docking of 80 drugs into the putative active site of P-gp. Accordingly, digoxin, itraconazole, risperidone, ketoconazole, prazosin, verapamil, cyclosporine A, and ranitidine were selected for further in vitro assay. Subsequently, cell-based P-gp inhibition assay was performed on Caco-2 cells while 99m Tc-methoxyisobutylisonitrile (MIBI) was used as a P-gp efflux substrate for calculating IC50 values. Results of the 99m Tc-MIBI uptake in drug-treated Caco-2 cells were in agreement with the previously reported activities. This study for the first time described the relation between molecular dynamics and flexible docking with cellular experiments using 99m Tc-MIBI radiotracer for evaluation of potencies of P-gp inhibitors. Finally, results showed that our radiotracer-cell-based assay is an accurate and fast screening tool for detecting P-gp inhibitors and non-inhibitors in drug development process.

Evaluation of the Effect of Resveratrol and Doxorubicin on 99mTc-MIBI Uptake in Breast Cancer Cell Xenografts in Mice.

Doxorubicin (DOX), despite having antitumor properties, also exhibits cardiotoxicity. Resveratrol has antitumor property for breast cancer cells. 99mTc-MIBI has higher absorption rate in human breast cancer cell line MCF-7. In the present study, the authors intend to investigate the effect of DOX and resveratrol on the absorption of 99mTc-MIBI in breast cancer cell xenografts in mice. Sixteen xenograft models in nude mice were divided into four groups. Group I (S, control) received 2% DMSO in 0.9% saline, group II (D) 2.5 mg/kg DOX, group III (D + R) 20 mg/kg/d resveratrol with 2.5 mg/kg DOX (total dose of 15 mg/kg in six injections), and group IV (R) 20 mg/kg/d resveratrol for 2 weeks. Single-photon emission computed tomography (SPECT) images were taken for the determination of 99mTc-MIBI absorption. Mice were sacrificed, and the percentage of injected dose per gram (%ID/g) of the heart, liver, tumor, and muscle was measured using a gamma counter. Hematoxylin-eosin staining and Masson's trichrome staining were used for investigation of histopathological changes. The %ID/g of tumor was lowest in group D + R. The severity of tumor necrosis or apoptosis was highest in group D + R, but there is no significant difference in pathological injuries and %ID/g of tumor between the group D + R and group D. In addition to the results of the %ID/g, the severity of pathological injuries to the liver and heart cells in group D + R was higher compared with group D. There is a significant difference in the %ID/g of the liver between the group D + R and group D. SPECT images showed that the lowest amount of %ID/g was observed in the tumor of group D + R. According to the results of pathology, biodistribution study, and imaging, the combination of DOX and resveratrol has shown higher antitumor effect; hence, 99mTc-MIBI can be used to evaluate their antitumor effect.

Absent 99mTc-MIBI Uptake in the Thyroid Gland during Early Phase of Parathyroid Scintigraphy in Patients with Primary and Secondary Hyperparathyroidism.

BACKGROUND:Thyroid uptake of technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) during parathyroid scintigraphy can be affected by various conditions.AIM:To evaluate the frequency of absent 99mTc-MIBI uptake by the thyroid gland in the early phase of dual-phase parathyroid scintigraphy.METHODS:The early planar images of dual phase Tc99m MIBI parathyroid scintigraphy from 217 patients performed between 2014 and 2017 were retrospectively analysed. Patients were divided into two groups. The first group included 147 patients with primary hyperparathyroidism and the second group included 70 patients with chronic renal failure. Patient records, laboratory and ultrasonographic data were analysed in all patients. Descriptive statistic was used for data analysis.RESULTS:Out of all patients in the first group, 18 patients (12.24%) showed absent thyroid uptake. Thyroidectomy was performed in 44.4% of these patients, and the rest of them had some thyroid disease. Only one patient had no thyroid or another chronic disease. In the second group, 8 patients (11.42%) presented with absent thyroid uptake of MIBI. Among them, 5 patients had no history of thyroid disease and had been on hemodialysis programme, and 3 patients had hypothyroidism.CONCLUSION:Absent 99mTc-MIBI uptake in the thyroid during the early phase of parathyroid scintigraphy is most frequently related to thyroid disease. A small proportion of patients with chronic renal failure can present with absent 99mTc-MIBI uptake in the thyroid as well. The mechanism for this alteration is still unclear and needs further investigation.

Treatment with 20(S)-ginsenoside Rg3 reverses multidrug resistance in A549/DDP xenograft tumors

Multidrug resistance (MDR) is an obstacle for cancer chemotherapy. It was reported that 20(S)-ginsenoside Rg3 (hereafter Rg3) was able to regulate MDR in mouse leukemia cells. The present study investigated the effect of Rg3 on the MDR of A549 lung cancer cells. A cell viability assay revealed that Rg3 treatment increased cisplatin (DDP) cytotoxicity in DDP resistant A549 cells (A549/DDP). Furthermore, Rg3 increases the antitumor effect of DDP on A549/DDP xenograft mice. The expression of MDR-mediated proteins, including P-glycoprotein (P-gp), multidrug resistance-associated protein (MPR1) and lung resistance protein 1 (LPR1), was detected in tumor tissue of A549/DDP xenograft mice. The results revealed that Rg3 treatment inhibited the expression of these MDR-associated proteins. Additionally, technetium-99m labeled hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) single-photon emission computed tomography was used to monitor the effect of Rg3 on cisplatin sensitivity of A549/DDP xenograft tumors. It was observed that uptake of 99mTc-MIBI was increased by Rg3 treatment, which indicated that Rg3 is able to effectively enhance chemotherapy sensitivity of A549/DDP xenograft tumors. Taken together, these results revealed that Rg3 may be able to reverse MDR of lung cancer via the downregulation of P-gp, MPR1 and LPR1.

Diagnosis performance of 99mTc-MIBI and multimodality imaging for hyperparathyroidism.

This study aimed to examine the diagnosis performance of 99mTc-methoxyisobutylisonitrisonitrile (99mTc-MIBI) and multimodality imaging [ultrasound, single-photon emission computed tomography/computed tomography (SPECT/CT)] for hyperparathyroidism (HPT). From Nov. 2009 to Dec. 2015, clinical data of a total of 43 HPT patients (16 males and 27 females; 26-70 years old, average age: 51.60±10.66 years old) were retrospectively analyzed. Among them, 19 patients with primary hyperparathyroidism (PHPT) underwent 99mTc-MIBI planar imaging, 24 [15 with PHPT and 9 with secondary hyperparathyroidism (SHPT)] underwent SPECT/CT hybrid imaging, and 41 (33 with PHPT and 8 with SHPT) had neck ultrasound imaging. Final diagnosis was determined by pathological examination after surgery. The positive rate was compared between different imaging modalities, and the correlation analysis was conducted between imaging results and lesion size or serum parathyroid hormone (PTH) level. The results showed that the total positive rates of 99mTc-MIBI imaging, ultrasound, and the two combined imaging in the 43 HPT cases were 90.70% (39/43), 58.54% (24/41), and 100% (41/41), respectively. According to lesion numbers, the positive rates were 79.10% (53/67), 53.23% (33/62), and 88.71% (55/62), respectively. SPECT/CT hybrid images were positive in all the 24 patients who underwent this examination. The mean maximum diameters of the lesions in 99mTc-MIBI positive and negative patients were 1.96±0.95 cm and 1.36±0.67 cm respectively, with statistically significant difference noted (P=0.03). The T/NT of 99mTc-MIBI imaging at the early phase was correlated positively with serum PTH level (r=0.40, P=0.01). The T/NT of 99mTc-MIBI imaging at both the early phase and the delay phase was correlated positively with lesion size (r=0.51, and r=0.45, respectively; P<0.01 for both). It was concluded that 99mTc-MIBI imaging presents significant value for location diagnosis of HPT, especially when combined with SPECT/CT hybrid imaging or ultrasound. The 99mTc-MIBI uptake correlates positively with serum PTH level and lesion size.