Prediction of sudden cardiac death in patients with chronic heart failure by regional washout rate in cardiac MIBG SPECT imaging.

BACKGROUND: The sympathetic nervous system provides an important trigger for major arrhythmic events through regional heterogeneity of sympathetic activity, which could be evaluated by SPECT imaging as the regional MIBG washout rate (WR). There is little information available on the prognostic value of regional WR in SPECT imaging for the prediction of sudden cardiac death (SCD) in patients with chronic heart failure (CHF). METHODS: We studied 73 CHF outpatients with LVEF < 40%. At study entry, the regional WR was measured in 17 segments on the polar map. We defined abnormal regional WR as both the regional WR range (maximum - minimum regional WR) and maximum regional WR > mean value + 2SD obtained in 15 normal controls. RESULTS: During a mean follow-up of 7.5 ± 4.1 years, 15 of 73 patients had SCD. The abnormal regional WR and abnormal global WR on planar images were significantly and independently associated with SCD. Patients with both the abnormal regional WR and global WR had a significantly higher risk of SCD than those with none of these criteria. CONCLUSIONS: The analysis of regional MIBG WR on SPECT imaging provides additional prognostic value to global WR on planar images for SCD prediction in CHF patients.

Role of cardiac 123I-mIBG imaging in predicting arrhythmic events in stable chronic heart failure patients with an ICD.

BACKGROUND: Despite therapeutic improvement, the prognosis of chronic heart failure (CHF) remains unfavorable partly due to arrhythmia and sudden cardiac death (SCD). This prospective study evaluated myocardial 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy as a predictor of arrhythmic events (AE) in CHF patients. METHODS: 170 CHF patients referred for implantable cardioverter-defibrillator (ICD) implantation for both primary and secondary prevention were enrolled. All patients underwent planar and SPECT imaging. Early and late heart-to-mediastinum (H/M) ratio, 123I-mIBG washout (WO), early and late summed SPECT scores were calculated The primary endpoint was an AE: sustained ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD therapy or SCD. The secondary endpoint was appropriate ICD therapy. RESULTS: During a median follow-up of 23.3 months, 69 patients experienced an AE. Early summed score (ESS) was the only independent predictor of AE [HR 1.023 (1.003-1.043)]. Focussing on only patients with an ICD for primary prevention, ESS was the only independent predictor of AE [HR 1.028 (1.007-1.050)]. 123I-mIBG-derived parameters failed to be independent predictors of appropriate ICD therapy. However there was a "bell-shaped" relation between 123I-mIBG scintigraphy-derived parameters and AE and appropriate ICD therapy, i.e., those with intermediate 123I-mIBG abnormalities tended to be at higher risk of events. CONCLUSION: Although SPECT 123I-mIBG scintigraphy was associated with AE in CHF patients with ICD implantation for primary and secondary prevention, no association was found between 123I-mIBG scintigraphy-derived parameters and appropriate ICD therapy.

Influence of ROI definition on the heart-to-mediastinum ratio in planar 123I-MIBG imaging.

BACKGROUND: Iodine-123-metaiodobenzylguanidine (123I-MIBG) imaging with estimation of the heart-to-mediastinum ratio (HMR) has been established for risk assessment in patients with chronic heart failure. Our aim was to evaluate the effect of different methods of ROI definition on the renderability of HMR to normal or decreased sympathetic innervation. METHODS AND RESULTS: The results of three different methods of ROI definition (clinical routine (CLI), simple standardization (STA), and semi-automated (AUT) were compared. Ranges of 95% limits of agreement (LoA) of inter-observer variabilities were 0.28 and 0.13 for STA and AUT, respectively. Considering a HMR of 1.60 as the lower limit of normal, 13 of 32 (41%) for method STA and 5 of 32 (16%) for method AUT of all HMR measurements could not be classified to normal or pathologic. Ranges of 95% LoA of inter-method variabilities were 0.72 for CLI vs AUT, 0.65 for CLI vs STA, and 0.31 for STA vs AUT. CONCLUSION: Different methods of ROI definition result in different ranges of the LoA of the measured HMR with relevance for rendering the results to normal or pathological innervation. We could demonstrate that standardized protocols can help keep methodological variabilities limited, narrowing the gray zone of renderability.

The vial kit formulation for preparation of no-carrier-added 131 I-MIBG.

We have developed a new set of lyophilized kits, composed of 3 different kits, for the instant preparation of no-carrier-added 131 I-MIBG in the clinic. We here discussed the formulation of the kits, optimization of radiolabelling, quality control of radiolabeled 131 I-MIBG, and studies of animal biodistribution. The no-carrier-added (nca) 131 I-MIBG injection could be prepared within 30 minutes in the clinic with the help of the lyophilized kits. The radiochemical purity and specific activity (SA) could achieve above 98% and 6700 MBq/mg, respectively.

Vesicular monoamine transporter protein expression correlates with clinical features, tumor biology, and MIBG avidity in neuroblastoma: a report from the Children's Oncology Group.

PURPOSE: Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. In neuroblastoma, the norepinephrine transporter (NET) has been investigated as the principal MIBG uptake protein, though some tumors without NET expression concentrate MIBG. We investigated VMAT expression in neuroblastoma and correlated expression with MIBG uptake and clinical features. METHODS: We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk metastatic disease treated in a uniform cooperative group trial (COG A3973). All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0 - 3+) and percent of tumor cells expressing the protein of interest. The association between VMAT1 and VMAT2 scores and clinical and biological features was tested using Wilcoxon rank-sum tests. RESULTS: Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched in patients with MIBG-nonavid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors and in tumors with high mitotic karyorrhectic index. MIBG-avid tumors had significantly higher VMAT2 scores than MIBG-nonavid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity. CONCLUSION: VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with other biological features. The expression level of VMAT2 but not that of VMAT1 correlates with avidity for MIBG.

Review of cardiovascular imaging in The Journal of Nuclear Cardiology in 2014: Part 1 of 2: Positron emission tomography, computed tomography, and neuronal imaging.

The year 2014 has been an exciting year for the cardiovascular imaging community with significant advances in the realm of nuclear and multimodality cardiac imaging. In this new feature of the Journal of Nuclear Cardiology, we will summarize some of the breakthroughs that were published in the Journal in 2014 in 2 sister articles. This first article will concentrate on publications dealing with cardiac positron emission tomography (PET), computed tomography (CT), and neuronal imaging.

Accuracy and cutoff values of delayed heart to mediastinum ratio with (123)I-metaiodobenzylguanidine cardiac scintigraphy for Lewy body disease diagnoses.

BACKGROUND: Different studies have found diminished cardiac metaiodobenzylguanidine (MIBG) uptake in Lewy body (LB) related conditions (Parkinson's disease (PD) and Lewy body dementia (LBD)). However, delayed heart/mediastinum (d-H/M) ratio diagnostic cutoff points are debated in parkinsonian syndromes. METHODS: We performed a monocentric retrospective analysis on 62 consecutive parkinsonian patients who underwent an (123)I-MIBG scintigraphy, brain imaging and dopaminergic imaging using (123)I-Ioflupane single photon emission computed tomography (SPECT) from 2009 to 2013. The optimal d-H/M ratio was determined from a Receiver Operating Characteristic (ROC) curve and the sensitivity (Se), specificity (Sp) and likelihood ratios (LR) were calculated. 42 patients were diagnosed with LB diseases (20 PD, 22 LBD) and 20 patients with other diseases. RESULTS: (123)I-MIBG scintigraphy helped to distinguish PD (p < 0.001) and LBD (p = 0.03) from other diseases. The optimal d-H/M ratio was 1.48 (0.85 area under the ROC curve). Se and Sp were 83.3 %, and 85 % respectively with positive and negative LR of 5.5 and 0.2 respectively. Patients with LBD had a lower d-H/M ratio than patients with PD (result not statistically significant) and a cutoff point at 1.2 could help to differentiate the two diseases. We did not find any correlation between the d-H/M ratio and clinical or (123)I-Ioflupane SPECT data. CONCLUSION: According to our population, the d-H/M ratio at 1.48 led to the best performance diagnosis with good Se, Sp and accuracy. In addition, a d-H/M ratio cutoff at 1.2 could help to differentiate PD from LBD.

Nuclear imaging modalities for cardiac amyloidosis.

Amyloidosis is a heterogeneous group of diseases characterized by localized or systemic deposition of insoluble extracellular fibrillary proteins in organs and tissues. Several types of amyloid can infiltrate the heart resulting in a restrictive cardiomyopathy, heart failure, and atrial and ventricular arrhythmias. Scintigraphy is a noninvasive method that may facilitate early diagnosis, distinguish various forms of cardiac amyloid, and may be useful in following disease burden. The amyloid-specific tracers presented in this article have been used with planar imaging and/or single-photon emission computed tomography. To date, there are no approved cardiac amyloid tracers although investigational tracers are currently under examination. This article serves to review the current nuclear imaging modalities available in the detection of cardiac amyloid.

Establishment of a fast and high yield method for routine production of [(131) I]MIBG and investigation of its radiochemical stability for diagnosis and treatment uses.

In this work, exchange radioiodination of metaiodobenzylguanidine (MIBG) was carried out at optimum conditions that facilitates the production of [(131) I]MIBG both quickly and efficiently. The radiochemical purity and yield of the labeled product are typically as high as 99% and 90% for diagnostic dose and 95% and 80% for therapeutic dose, respectively. Stability studies show that labeled material at the room temperature met the demand of the clinical application. This labeling procedure will be used in the routine production process of [(131) I]MIBG for diagnosis and treatment uses.

Development and validation of a LC-MS/MS method for in vivo quantification of meta-iodobenzylguanidine (mIBG).

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 → 217.0 for mIBG and 222.1 → 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.

Cardiac Imaging With 123I-meta-iodobenzylguanidine and Analogous PET Tracers: Current Status and Future Perspectives.

Autonomic innervation plays an important role in proper functioning of the cardiovascular system. Altered cardiac sympathetic function is present in a variety of diseases, and can be assessed with radionuclide imaging using sympathetic neurotransmitter analogues. The most studied adrenergic radiotracer is cardiac 123I-meta-iodobenzylguanidine (123I-mIBG). Cardiac 123I-mIBG uptake can be evaluated using both planar and tomographic imaging, thereby providing insight into global and regional sympathetic innervation. Standardly assessed imaging parameters are the heart-to-mediastinum ratio and washout rate, customarily derived from planar images. Focal tracer deficits on tomographic imaging also show prognostic utility, with some data suggesting that the best approach to tomographic image interpretation may differ from conventional methods. Cardiac 123I-mIBG image findings strongly correlate with the severity and prognosis of many cardiovascular diseases, especially heart failure and ventricular arrhythmias. Cardiac 123I-mIBG imaging in heart failure is FDA approved for prognostic purposes. With the robustly demonstrated ability to predict occurrence of potentially fatal arrhythmias, cardiac 123I-mIBG imaging shows promise for better selecting patients who will benefit from an implantable cardioverter defibrillator, but clinical use has been hampered by lack of the randomized trial needed for incorporation into societal guidelines. In patients with ischemic heart disease, cardiac 123I-mIBG imaging aids in assessing the extent of damage and in identifying arrhythmogenic regions. There have also been studies using cardiac 123I-mIBG for other conditions, including patients following heart transplantation, diabetic related cardiac abnormalities and chemotherapy induced cardiotoxicity. Positron emission tomographic adrenergic radiotracers, that improve image quality, have been investigated, especially 11C-meta-hydroxyephedrine, and most recently 18F-fluorbenguan. Cadmium-zinc-telluride cameras also improve image quality. With better spatial resolution and quantification, PET tracers and advanced camera technologies promise to expand the clinical utility of cardiac sympathetic imaging.

18F-meta-fluorobenzylguanidine (18F-mFBG) to monitor changes in norepinephrine transporter expression in response to therapeutic intervention in neuroblastoma models.

Targeted radiotherapy with 131I-mIBG, a substrate of the human norepinephrine transporter (NET-1), shows promising responses in heavily pre-treated neuroblastoma (NB) patients. Combinatorial approaches that enhance 131I-mIBG tumour uptake are of substantial clinical interest but biomarkers of response are needed. Here, we investigate the potential of 18F-mFBG, a positron emission tomography (PET) analogue of the 123I-mIBG radiotracer, to quantify NET-1 expression levels in mouse models of NB following treatment with AZD2014, a dual mTOR inhibitor. The response to AZD2014 treatment was evaluated in MYCN amplified NB cell lines (Kelly and SK-N-BE(2)C) by Western blot (WB) and immunohistochemistry. PET quantification of 18F-mFBG uptake post-treatment in vivo was performed, and data correlated with NET-1 protein levels measured ex vivo. Following 72 h AZD2014 treatment, in vitro WB analysis indicated decreased mTOR signalling and enhanced NET-1 expression in both cell lines, and 18F-mFBG revealed a concentration-dependent increase in NET-1 function. AZD2014 treatment failed however to inhibit mTOR signalling in vivo and did not significantly modulate intratumoural NET-1 activity. Image analysis of 18F-mFBG PET data showed correlation to tumour NET-1 protein expression, while further studies are needed to elucidate whether NET-1 upregulation induced by blocking mTOR might be a useful adjunct to 131I-mIBG therapy.

[123I]Metaiodobenzylguanidine (MIBG) Cardiac Scintigraphy and Automated Classification Techniques in Parkinsonian Disorders.

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.

Standardization of the heart-to-mediastinum ratio of 123I-labelled-metaiodobenzylguanidine uptake using the dual energy window method: feasibility of correction with different camera-collimator combinations.

BACKGROUND: Although the heart-to-mediastinum (H/M) ratio in a planar image has been used for practical quantification in (123)I-metaiodobenzylguanidine (MIBG) imaging, standardization of the parameter is not yet established. We hypothesized that the value of the H/M ratio could be standardized to the various camera-collimator combinations. METHODS AND RESULTS: Standard phantoms consisting of the heart and mediastinum were made. A low-energy high-resolution (LEHR) collimator and a medium-energy (ME) collimator were used. We examined multi-window correction methods with (123)I- dual-window (IDW) acquisition, and planar images were obtained with IDW correction and the LEHR collimator. The images were obtained using the following gamma camera systems: GCA 9300A (Toshiba, Tokyo), E.CAM Signature (Toshiba/Siemens, Tokyo) and Varicam (GE, Tokyo). Cardiac phantom studies demonstrated that contamination of the H/M count ratio was greater with the LEHR collimator and least with the ME collimator. The corrected H/M ratio with the LEHR collimator was similar to that with ME collimators. The uncorrected H/M ratio with the ME collimator was linearly related to the H/M ratio with IDW correction with the LEHR collimator. The relationship between the uncorrected H/M ratios determined with the LEHR (E.CAM) and the ME collimators was y = 0.56x + 0.49, where y = H/M ratio with the E.CAM and x = H/M ratio with the ME collimator. The average normal values for the low-energy collimator (n=18) were 2.2+/-0.2 (initial H/M ratio) and 2.42+/-0.2 (delayed H/M ratio), and for the low/medium-energy (LME) collimator (n=14) were 2.63+/-0.25 (initial H/M ratio) and 2.87+/-0.19 (delayed H/M ratio). H/M ratios in previous clinical studies using LEHR collimators are comparable to those with ME collimators. CONCLUSION: The IDW-corrected H/M ratios determined with the LEHR collimator were similar to those determined with the ME collimator. This finding could make it possible to standardize the H/M ratio in planar imaging among various collimators in the clinical setting.

Use of ESI-MS for semi-quantitative estimation of inactive precursor in no-carrier-added 131I- meta-Iodobenzylguanidine radiopharmaceutical preparation.

No-carrier-added (nca)-131I-meta-Iodobenzylguadine (mIBG) is a clinical agent used for the therapy of Neuroendocrine tumors. It is prepared by reaction of radioiodine with precursors that are chemically different from mIBG. The precursor in few cases is structurally similar and may co-elute along during purification step. Presence of these precursors in final radiolabeled formulation may affect the clinical behaviour of the radiopharmaceutical. The present paper describes the use of Electron-spray ionization-Mass Spectrometry (ESI-MS) where up to nano-molar concentrations of these precursors could be estimated with high precision in the final radiolabeled formulation.

Synthesis and evaluation of 99mTc-analogues of [123/131I]mIBG prepared via [99mTc][Tc(CO)3(H2O)3]+ synthon for targeting norepinephrine transporter.

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.

Novel Meta-iodobenzylguanidine-Based Copper Thiosemicarbazide-1-guanidinomethylbenzyl Anticancer Compounds Targeting Norepinephrine Transporter in Neuroblastoma.

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.

A convenient solution-phase method for the preparation of meta-iodobenzylguanidine in high effective specific activity.

INTRODUCTION: There is a need for new methods of producing receptor-targeted molecular radioimaging and radiotherapy agents in high effective specific activity. This is particularly true for targets that are expressed in relatively low concentrations. METHODS: A highly fluorinated (fluorous) tin precursor of meta-iodobenzylguanidine (MIBG) was prepared, such that upon labeling, the desired product was formed with concomitant release of the fluorous group. The desired product was then readily separated from the starting material and fluorous by-products by chemoselective filtration using a fluorous solid-phase extraction cartridge. RESULTS: High purity [(125)I]- and [(123)I]MIBG were produced in 81+/-3% and 80% radiochemical yield respectively in less than 20 min without high-performance liquid chromatography (HPLC) purification. The purified product contained less than 1 ppm tin as determined by inductively coupled plasma-mass spectrometry (ICP-MS). CONCLUSIONS: A convenient, solution-phase method to produce radioiodinated MIBG in high effective specific activity without employing preparative HPLC was developed. Using the reported approach, a kit for the production of (123)I- and (125)I-MIBG is feasible and is currently being developed.

Biodistribution and Dosimetry of 18F-Meta-Fluorobenzylguanidine: A First-in-Human PET/CT Imaging Study of Patients with Neuroendocrine Malignancies.

123I-meta-iodobenzylguanidine (123I-MIBG) imaging is currently a mainstay in the evaluation of many neuroendocrine tumors, especially neuroblastoma. 123I-MIBG imaging has several limitations that can be overcome by the use of a PET agent. 18F-meta-fluorobenzylguanidine (18F-MFBG) is a PET analog of MIBG that may allow for single-day, high-resolution quantitative imaging. We conducted a first-in-human study of 18F-MFBG PET imaging to evaluate the safety, feasibility, pharmacokinetics, and dosimetry of 18F-MFBG in neuroendocrine tumors (NETs). Methods: Ten patients (5 with neuroblastoma and 5 with paraganglioma/pheochromocytoma) received 148-444 MBq (4-12mCi) of 18F-MFBG intravenously followed by serial whole-body imaging at 0.5-1, 1-2, and 3-4 after injection. Serial blood samples (a total of 6) were also obtained starting at 5 min after injection to as late as 4 h after injection; whole-body distribution and blood clearance data, lesion uptake, and normal-tissue uptake were determined, and radiation-absorbed doses to normal organs were calculated using OLINDA. Results: No side effects were seen in any patient after 18F-MFBG injection. Tracer distribution showed prominent activity in the blood pool, liver, and salivary glands that decreased with time. Mild uptake was seen in the kidneys and spleen, which also decreased with time. Urinary excretion was prominent, with an average of 45% of the administered activity in the bladder by 1 h after injection; whole-body clearance was monoexponential, with a mean biologic half-life of 1.95 h, whereas blood clearance was biexponential, with a mean biologic half-life of 0.3 h (58%) for the rapid α phase and 6.1 h (42%) for the slower ß phase. The urinary bladder received the highest radiation dose with a mean absorbed dose of 0.186 ± 0.195 mGy/MBq. The mean total-body dose was 0.011 ± 0.011 mGy/MBq, and the effective dose was 0.023 ± 0.012 mSv/MBq. Both skeletal and soft-tissue lesions were visualized with high contrast. The SUVmax (mean ± SD ) of lesions at 1-2 h after injection was 8.6 ± 9.6. Conclusion: Preliminary data show that 18F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. PET imaging with 18F-MFBG allows for same-day imaging of NETs. 18F-MFBG appears highly promising for imaging of patients with NETs, especially children with neuroblastoma.