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/metabolismoRESUMO
PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.
Assuntos
Neoplasias das Glândulas Suprarrenais , Feocromocitoma , Adulto , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , 3-Iodobenzilguanidina/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , Feocromocitoma/diagnóstico por imagem , Estudos Prospectivos , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagemRESUMO
meta-iodobenzylguanidine (mIBG) is a radiopharmaceutical used for the diagnosis and treatment of neuroendocrine cancers. Previous quantification of mIBG in biodistribution and pharmacokinetic studies mainly relied on the use of radiolabeled mIBG, which involves the handling of highly radioactive materials. The goal of this study was to develop a nonradioactive analytical method for quantifying mIBG in mouse plasma and tissue homogenates using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Samples were prepared for analysis using a protein precipitation method. Mass spectrometry analysis was performed using 4-hydroxyphenformin as the internal standard, and the mass-to-charge transitions were 276.1 â 217.0 for mIBG and 222.1 â 121.0 for 4-hydroxyphenformin. The quantification limit of mIBG was 0.98 ng/mL, and the method was linear up to 500 ng/mL. The accuracy, inter-day and intra-day precision were 96-112%, 5.5-14.4%, and 3.7-14.1%, respectively, suggesting that the method was accurate and precise in quantifying mIBG at multiple concentrations in mouse plasma and liver homogenates. The extraction recovery was 96-106% and the matrix effect was 95-110%, indicating that the method was reproducible in quantifying mIBG with minimal impact from the biological matrices. In summary, we have developed and validated a fast, high-throughput quantification method of non-radiolabeled mIBG using LC-MS/MS. This method is reproducible, accurate, and precise, and can be used to quantify mIBG in plasma and tissue matrices to determine the pharmacokinetics and biodistribution of mIBG in preclinical animal models.
Assuntos
3-Iodobenzilguanidina/análise , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , 3-Iodobenzilguanidina/química , 3-Iodobenzilguanidina/farmacocinética , Animais , Limite de Detecção , Modelos Lineares , Fígado/metabolismo , Camundongos , Reprodutibilidade dos Testes , Distribuição TecidualRESUMO
PURPOSE: Many novel therapies for relapsed and refractory neuroblastoma require tumor tissue for genomic sequencing. We analyze our experience with image-guided biopsy in these patients, focusing on safety, yield, adequacy for next-generation sequencing (NGS), and correlation of tumor cell percent (TC%) with quantitative uptake on 123I-meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography with computed tomography (SPECT/CT). MATERIALS AND METHODS: An 11-year retrospective review of image-guided biopsy on 66 patients (30 female), with a median age of 8.7 years (range, 0.9-49 years), who underwent 95 biopsies (55 bone and 40 soft tissue) of relapsed or refractory neuroblastoma lesions was performed. RESULTS: There were seven minor complications (7%) and one major complication (1%). Neuroblastoma was detected in 88% of MIBG- or fluorodeoxyglucose-avid foci. The overall NGS adequacy was 69% (64% in bone and 74% in soft tissue, P = .37). NGS adequacy within neuroblastoma-positive biopsies was 88% (82% bone and 96% soft tissue, P = .11). NGS-adequate biopsies had a greater mean TC% than inadequates (51% v 18%, P = .03). NGS-adequate biopsies had a higher mean number of needle passes (7.5 v 3.4, P = .0002). The mean tissue volume from NGS-adequate soft-tissue lesions was 0.16 cm3 ± 0.12. Lesion:liver and lesion:psoas MIBG uptake ratios correlated with TC% (r = 0.74, r = 0.72, and n = 14). Mean TC% in NGS-adequate samples was 51%, corresponding to a lesion:liver ratio of 2.9 and a lesion:psoas ratio of 9.0. Thirty percent of biopsies showed an actionable ALK mutation or other therapeutically relevant variant. CONCLUSION: Image-guided biopsy for relapsed or refractory neuroblastoma was safe and likely to provide NGS data to guide therapy decisions. A lesion:liver MIBG uptake ratio of ≥ 3 or a lesion:psoas ratio of > 9 was associated with a TC% sufficient to deliver NGS results.
Assuntos
3-Iodobenzilguanidina , Biópsia Guiada por Imagem , Recidiva Local de Neoplasia/patologia , Neuroblastoma/genética , Neuroblastoma/patologia , Compostos Radiofarmacêuticos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Sequenciamento Completo do Genoma , 3-Iodobenzilguanidina/farmacocinética , Adolescente , Adulto , Criança , Pré-Escolar , Correlação de Dados , Feminino , Humanos , Biópsia Guiada por Imagem/efeitos adversos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Neuroblastoma/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. METHODS: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. RESULTS: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. CONCLUSIONS: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.
Assuntos
Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Hipoventilação/diagnóstico por imagem , Imagem de Perfusão do Miocárdio , Transtornos Parkinsonianos/diagnóstico por imagem , 3-Iodobenzilguanidina/farmacocinética , Idoso , Doenças do Sistema Nervoso Autônomo/etiologia , Biomarcadores , Depressão/complicações , Depressão/diagnóstico por imagem , Depressão/genética , Complexo Dinactina/genética , Feminino , Humanos , Hipoventilação/complicações , Hipoventilação/genética , Japão , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/genética , Linhagem , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
PURPOSE: Cardiac 123I-MIBG image interpretation is affected by population differences and technical factors. We recruited older adults without cognitive decline and compared their cardiac MIBG uptake with results from the literature. METHODS: Phantom calibration confirmed that cardiac uptake results from Japan could be applied to our center. We recruited 31 controls, 17 individuals with dementia with Lewy bodies (DLB) and 15 with Alzheimer's disease (AD). Images were acquired 20 minutes and four hours after injection using Siemens cameras with medium-energy low-penetration (MELP) collimators. Local normal heart-to-mediastinum (HMR) ratios were compared to Japanese results. RESULTS: Siemens gamma cameras with MELP collimators should give HMRs very close to the calibrated values used in Japan. However, our cut-offs with controls were lower at 2.07 for early and 1.86 for delayed images. Applying our lower cut-off to the dementia patients may increase the specificity of cardiac MIBG imaging for DLB diagnosis in a UK population without reducing sensitivity. CONCLUSIONS: Our local HMR cut-off values are lower than in Japan, higher than in a large US study but similar to those found in another UK center. UK centers using other cameras and collimators may need to use different cut-offs to apply our results.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Doença de Alzheimer/metabolismo , Radioisótopos do Iodo/farmacocinética , Doença por Corpos de Lewy/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Masculino , Pessoa de Meia-IdadeAssuntos
3-Iodobenzilguanidina/farmacocinética , Doença de Alzheimer/metabolismo , Radioisótopos do Iodo/farmacocinética , Doença por Corpos de Lewy/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Pessoa de Meia-Idade , Probabilidade , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Abnormalities of cardiac sympathetic innervation have been demonstrated in Anderson-Fabry disease (AFD). We aimed to investigate the relationship between regional left ventricular (LV) denervation and regional function abnormalities. METHODS: Twenty-four AFD patients (43.7 ± 12.8 years) were studied by 123I-metaiodobenzylguanidine (MIBG) cardiac imaging and speckle-tracking echocardiography. Segmental tracer uptake was estimated according to 0 to 4 score, and total defect score (TDS) was calculated for each patient. RESULTS: Segmental longitudinal strain worsened as MIBG uptake score increased (P < 0.001). By ROC analysis, a segmental longitudinal strain > - 16.2% predicted a segmental MIBG uptake score ≥1, with 79.7% sensitivity and 65.3% specificity. Segmental MIBG uptake defects were found in 13 out 24 AFD patients. LV mass index (60.8 ± 10.1 vs. 41.4 ± 9.8 g/h2.7), relative wall thickness (0.51 ± 0.06 vs. 0.40 ± 0.06), systolic pulmonary artery pressure (35.2 ± 6.7 vs. 27.2 ± 4.2 mmHg), and longitudinal strain (- 14.3 ± 2.7 vs. -19.4 ± 1.8%) were significantly higher in patients with segmental defect (all P < 0.01). At multivariate linear regression analysis, global longitudinal strain was independently associated with TDS (B = 3.007, 95% confidence interval 1.384 to 4.630, P = 0.001). CONCLUSIONS: Reduced cardiac MIBG uptake reflects the severity of cardiac involvement in AFD patients. LV longitudinal function impairment seems to be an earlier disease feature than regional myocardial denervation.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Doença de Fabry/fisiopatologia , Compostos Radiofarmacêuticos/farmacocinética , Sistema Nervoso Simpático/fisiopatologia , Sístole/fisiologia , Disfunção Ventricular Esquerda/etiologia , Adulto , Doença de Fabry/complicações , Feminino , Ventrículos do Coração/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único , Adulto JovemRESUMO
OBJECTIVE: We aimed to estimate in vivo 211At-labeled meta-benzylguanidine (211At-MABG) absorbed doses by the two dose conversion methods, using 131I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works. METHODS: We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131I to that of 211At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g. RESULTS: Virtual experiments showed that 211At-MABG and 131I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211At-MABG dose. Simulated 211At-MABG doses from 131I-MIBG using the RAP method were in agreement with those from 211At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data. CONCLUSIONS: The present RAP dose conversion method could estimate 211At-MABG absorbed doses from the pharmacokinetics of 131I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Guanidina/análogos & derivados , Método de Monte Carlo , Doses de Radiação , Meia-Vida , Humanos , Neuroblastoma/metabolismo , Distribuição TecidualRESUMO
Radiolabeled meta-iodobenzylguanidine (mIBG) is an important radiopharmaceutical used in the diagnosis and treatment of neuroendocrine cancers. mIBG is known to enter tumor cells through the norepinephrine transporter. Whole-body scintigraphy has shown rapid mIBG elimination through the kidney and high accumulation in several normal tissues, but the underlying molecular mechanisms are unclear. Using transporter-expressing cell lines, we show that mIBG is an excellent substrate for human organic cation transporters 1-3 (hOCT1-3) and the multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K), but not for the renal organic anion transporter 1 and 3 (hOAT1/3). Kinetic analysis revealed that hOCT1, hOCT2, hOCT3, hMATE1, and hMATE2-K transport mIBG with similar apparent affinities (K m of 19.5 ± 6.9, 17.2 ± 2.8, 14.5 ± 7.1, 17.7 ± 10.9, 12.6 ± 5.6 µM, respectively). Transwell studies in hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cells showed that mIBG transport in the basal (B)-to-apical (A) direction is much greater than in the A-to-B direction. Compared with control cells, the B-to-A permeability of mIBG increased by 20-fold in hOCT2/hMATE1 double-transfected cells. Screening of 23 drugs used in the treatment of neuroblastoma identified several drugs with the potential to inhibit hOCT- or hMATE-mediated mIBG uptake. Interestingly, irinotecan selectively inhibited hOCT1, whereas crizotinib potently inhibited hOCT3-mediated mIBG uptake. Our results suggest that mIBG undergoes renal tubular secretion mediated by hOCT2 and hMATE1/2-K, and hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. SIGNIFICANCE STATEMENT: mIBG is eliminated by the kidney and extensively accumulates in several tissues known to express hOCT1 and hOCT3. Our results suggest that hOCT2 and human multidrug and toxin extrusion proteins 1 and 2-K are involved in mIBG renal elimination, whereas hOCT1 and hOCT3 may play important roles in mIBG uptake into normal tissues. These findings may help to predict and prevent adverse drug interaction with therapeutic [131I]mIBG and develop clinical strategies to reduce [131I]mIBG accumulation and toxicity in normal tissues and organs.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição de Octâmero/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Fatores de Transcrição/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Crizotinibe/farmacologia , Cães , Células HEK293 , Humanos , Irinotecano/farmacologia , Células Madin Darby de Rim CaninoRESUMO
PURPOSE: To provide reliable and reproducible heart/mediastinum (H/M) ratio cut-off values for parkinsonian disorders using two machine learning techniques, Support Vector Machines (SVM) and Random Forest (RF) classifier, applied to [123I]MIBG cardiac scintigraphy. PROCEDURES: We studied 85 subjects, 50 with idiopathic Parkinson's disease, 26 with atypical Parkinsonian syndromes (P), and 9 with essential tremor (ET). All patients underwent planar early and delayed cardiac scintigraphy after [123I]MIBG (111 MBq) intravenous injection. Images were evaluated both qualitatively and quantitatively; the latter by the early and delayed H/M ratio obtained from regions of interest (ROIt1 and ROIt2) drawn on planar images. SVM and RF classifiers were finally used to obtain the correct cut-off value. RESULTS: SVM and RF produced excellent classification performances: SVM classifier achieved perfect classification and RF also attained very good accuracy. The better cut-off for H/M value was 1.55 since it remains the same for both ROIt1 and ROIt2. This value allowed to correctly classify PD from P and ET: patients with H/M ratio less than 1.55 were classified as PD while those with values higher than 1.55 were considered as affected by parkinsonism and/or ET. No difference was found when early or late H/M ratio were considered separately thus suggesting that a single early evaluation could be sufficient to obtain the final diagnosis. CONCLUSIONS: Our results evidenced that the use of SVM and CT permitted to define the better cut-off value for H/M ratios both in early and in delayed phase thus underlining the role of [123I]MIBG cardiac scintigraphy and the effectiveness of H/M ratio in differentiating PD from other parkinsonism or ET. Moreover, early scans alone could be used for a reliable diagnosis since no difference was found between early and late. Definitely, a larger series of cases is needed to confirm this data.
Assuntos
3-Iodobenzilguanidina , Coração/diagnóstico por imagem , Radioisótopos do Iodo , Mediastino/diagnóstico por imagem , Transtornos Parkinsonianos/classificação , Transtornos Parkinsonianos/diagnóstico por imagem , Cintilografia/métodos , 3-Iodobenzilguanidina/química , 3-Iodobenzilguanidina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Radioisótopos do Iodo/química , Radioisótopos do Iodo/farmacocinética , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/patologia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Estudos Retrospectivos , Máquina de Vetores de SuporteRESUMO
BACKGROUND: Nuclear imaging modalities using 123Iodine-metaiodobenzylguanidine (123I-MIBG) and bone seeking tracers identify early cardiac involvement in ATTRm amyloidosis patients. However, little is known whether results from 123I-MIBG scintigraphy actually correlate to markers for either cardiac autonomic neuropathy or cardiomyopathy. METHODS: All TTR mutation carriers and ATTRm patients who underwent both 123I-MIBG and 99mTechnetium-hydroxymethylene diphosphonate (99mTc-HDP) scintigraphy were included. Cardiomyopathy was defined as NT-proBNP > 365 ng/L, and cardiac autonomic neuropathy as abnormal cardiovascular reflexes at autonomic function tests. Late 123I-MIBG heart-to-mediastinum ratio (HMR) < 2.0 or wash-out > 20%, and any cardiac 99mTc-HDP uptake were considered as abnormal. RESULTS: 39 patients (13 carriers and 26 ATTRm patients) were included in this study. Patients with cardiomyopathy, with or without cardiac autonomic neuropathy, had lower late HMR than similar patients without cardiomyopathy [median 1.1 (range 1.0-1.5) and 1.5(1.2-2.6) vs 2.4 (1.4-3.8) and 2.5 (1.5-3.7), respectively, P < 0.001]. Late HMR and wash-out (inversely) correlated with NT-proBNP r = - 0.652 (P < 0.001) and r = 0.756 (P < 0.001), respectively. Furthermore, late HMR and wash-out (inversely) correlated with cardiac 99mTc-HDP uptake r = - 0.663 (P < 0.001) and r = 0.617 (P < 0.001), respectively. CONCLUSION: In case of heart failure, 123I-MIBG scintigraphy reflects cardiomyopathy rather than cardiac autonomic neuropathy in ATTRm patients and TTR mutation carriers. 123I-MIBG scintigraphy may already be abnormal before any cardiac bone tracer uptake is visible.
Assuntos
Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico por imagem , Doenças do Sistema Nervoso Autônomo/etiologia , Insuficiência Cardíaca/etiologia , Coração/diagnóstico por imagem , Coração/inervação , 3-Iodobenzilguanidina/farmacocinética , Adulto , Idoso , Neuropatias Amiloides Familiares/metabolismo , Doenças do Sistema Nervoso Autônomo/diagnóstico por imagem , Doenças do Sistema Nervoso Autônomo/metabolismo , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Difosfonatos/farmacocinética , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Mediastino/diagnóstico por imagem , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Compostos de Organotecnécio/farmacocinética , Fragmentos de Peptídeos/sangue , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Pré-Albumina/genética , Compostos Radiofarmacêuticos/farmacocinética , Estudos Retrospectivos , Adulto JovemAssuntos
Doenças dos Gânglios da Base/diagnóstico por imagem , Glândula Parótida/diagnóstico por imagem , Glândula Submandibular/diagnóstico por imagem , Paralisia Supranuclear Progressiva/diagnóstico por imagem , 3-Iodobenzilguanidina/farmacocinética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
Imaging of cardiac sympathetic innervation is only possible by nuclear cardiology techniques and its assessment is key in the evaluation of and decision-making for patients with cardiac sympathetic impairment. This review includes the basis of cardiac sympathetic scintigraphy with 123I-meta-iodobenzylguanidine (123I-MIBG), recommended protocols, patient preparation, image acquisition and quantification, reproducibility, dosimetry, etc., and also the clinical indications for cardiac patients, mainly with regard to heart failure, arrhythmia, coronary artery disease, cardiotoxicity, including its contribution to establishing the indication for and monitoring the response to implantable cardiac devices, pharmacological treatment, heart transplantation and other.
Assuntos
3-Iodobenzilguanidina , Sistema de Condução Cardíaco/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Coração/inervação , Radioisótopos do Iodo , Compostos Radiofarmacêuticos , Sistema Nervoso Simpático/diagnóstico por imagem , 3-Iodobenzilguanidina/administração & dosagem , 3-Iodobenzilguanidina/farmacocinética , Dispositivos de Terapia de Ressincronização Cardíaca , Pré-Escolar , Tomada de Decisão Clínica , Desfibriladores Implantáveis , Coração/diagnóstico por imagem , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Transplante de Coração , Humanos , Processamento de Imagem Assistida por Computador , Infusões Intravenosas , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/farmacocinética , Norepinefrina/fisiologia , Percloratos/administração & dosagem , Compostos de Potássio/administração & dosagem , Prognóstico , Radiometria , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Receptores Adrenérgicos/fisiologia , Reprodutibilidade dos Testes , Sistema Nervoso Simpático/fisiopatologia , Glândula Tireoide/efeitos dos fármacos , Resultado do TratamentoRESUMO
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-4â¯+â¯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-4â¯+â¯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 TecidualAssuntos
3-Iodobenzilguanidina/farmacocinética , Rim/diagnóstico por imagem , Rim/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/metabolismo , Glândulas Suprarrenais/fisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
We examined the correlations between cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) and imaging assessment scores, using 123I-Ioflupane SPECT and 123I-MIBG myocardial scintigraphy in 23 drug naïve PD patients. The CSF 5-HIAA concentration correlated with the H/M ratio of the delayed image (r = 0.458, p < 0.05) and the washout rate (r = - 0.642, p < 0.01) of 123I-MIBG myocardial scintigraphy. These correlations suggest some unclarified pathophysiological links between the central serotonergic and cardiac sympathetic systems.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Radioisótopos do Iodo/farmacocinética , Imagem de Perfusão do Miocárdio , Miocárdio/metabolismo , Nortropanos/farmacocinética , Doença de Parkinson/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Fibras Autônomas Pós-Ganglionares/metabolismo , Biomarcadores , Disfunção Cognitiva/etiologia , Demência/etiologia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/psicologia , Serotonina/metabolismoRESUMO
Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18F-FDG, 18F-DOPA and 68Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.
Assuntos
Diagnóstico por Imagem/métodos , Neuroblastoma/diagnóstico por imagem , Medicina Nuclear , Guias de Prática Clínica como Assunto , 3-Iodobenzilguanidina/metabolismo , 3-Iodobenzilguanidina/farmacocinética , Humanos , Neuroblastoma/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
PURPOSE: I-metaiodobenzylguanidine (I-MIBG) has been used in the diagnosis and therapy of neuroblastoma in adult and pediatric patients for many years. In this study, we evaluated whole-body I-MIBG clearance and radiation doses received by patients, family caregivers, and medical staff to establish appropriate radiation safety measures to be used in therapy applications. METHODS: Research was focused on 23 children and adolescents with metastatic neuroblastoma, with ages ranging from 1.8 to 13 years, being treated with I-MIBG. Based on measured external dose rates from patients, dosimetric data to patients, family members, and others were calculated. RESULTS: The mean ± SD I-MIBG activity administered was 8.55 ± 1.69 GBq. Percent whole-body retention rates of I-MIBG at 24, 48, and 72 hours after administration were 48% ± 7%, 23% ± 7%, and 12% ± 6%, with a whole-body I-MIBG effective half-life of 23 ± 5 hours for all patients. The mean doses for patients were 0.234 ± 0.096 mGy·MBq to red-marrow and 0.251 ± 0.101 mGy·MBq to whole body. The maximum potential radiation doses transmitted by patients to others at 1.0 m was estimated to be 11.9 ± 3.4 mSv, with 97% of this dose occurring over 120 hours after therapy administration. Measured mean dose received by the 22 family caregivers was 1.88 ± 1.85 mSv, and that received by the 19 pediatric physicians was 43 ± 51 µSv. CONCLUSION: In this study, we evaluated the whole-body clearance of I-MIBG in 23 pediatric patients, and the radiation doses received by family caregivers and medical staff during these therapy procedures, thus facilitating the establishment of radiation safety measures to be applied in pediatric therapy.
Assuntos
3-Iodobenzilguanidina/uso terapêutico , Neoplasias Encefálicas/radioterapia , Taxa de Depuração Metabólica , Neuroblastoma/radioterapia , Doses de Radiação , Compostos Radiofarmacêuticos/uso terapêutico , 3-Iodobenzilguanidina/administração & dosagem , 3-Iodobenzilguanidina/farmacocinética , Adolescente , Adulto , Cuidadores , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Corpo Clínico , Lesões por Radiação/prevenção & controle , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Dosagem Radioterapêutica , SegurançaRESUMO
INTRODUCTION: Plasma norepinephrine concentration reflects lesions causing OH. We investigate whether patients with high norepinephrinergic orthostatic hypotension (OH) whose supine plasma norepinephrine concentration (NEsupine) is above the mean value in all patients with Parkinson's disease (PD) have central sympathetic denervation. METHODS: We analyzed data from 110 non-demented patients with early de novo PD who underwent cardiovascular examinations. We divided the patients into three groups according to the presence or absence of orthostatic hypotension and NEsupine: patients without OH, patients with OH+high NEsupine, and patients with OH+low NEsupine. RESULTS: The mean NEsupine in all patients was 251.6 pg/ml. Twelve patients (10.9%) had OH+high NEsupine (≥251.6 pg/ml), and 45 patients (40.9%) had OH+low NEsupine (<251.6 pg/ml). OH was more pronounced in patients with OH+high NEsupine than in those with OH+low NEsupine (p = 0.024). Vasopressin release and percent increase of NE after orthostatic stress were well preserved in patients with OH+low NEsupine, but not in patients with OH+high NEsupine. Cognition was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (pâ¯=â¯0.019) and was associated with vasopressin release during orthostatic stress on multiple regression analysis. The degree of cardiac sympathetic denervation did not differ between two groups with OH. CONCLUSIONS: Patient with PD and high norepinephrinergic OH are a subset of patients who have early cognitive decline and impaired vasopressin release. Vasopressin release after orthostatic stress was closely related to global cognition in PD.