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1.
Drug Metab Dispos ; 52(8): 899-905, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38811159

RESUMO

Heart failure (HF) is a chronic disease affecting 1%-2% of the global population.123I-labeled meta-iodobenzylguanidine (mIBG) is US Food and Drug Administration-approved for cardiac imaging and prognosis risk assessment in patients with HF. As a norepinephrine analog, mIBG is believed to be transported into adrenergic nerve terminals by the neuronal norepinephrine transporter (NET) and hence image sympathetic innervation of the myocardium. We previously showed that mIBG is an excellent substrate of organic cation transporter 3 (OCT3), an extraneuronal transporter expressed in cardiomyocytes. Here, we evaluated the in vivo impact of Oct3 on mIBG disposition and tissue distribution using Oct3 knockout mice. Oct3 +/+ and Oct3 -/- mice were administered with mIBG intravenously, and mIBG plasma pharmacokinetics and tissue exposures were determined. In Oct3 +/+ mice, mIBG exhibited extensive accumulation in multiple tissues (heart, salivary gland, liver, and adrenal gland). No difference was observed in overall plasma exposure between Oct3 +/+ and Oct3 -/- mice. Strikingly, cardiac mIBG was depleted in Oct3 -/- mice, resulting in 83% reduction in overall cardiac exposure (AUC0-24 h: 12.7 vs. 2.1 µg × h/g). mIBG tissue exposure (AUC0-24 h) was also reduced by 66%, 36%, and 31% in skeletal muscle, salivary gland, and lung, respectively, in Oct3 -/- mice. Our data demonstrated that Oct3 is the primary transporter responsible for cardiac mIBG uptake in vivo and suggested that cardiac mIBG imaging mainly measures OCT3 activity in cardiomyocytes but not NET-mediated uptake in adrenergic nerve endings. Our findings challenge the current paradigm in interpreting cardiac mIBG imaging results and suggest OCT3 as a potential genetic risk marker for HF prognosis. SIGNIFICANCE STATEMENT: 123I-labeled meta-iodobenzylguanidine is used for cardiac imaging and risk assessment in heart failure patients. Contrary to the current belief that meta-iodobenzylguanidine (mIBG) tracks cardiac sympathetic innervation due to its uptake by the neuronal norepinephrine transporter, the authors demonstrated that cardiac mIBG uptake is mediated by the extraneuronal transporter Oct3. Their findings warrant a re-evaluation of the scientific rationale behind cardiac mIBG scan and further suggest organic cation transporter 3 as a risk factor for disease progression in heart failure patients.


Assuntos
3-Iodobenzilguanidina , Camundongos Knockout , Miocárdio , Fator 3 de Transcrição de Octâmero , Animais , Camundongos , 3-Iodobenzilguanidina/farmacocinética , 3-Iodobenzilguanidina/metabolismo , Miocárdio/metabolismo , Distribuição Tecidual , Masculino , Fator 3 de Transcrição de Octâmero/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Coração/diagnóstico por imagem , Coração/inervação , Camundongos Endogâmicos C57BL , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo
2.
Nucl Med Biol ; 112-113: 44-51, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35802985

RESUMO

INTRODUCTION: Meta-[211At]astato-benzylguanidine ([211At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also distributed in normal tissues non-specifically. Meta-[131I]iodo-benzylguanidine ([131I]MIBG), an iodine-labeled analog of [211At]MABG, is known to be transported by not only NET but also organic cation transporter (OCT). The involvement of OCT in [211At]MABG uptake is still largely unknown. We investigated the involvement of OCT in the non-NET-driven uptake of [211At]MABG both in vitro and in vivo. METHODS: [123I]MIBG and [211At]MABG uptake was investigated in PC-12 (rat pheochromocytoma cell line), NIH/3T3 (mouse fibroblasts cell line), ACHN (human renal cancer cell line), and BxPC-3 (human pancreatic cancer cell line). Herein, we used desipramine and dl-norepinephrine to inhibit NET, and we used steroids (hydrocortisone and prednisolone) to inhibit OCT3. The [211At]MABG uptake in OCT3-knockdown cells established with OCT3-selective siRNA was also investigated. We investigated the biodistribution of [211At]MABG in PC-12 tumor-bearing mice after a preloading of phosphate-buffered saline (PBS) or hydrocortisone solution. RESULTS: The uptake of both [123I]MIBG and [211At]MABG was significantly inhibited by desipramine in PC-12 cells but not the other cell lines. The expression of OCT3 was relatively higher than those of the other OCT subtypes in ACHN and BxPC-3 cells. The expression of OCTs was not observed in NIH/3T3 cells. The uptake of both [123I]MIBG and [211At]MABG in ACHN and BxPC-3 cells was significantly inhibited by the steroid treatments. The [211At]MABG uptake was also reduced in OCT3-knockdown cells (p < 0.001). The radioactivity of [211At]MABG was significantly reduced in normal tissues by the preloading of hydrocortisone. In contrast, there was an increasing trend of [211At]MABG uptake in the PC-12 tumors. The tumor-to-normal tissue ratio was significantly increased by the preloading of hydrocortisone compared to that of PBS. CONCLUSION: Our results suggest that OCT3 is involved in non-NET-driven [211At]MABG uptake. The preloading of hydrocortisone selectively reduced [211At]MABG accumulation in normal organs in vivo. OCT3 inhibition may therefore be beneficial for a reduction of the radiation risk in healthy organs in the treatment of malignant pheochromocytomas.


Assuntos
Neoplasias das Glândulas Suprarrenais , Feocromocitoma , 3-Iodobenzilguanidina/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Animais , Cátions/metabolismo , Desipramina , Guanidinas , Humanos , Hidrocortisona , Radioisótopos do Iodo , Camundongos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Feocromocitoma/diagnóstico por imagem , Feocromocitoma/genética , Feocromocitoma/metabolismo , Fosfatos/metabolismo , Prednisolona , RNA Interferente Pequeno , Ratos , Distribuição Tecidual
3.
Medicine (Baltimore) ; 100(33): e26995, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414983

RESUMO

ABSTRACT: Parkinson disease (PD) is a heterogeneous neurodegenerative disorder. Dopamine transporter imaging using 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (FP-CIT) and noradrenergic cardiac imaging using 123I-meta-iodobenzylguanidine (MIBG) have been used in combination or separately to study PD patients. Published results regarding uptake of the 2 tracers in each motor subtype are fairly abundant and mostly in agreement. However, data on the intrasubject association between dopaminergic and noradrenergic systems in PD patients are relatively scant and vary. We aimed to assess the intrasubject relationship between striatal dopamine transporter density using a PET tracer and cardiac sympathetic innervation in tremor-dominant subtype (TD) and akinetic-rigid subtype (AR) of PD.This study has a cross-sectional design. Thirty-one patients with early PD (17 TD/14 AR) who underwent both 123I-MIBG cardiac scintigraphy and 18F-FP-CIT PET/CT were retrospectively selected. We assessed the relationship between heart-to-mediastinum ratio (H/M) of 123I-MIBG and specific (striatal)-to-nonspecific (cerebellar) dopamine transporter binding ratio (S/N) measured from 4 separate regions-of-interest (bilateral caudate nuclei and lentiform nuclei) of 18F-FP-CIT in each motor subtype.S/N of all 4 striatal regions were significantly lower in the AR subgroup than in the TD subgroup. H/M was not significantly different. There was a significant intrasubject correlation between H/M and S/N of the lentiform nucleus in AR-PD but no correlation between H/M and any of 4 S/N in TD-PD.Our data suggest a coupled degeneration of nigrostriatal dopaminergic and myocardial sympathetic denervation in AR subtype, but not in TD subtype, of early PD patients. These different results between the 2 motor subtypes likely reflects the heterogeneous pathophysiology of PD.


Assuntos
3-Iodobenzilguanidina/metabolismo , Radioisótopos do Iodo/metabolismo , Miocárdio/metabolismo , Doença de Parkinson/metabolismo , 3-Iodobenzilguanidina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Radioisótopos do Iodo/análise , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio/métodos , Tomografia por Emissão de Pósitrons/métodos
4.
Clin Nucl Med ; 46(4): 329-331, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33315681

RESUMO

ABSTRACT: 123I-metaiodobenzylguanidine scintigraphy is used to differentiate Lewy body disease from other neurodegenerative disorders. We identified 2 cases with remarkably changed pulmonary uptake between 2 metaiodobenzylguanidine scintigraphies; pulmonary uptake was reduced when patients were taking selective serotonin reuptake inhibitor/serotonin noradrenaline reuptake inhibitor and preserved during the medication-naive or withdrawal state, suggesting that pulmonary uptake involves not only the noradrenaline transporter, but also the serotonin transporter. Pulmonary accumulation may affect the heart-to-mediastinum ratio as the region of interest on the planner image is usually placed on the heart and includes part of the lung. Therefore, we should pay attention to the medication state of patients with decreased pulmonary uptake.


Assuntos
3-Iodobenzilguanidina/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Transporte Biológico/efeitos dos fármacos , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Cintilografia
5.
Clin Nucl Med ; 46(3): 227-228, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33351513

RESUMO

ABSTRACT: A 30-year-old man presented with repeated episodes of painless injuries in his feet and abnormally high body temperature. He was diagnosed with congenital insensitivity to pain with anhidrosis-a rare hereditary peripheral neuropathy characterized by decreased pain, reduced sweating, and autonomic neuropathy. Congenital insensitivity to pain with anhidrosis is also called hereditary sensory and autonomic neuropathy type IV. 123I-MIBG myocardial scintigraphy showed reduced myocardial uptake (heart-to-mediastinum ratio: 1.56 and 1.42 in the early and late phases, respectively; washout ratio, 49%), indicating autonomic dysfunction. This finding may contribute to the diagnosis of congenital insensitivity to pain with anhidrosis and the semiquantitative evaluation of an autonomic dysfunction.


Assuntos
3-Iodobenzilguanidina/metabolismo , Neuropatias Hereditárias Sensoriais e Autônomas/metabolismo , Miocárdio/metabolismo , Adulto , Transporte Biológico , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico por imagem , Humanos , Masculino , Imagem de Perfusão do Miocárdio
6.
Clin Nucl Med ; 46(2): 168-170, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33181757

RESUMO

ABSTRACT: A 3-year-old boy with high-risk neuroblastoma underwent 123I-MIBG scan to evaluate the disease status after surgery and chemotherapy. 123I-MIBG SPECT/CT demonstrated liver metastasis. In addition, mildly increased uptake in the inferior left erector spinae was noted. Contrast-enhanced CT suggested intramuscular hemangioma. The 123I-MIBG accumulation in the intramuscular hemangioma persisted during the follow-up scan, whereas the abnormal activity in the liver was resolved.


Assuntos
3-Iodobenzilguanidina , Hemangioma/diagnóstico por imagem , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , 3-Iodobenzilguanidina/metabolismo , Transporte Biológico , Pré-Escolar , Hemangioma/metabolismo , Humanos , Masculino
7.
Nucl Med Biol ; 90-91: 49-54, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33032192

RESUMO

INTRODUCTION: 131I-labeled m-iodobenzylguanidine ([131I]MIBG) has been used to treat neuroblastoma patients, but [131I]MIBG may be immediately excreted from the cancer cells by the adenosine triphosphate binding cassette transporters, similar to anticancer drugs. The purpose of this study was to clarify the efflux mechanism of [131I]MIBG in neuroblastomas and improve accumulation by inhibition of the transporter in neuroblastomas. METHODS: [131I]MIBG was incubated in human embryonic kidney (HEK)293 cells expressing human organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic anion transporter (OAT)1 and OAT2, organic cation transporter (OCT)1 and OCT2, and sodium taurocholate cotransporting polypeptide, and in vesicles expressing P-glycoprotein (MDR1), multidrug resistance associated protein (MRP)1-4, or breast cancer resistance protein with and without MK-571 and probenecid (MRP inhibitors). Time activity curves of [131I]MIBG with and without MK-571 and probenecid were established using an SK-N-SH neuroblastoma cell line, and transporter expression of multiple drug resistance was measured. Biodistribution and SPECT imaging examinations were conducted using [123I]MIBG with and without probenecid in SK-N-SH-bearing mice. RESULTS: [131I]MIBG uptake was significantly higher in OAT1, OAT2, OCT1, and OCT2 than in mock cells. Uptake via OCT1 and OCT2 was little inhibited by MK-571 and probenecid. [131I]MIBG uptake into vesicles that highly expressed MRP1 or MRP4 was significantly higher in ATP than in AMP, and these inhibitors restored uptake to levels similar to that in AMP. Examining the time activity curves for [131I]MIBG in SK-N-SH cells, higher expressions of MDR1, MRP1, MRP4, and MK-571, or probenecid loading produced significantly higher uptake than in control at most incubation times. The ratios of tumors to blood or muscle in SK-N-SH-bearing mice were significantly increased by probenecid loading in comparison with normal mice. CONCLUSIONS: [131I]MIBG exports via MRP1 and MRP4 in neuroblastoma. The accumulation and tumor-to-blood or muscle ratios of [131I]MIBG are improved by inhibition of MRPs with probenecid in neuroblastoma. ADVANCES IN KNOWLEDGE: [131I]MIBG, widely used for treatment of neuroendocrine tumors including neuroblastoma, is excreted via MRP1 and MRP4 in neuroblastoma. IMPLICATIONS FOR PATIENT CARE: Loading with probenecid, OAT, and MRP inhibitors improves [131I]MIBG accumulation.


Assuntos
3-Iodobenzilguanidina/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neuroblastoma/patologia , Animais , Transporte Biológico , Linhagem Celular Tumoral , Células HEK293 , Humanos , Camundongos , Distribuição Tecidual
8.
J Gastroenterol Hepatol ; 35(12): 2151-2157, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32410288

RESUMO

BACKGROUND AND AIM: Imaging noradrenergic uptake in the liver with norepinephrine analog 123 I-meta-iodobenzylguanidine (mIBG) was explored in normal controls and patients with heart failure (HF). METHODS: A total of 961 HF (343 with diabetes mellitus [DM]) and 94 control subjects underwent anterior planar mIBG images including upper abdomen at 15 min (early) and 3 h 50 min (late) post-injection. Decay-corrected liver activity normalized to injected activity and body surface area (counts/pixel [cpp]/MBq/m2 ) was compared in three groups: HF with DM; HF without DM; and controls. Associations with plasma norepinephrine, liver function tests, and level of cardiac innervation were explored. RESULTS: In controls, liver mIBG activity decreased over time (early: 2.78 vs late: 2.43 cpp/MBq/m2 , P < 0.0001); in HF subjects, activity increased during this interval (HF without DM: 2.85 vs 2.93 [P = 0.005]; HF with DM: 2.37 vs 2.43 [P = 0.054]). Early liver activity was lower in HF with DM subjects than in the other groups (P < 0.001); late liver activity was higher in HF without DM than in the other two groups (P < 0.01). Subjects with elevated plasma norepinephrine (> 520 pg/mL) or ≥ 1 abnormal liver function test had lower early and late liver activity. In subjects with preserved cardiac mIBG uptake, HF subjects had higher and control subjects lower liver activity than comparable subjects with decreased cardiac innervation. CONCLUSIONS: In HF subjects, liver mIBG activity increased over time, reversing the normal washout pattern, suggesting a compensatory change in sympathetic nerve function. DM, abnormal liver function tests, and decreased cardiac innervation were associated with decreased liver mIBG uptake in HF.


Assuntos
3-Iodobenzilguanidina , Diabetes Mellitus/metabolismo , Diagnóstico por Imagem , Insuficiência Cardíaca/metabolismo , Radioisótopos do Iodo , Fígado/diagnóstico por imagem , Fígado/metabolismo , Compostos Radiofarmacêuticos , 3-Iodobenzilguanidina/metabolismo , Idoso , Feminino , Humanos , Radioisótopos do Iodo/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/metabolismo
9.
PLoS One ; 15(3): e0229860, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32134983

RESUMO

PURPOSE: We have evaluated the clinical significance of the washout rate (WR) on I-123 MIBG scans through the analysis of the relationship between the I-123 MIBG scans and autonomic status in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Sixty patients with clinical PD who had decreased HMR were enrolled. An autonomic symptom was evaluated using a head-up tilt test and the Composite Autonomic Severity Score (CASS). An I-123 MIBG scan and F-18 FP-CIT positron emission tomography (PET) were performed. All of the patients were classified into three groups according to the WR. The differences in patient characteristics and the imaging parameters among the three groups were evaluated, and a correlation analysis was also performed. RESULTS: The frequency of orthostatic hypotension was significantly different among the three groups. The difference in systolic pressure (dSysPr) and the difference in diastolic pressure (dDiaPr) of group 3 was significantly larger than those of groups 1 and 2. From the correlation analysis, it can be seen that age, Hoehn and Yahr (H&Y) stage, dSysPr, and dDiaPr had a weak positive correlation with the WR. The total CASS score was significantly higher in group 3 compared with groups 1 and 2. The WR had a moderate positive correlation with the cardiosympathetic score and the total CASS score. CONCLUSION: The WR is related to autonomic dysfunction. An I-123 MIBG cardiac scan is considered to be a good method to evaluate not only the differential diagnosis of Parkinson's disease but also the degree of autonomic dysfunction.


Assuntos
3-Iodobenzilguanidina/administração & dosagem , Sistema Nervoso Autônomo/diagnóstico por imagem , Radioisótopos do Iodo/administração & dosagem , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/administração & dosagem , 3-Iodobenzilguanidina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , Feminino , Radioisótopos de Flúor/administração & dosagem , Radioisótopos de Flúor/metabolismo , Coração/diagnóstico por imagem , Humanos , Hipotensão Ortostática/diagnóstico , Radioisótopos do Iodo/metabolismo , Masculino , Mediastino/diagnóstico por imagem , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos , Tropanos/administração & dosagem , Tropanos/metabolismo
10.
BMJ Case Rep ; 13(3)2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32169989

RESUMO

Paraganglioma of the bladder is a rare tumour accounting for less than 0.06% of all urinary bladder tumours and has varied presentations. It may present with clinical symptoms of phaeochromocytoma, may be non-functioning and asymptomatic or may present with haematuria. Hence, paragangliomas are occasionally misdiagnosed, and this results in unanticipated intraoperative hypertensive crisis. We present the case of a 44-year-old woman with urinary bladder paraganglioma who presented with young onset hypertension, recurrent micturition syncope with prior history of coronary artery disease and stroke. She was stabilised preoperatively with alpha blocking agents and subsequently underwent successful transurethral resection of the same.


Assuntos
Paraganglioma/cirurgia , Síncope/etiologia , Neoplasias da Bexiga Urinária/complicações , 3-Iodobenzilguanidina/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Adulto , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Hipertensão/complicações , Normetanefrina/urina , Prazosina/uso terapêutico , Cuidados Pré-Operatórios , Síncope/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia
11.
Q J Nucl Med Mol Imaging ; 64(1): 131-138, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29409315

RESUMO

BACKGROUND: The aim of this study was to assess the prognostic value of postoperative 123I-MIBG scintigraphy, including systematic SPECT/CT and semiquantification of the uptake at the surgical site, in a prospective series of NB patients. METHODS: Patients operated for neuroblastoma and who had benefited from postoperative 123I-MIBG scintigraphy were prospectively and consecutively included. Completeness of surgery was assessed on operative report. One month postoperative 123I-MIBG scintigraphy included planar acquisition and SPECT/CT. Semi-quantification of the 123I-MIBG SPECT/CT uptake at the surgical site was performed and ratios to reference (liver and mediastinum) areas were calculated. RESULTS: Thirty patients were included between August 2012 and July 2015. Median follow-up was 36 months (range 10-98). Surgery was considered as complete in 23 patients and incomplete in 7 patients. Eight patients (26.7%) presented progressive disease (1 progression and 7 recurrences). Seven patients died (23.3%), all from NB. Six (20%) patients had positive 123I-MIBG scintigraphy (3 on planar acquisitions and 6 on SPECT/CT) and 24 patients had negative 123I-MIBG scintigraphy. Five of the 6 patients (83%) with positive 123I-MIBG scintigraphy presented progressive disease. Ratio of the uptake at the surgical site to mediastinum was strongly and independently correlated with disease-free interval and overall survival (P=0.02 and 0.01 respectively). The amplified MYCN status was also confirmed as correlated with poorer outcomes. CONCLUSIONS: Postoperative 123I-MIBG scintigraphy including SPECT/CT and semiquantification of the uptake at the surgical site appeared to be a valuable prognostic tool in neuroblastoma.


Assuntos
3-Iodobenzilguanidina/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Transporte Biológico , Criança , Pré-Escolar , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/metabolismo , Neuroblastoma/cirurgia , Período Pós-Operatório , Prognóstico
12.
Eur J Nucl Med Mol Imaging ; 47(7): 1657-1667, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31502014

RESUMO

PURPOSE: The effects of transcatheter aortic valve replacement (TAVR) on cardiac sympathetic nervous (CSN) function have not been fully explored. This study aimed to investigate the early (within 2 weeks) effects of TAVR on CSN function in patients with severe aortic valve stenosis (AS) using 123I-metaiodobenzylguanidine (MIBG) scintigraphy. METHODS: Of 143 consecutive patients who were scheduled to undergo TAVR, 67 (18 men; median age 86 years) were evaluated in this single-centre prospective observational study. MIBG scintigraphy was performed at baseline and 3-14 days after the TAVR procedure to evaluate the heart-mediastinum ratio (H/M) and washout rate (WR). Differences between baseline and post-TAVR MIBG parameters were analysed. MIBG parameter changes were compared with echocardiographic parameters. Furthermore, factors involved in the improvement in MIBG parameters were investigated. RESULTS: All patients successfully underwent TAVR with improved echocardiographic parameters, including aortic valve area (AVA; 0.6 cm2 vs. 1.6 cm2), peak velocity (4.5 m/s vs. 2.0 m/s), mean pressure gradient (50 mmHg vs. 9 mmHg), and left ventricular ejection fraction (56% vs. 62%) (all p < 0.001). On MIBG imaging, delayed H/M significantly increased (2.57 vs. 2.68, p < 0.001), whereas WR decreased (32.2% vs. 26.8%, p < 0.001). In multivariate analysis, higher baseline WR was associated with improvement in WR (> 3%). Female sex, Clinical Frailty Scale score ≤ 5, baseline estimated glomerular filtration rate, and baseline AVA were predictors of improvement in delayed H/M (> 0.1). Baseline AVA and E/E' were independent predictors of improvement in both WR and delayed H/M. CONCLUSIONS: The CSN function was impaired in patients with AS, as assessed using MIBG scintigraphy. WR and delayed H/M improved immediately after TAVR. Improvement in CSN function may be related to echocardiographic AS severity at baseline before TAVR.


Assuntos
Estenose da Valva Aórtica , Coração , Radioisótopos do Iodo , Cintilografia , Sistema Nervoso Simpático , Substituição da Valva Aórtica Transcateter , 3-Iodobenzilguanidina/metabolismo , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Feminino , Coração/diagnóstico por imagem , Coração/inervação , Humanos , Masculino , Índice de Gravidade de Doença , Fatores Sexuais , Volume Sistólico , Sistema Nervoso Simpático/diagnóstico por imagem , Substituição da Valva Aórtica Transcateter/normas , Resultado do Tratamento , Função Ventricular Esquerda
13.
Clin Nucl Med ; 45(3): e156-e157, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31714281

RESUMO

We report a case of an adult male patient with multifocal urinary bladder paragangliomas, which were negative on Ga-DOTATATE PET/CT scan, but positive on I-MIBG SPECT/CT scan. While the Ga-DOTA analog PET/CT exhibits superior performance in diagnosis and staging of pheochromocytoma and paraganglioma, our case demonstrates negative somatostatin receptor expression in this rare entity and indicates that I-MIBG SPECT/CT still plays a vital role in characterization of bladder paraganglioma.


Assuntos
3-Iodobenzilguanidina/metabolismo , Compostos Organometálicos/metabolismo , Paraganglioma/diagnóstico , Paraganglioma/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/metabolismo , Transporte Biológico , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Somatostatina/metabolismo
14.
J Med Chem ; 62(15): 6985-6991, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31283215

RESUMO

Meta-iodobenzylguanidine (MIBG) is a ligand with high affinity against norepinephrine transporter (NET) that has been used for diagnostic imaging and radionuclide therapy of NET-expressing tumors, such as neuroblastoma. We hypothesize that MIBG can be used as a ligand for development of new anticancer drugs targeting NET-expressing neuroblastoma (NB). To test our hypothesis, we synthesized two MIBG-based anticancer copper complexes [Cu(m-TSBG)2 and Cu(p-TSBG)2] by conjugation of a thiosemicarbazone copper group onto MIBG ligand. Both Cu(m-TSBG)2 and Cu(p-TSBG)2 compounds showed potent anticancer activity against NB cells (BE2C and SK-N-DZ cells). The NB-specific anticancer activity of Cu(m-TSBG)2 and Cu(p-TSBG)2 was further demonstrated by the reduced anticancer activities when nonconjugated MIBG ligand was used to competitively block binding of Cu(m-TSBG)2 or Cu(p-TSBG)2 onto NET-expressing NB cells. Both Cu(m-TSBG)2 or Cu(p-TSBG)2 compounds hold potential as promising new drugs for targeted therapy of neuroblastoma and other NET-expressing tumors.


Assuntos
3-Iodobenzilguanidina/metabolismo , Antineoplásicos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Neuroblastoma/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Semicarbazidas/metabolismo , 3-Iodobenzilguanidina/química , 3-Iodobenzilguanidina/farmacologia , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Cobre/química , Cobre/metabolismo , Cobre/farmacologia , Guanidinas/química , Guanidinas/metabolismo , Guanidinas/farmacologia , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Semicarbazidas/química , Semicarbazidas/farmacologia
15.
Clin Nucl Med ; 44(9): 761-763, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31058691

RESUMO

Although increased MIBG activity in the colon is a well-described and well-known normal variant, elevated MIBG activity in the stomach is rarely seen. We describe increased I-MIBG accumulation in the stomach in a 13-year-old girl who had recurrent metastatic neuroblastoma. The activity appeared to be a new MIBG-avid lesion on the planar images. However, the SPECT/CT images revealed that the activity was inside the gastric lumen without anatomical abnormality. On a follow-up I-MIBG scan acquired 3 months later, the stomach no longer had elevated MIBG activity, while the other abnormal activity on prior study remained the same.


Assuntos
3-Iodobenzilguanidina/metabolismo , Mucosa Gástrica/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Estômago/diagnóstico por imagem , Adolescente , Transporte Biológico , Feminino , Humanos , Metástase Neoplásica , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Recidiva , Estômago/patologia
16.
Psychogeriatrics ; 19(6): 566-573, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30809892

RESUMO

BACKGROUND: Recently, depression with Lewy body pathology before the appearance of parkinsonism and cognitive dysfunction has been drawing attention. Low cardiac metaiodobenzylguanidine (MIBG) uptake is helpful for early differentiation of Lewy body disease (LBD) from late-onset psychiatric disorders even before parkinsonism or dementia appears. In this study, we used MIBG uptake as a tool in suspected LBD, and evaluated the relationship of MIBG results to clinical characteristics and depressive symptoms. METHODS: Fifty-two elderly inpatients with depression were included in this study. The Hamilton Depression Rating Scale (HDRS) was administered at admission, and 123 I-MIBG cardiac scintigraphy was performed. Of 52 patients, 38 had normal and 14 had reduced MIBG uptake. RESULTS: Correlation analyses of the late phase heart-to-mediastinum (H/M) ratio on the MIBG test and each item of the HDRS revealed that the H/M ratio was significantly correlated with scores of 'agitation', 'anxiety-somatic', and 'retardation' on the HDRS. Mean HDRS composite scores of 'somatic and psychic anxiety (Marcos)' and 'somatic anxiety/somatization factor (Pancheri)' were higher in the low uptake group than in the normal uptake group. CONCLUSION: Elderly patients with depression who manifested an obvious somatic anxiety tend to show low MIBG uptake, and are more likely to have Lewy body pathology.


Assuntos
3-Iodobenzilguanidina/metabolismo , Depressão/diagnóstico , Coração/diagnóstico por imagem , Doença por Corpos de Lewy/diagnóstico , Imagem de Perfusão do Miocárdio/métodos , Cintilografia/métodos , Compostos Radiofarmacêuticos/metabolismo , 3-Iodobenzilguanidina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Coração/fisiopatologia , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/administração & dosagem
17.
Nucl Med Biol ; 68-69: 49-57, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30770228

RESUMO

INTRODUCTION: meta-[123/131I]Iodobenzylguanidine (mIBG) is a clinical agent used for imaging neuroendocrine tumors, where uptake in tumor is via active transport mechanism through norepinephrine transporters (NET). Our group in past have evaluated a 99mTc-analogue of the above tracer, based on 99mTc-4 + 1 labeling approach, which exhibited significant affinity for NET but suffered from reduced specific uptake in comparison to reference standard no-carrier-added (n.c.a.) [125I]mIBG. The present work attempts to synthesize two new 99mTc-analogues of the radio-iodinated derivative following [99mTc]Tc(CO)31+ approach with an aim to improve the above specific uptake content. METHODS: Two different precursors, xylylenediamine and 1,3-bis(chloromethyl)benzene, were synthetically modified to yield meta-functionalized benzylguanidine derivatives bearing iminodiacetate (IDA) and aminoethylglycine (AEG) tridentate chelating moieties, respectively. These ligands were labeled with technetium-99m via [99mTc][Tc(CO)3(H2O)3]+ synthon to form desired radioactive complexes 9 and 10. The radiolabeling yields of the complexes obtained were >90% as confirmed by radio-HPLC. The HPLC purified complexes were used for in vitro and in vivo evaluation to understand the true biological efficacy. Structural characterization of the radiolabeled complexes was carried after synthesizing and characterizing their Re-analogues. RESULTS: Cell uptake studies with the radiolabeled complexes in SK-N-SH neuroblastoma cell lines revealed reduced uptake in the cells (<1% of incubated radioactivity/106 cells) in comparison to n.c.a. [125I]mIBG (~12%). However, limited specificity (~60%) was observed for the complexes as ascertained through desmethylimipramine (DMI) inhibition. Biodistribution studies in normal Wistar rats exhibited desired non-target clearance pharmacokinetics for the complexes but in vivo NET efficacy in myocardium for the neutral complex 10 could not be established. CONCLUSIONS: Tridentate [99mTc]Tc(CO)31+ chelation approach severely affects biological behavior of the present small bioactive molecule under study to a significant extent in comparison to monodentate ligation in 99mTc-4 + 1 strategy.


Assuntos
3-Iodobenzilguanidina/síntese química , 3-Iodobenzilguanidina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Tecnécio/química , 3-Iodobenzilguanidina/química , 3-Iodobenzilguanidina/farmacocinética , Animais , Linhagem Celular Tumoral , Técnicas de Química Sintética , Estabilidade de Medicamentos , Humanos , Radioquímica , Ratos , Ratos Wistar , Distribuição Tecidual
18.
Clin Nucl Med ; 44(3): e170-e171, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30672756

RESUMO

An 84-year-old man with parkinsonism was referred for I-MIBG scintigraphy. Abnormal uptake in the right upper abdomen was incidentally seen in planar image, and SPECT revealed focal uptake in the medial segment (S4) of the liver. Subsequent triple-phase contrast-enhanced CT showed no evidence of hepatic tumors, although in the arterial phase, there were an enhanced region corresponding to the uptake area and the enhanced vein of Sappey that flowed into S4. In this case, the focal I-MIBG uptake would be attributable to hemodynamic change in the liver.


Assuntos
3-Iodobenzilguanidina/metabolismo , Fígado/diagnóstico por imagem , Fígado/metabolismo , Idoso de 80 Anos ou mais , Transporte Biológico , Humanos , Achados Incidentais , Masculino , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
19.
Mol Imaging Biol ; 21(3): 482-490, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30187232

RESUMO

PURPOSE: The aim of the present study was to evaluate the expression of the cardiac norepinephrine transporter (NET) in the left ventricle (LV) of healthy pigs and its relationship with regional meta-[123I]iodobenzylguanidine ([123I]MIBG) myocardial uptake. PROCEDURES: Experiments were performed on animals injected with [123I]MIBG and acquired 2 h later using an ultrafast CZT gamma camera to assess the regional myocardial uptake. After image acquisition, animals were euthanized; the heart was quickly excised and underwent to an ex vivo single photon emission tomography (SPECT) imaging. Four small samples of tissue were then harvested from mid-walls and apex of the left ventricle; NET densities were evaluated and further normalized for protein loading per cardiac region. RESULTS: Three variants of NET protein with different molecular weights were detected. The expression of NET was not homogenous in the LV, with the highest density in the inferior wall and the lowest one in the apical area. The regional in vivo [123I]MIBG uptake revealed an analogous trend, showing a good linear relationship with NET expression. Parallel results were obtained from the ex vivo study. CONCLUSION: This study elucidates the expression of three different variants of NET proteins into the left ventricular myocardium of a healthy pig. NET expression into the LV was not homogeneous and paralleled by differences in regional [123I]MIBG uptake. Moreover, the correlation and the agreement between measurements of regional expression of NET variants and [123I]MIBG uptake represent a relevant finding for inferences about NET expression in the context of clinical imaging.


Assuntos
3-Iodobenzilguanidina/metabolismo , Radioisótopos do Iodo/química , Miocárdio/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Animais , Ventrículos do Coração/metabolismo , Perfusão , Suínos , Tomografia Computadorizada de Emissão de Fóton Único
20.
J Neurol Sci ; 396: 3-7, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30391822

RESUMO

BACKGROUND AND OBJECTIVES: Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is an effective tool for distinguishing Parkinson's disease (PD) from other diseases accompanied by parkinsonism. Unlike other Parkinsonian diseases, in PD, MIBG accumulation in the heart tends to decrease. However, previous studies have reported that a decrease in MIBG accumulation also occurs in progressive supranuclear palsy (PSP). Thus, we analyzed the relationship between the degree of MIBG accumulation decrease, clinical symptoms, and brainstem atrophy in PSP. METHODS: We retrospectively collected data from patients who underwent MIBG myocardial scintigraphy and compared MIBG indices (heart to mediastinum [H/M] ratio, washout rate) between subjects with PSP and other diseases including PD. In addition, we evaluated the relationship between clinical characteristics, MIBG accumulation, and brainstem atrophy in patients with PSP. RESULTS: Patients with PSP had a significantly lower early H/M ratio compared with multiple system atrophy with predominant parkinsonism (MSA-P) patients, and a control group. In PSP patients there was a correlation between the decrease in delay H/M ratio, atrophy of the pons, and clinical severity as evaluated by Hoehn and Yahr score. CONCLUSION: Unlike in PD, PSP patients exhibited a mild decrease in MIBG accumulation in MIBG myocardial scintigraphy, which may be related to brainstem atrophy.


Assuntos
3-Iodobenzilguanidina/metabolismo , Imagem de Perfusão do Miocárdio/métodos , Compostos Radiofarmacêuticos/metabolismo , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Atrofia/etiologia , Tronco Encefálico/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Estudos Retrospectivos
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