Overexpression of miR-375 and L-type Amino Acid Transporter 1 in Pheochromocytoma and Their Molecular and Functional Implications.

Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)-positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between 18F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing 18F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between 18F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of 18F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo.

Retrospective analysis of 23 Chinese children with congenital hyperinsulinism undergoing pancreatectomy.

INTRODUCTION: The aim of the study was to discuss therapeutic effect and prognosis of pancreatectomy in the treatment of congenital hyperinsulinism (CHI). MATERIAL AND METHODS: A total of 23 Chinese children with CHI, who had undergone pancreatectomy, were selected as the study objects. The clinical data, the results of the ¹8Fluoro-L-3-4 dihydroxyphenylalanine positron emission tomography/computerized tomography (¹8F-DOPA PET/CT) scanning, and the diagnosis, treatment, and follow-up were analysed retrospectively. RESULTS: Among the 23 cases, 14 patients were diagnosed with focal-type CHI via a ¹8F-DOPA PET/CT scan prior to the operation, with the lesions removed via partial pancreatectomy. After the operation, ten patients (71%) had normal blood glucose levels, while frequent feeding was required in four patients (29%) to control the hypoglycaemia. Three cases were diagnosed as diffuse-type CHI via preoperative scanning, two of which were treated by subtotal pancreatectomy. The other case was treated by near-total pancreatectomy, and the blood glucose level was normal following the operation. The remaining six cases were not diagnosed via the pancreatic scanning prior to the operation due to the limitation of certain conditions. Here, pancreatectomy was performed directly due to severe hypoglycaemia. CONCLUSIONS: ¹8F-DOPA PET/CT scanning was a reliable method for determining the histological type and localizing the lesion before the operation. Partial pancreatectomy for focal-type CHI had a high cure rate.

Correlation of multimodal 18F-DOPA PET and conventional MRI with treatment response and survival in children with diffuse intrinsic pontine gliomas.

To evaluate the contribution of 18F-dihydroxyphenylalanine (DOPA) PET in association with conventional MRI in predicting treatment response and survival outcome of pediatric patients with diffuse intrinsic pontine gliomas (DIPGs). Methods: We retrospectively analyzed 19 children with newly diagnosed DIPGs who underwent 18F-DOPA PET/CT and conventional MRI within one week of each other at admission and subsequent MRI follow-up. Following co-registration and fusion of PET and MRI, 18F-DOPA uptake avidity and extent (PET tumor volume and uniformity) at admission, along with MRI indices including presence of ring contrast-enhancement, tumor volume at admission and at maximum response following first-line treatment, were evaluated and correlated with overall survival (OS). The association between 18F-DOPA uptake tumor volume at admission and MRI tumor volume following treatment was evaluated. Statistics included Wilcoxon signed-rank and Mann-Whitney U tests, Kaplan-Meier OS curve and Cox analysis. Results: DIPGs with a 18F-DOPA uptake Tumor/Striatum (T/S) ratio >1 presented an OS ≤ 12 months and lower degree of tumor volume reduction following treatment (p = 0.001). On multivariate analysis, T/S (p = 0.001), ring enhancement (p = 0.01) and the degree of MRI tumor volume reduction (p = 0.01) independently correlated with OS. In all patients, areas of increased 18F-DOPA uptake overlapped with regions demonstrating more prominent residual components/lack of response following treatment. Conclusions:18F-DOPA PET provides useful information for evaluating the metabolism of DIPGs. T/S ratio is an independent predictor of outcome. 18F-DOPA uptake extent delineates tumoral regions with a more aggressive biological behaviour, less sensitive to first line treatment.

Visual interpretation, not SUV ratios, is the ideal method to interpret 18F-DOPA PET scans to aid in the cure of patients with focal congenital hyperinsulinism.

INTRODUCTION: Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18F-DOPA PET scans and how this can influence outcomes. MATERIALS AND METHODS: After 18F-Fluoro-L-DOPA was injected intravenously into 50 subjects' arm at a dose of 2.96-5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. RESULTS: Visual interpretation had the combination of the best sensitivity and positive prediction values. CONCLUSIONS: In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.

The impact of 18F-FDOPA-PET/MRI image fusion in detecting liver metastasis in patients with neuroendocrine tumors of the gastrointestinal tract.

BACKGROUND: This study assesses the value of image fusion using 18F-fluoro-L-DOPA (18F-DOPA) positron emission tomography (PET) and magnetic resonance imaging (MRI) for examining patients with neuroendocrine tumors (NETs) and a suspicion of metastasis of the liver. METHODS: Eleven patients (five women and six men aged between 20 and 81, with a mean age of 54.6 years) were included in the study. All patients underwent whole-body 18F-DOPA PET examinations and contrast-enhanced MRI with diffusion-weighted sequences (DWS). Image fusion was performed using a semiautomatic voxel-based algorithm. Images obtained using PET and MRI were assessed separately. Side-by-side evaluations of fused PET/MRI images were also performed. RESULTS: In total, 55 liver lesions (52 liver metastases and 3 benign lesions) were detected in the 11 patients. Sensitivity detection for liver lesions was higher when using PET/CT than when using contrast-enhanced MRI without DWSs and lower than using MRI with DWSs. The sensitivity of PET/MRI image fusion in the detection of liver metastasis was significantly higher than that of MRI with DWSs (P < 0.05). CONCLUSION: Images of the liver obtained using PET and MRI in patients with NETs exhibited characteristic features. These findings suggest that an appropriate combination of available imaging modalities can optimize patient evaluations.

[F-DOPA PET/MR based target definiton in the 3D based radiotherapy treatment of glioblastoma multiforme patients. First Hungarian experiences]. / F-DOPA-jelzett PET/CT-PET/MR alapú modern 3D besugárzástervezés glioblastoma multiformés (GBM-) betegek komplex kezelésében. Az elso magyarországi tapasztalatok.

BACKGROUND AND PURPOSE: Radiotherapy plays important role in the complex oncological treatment of glioblastoma multiforme (GBM). The modern 3D radiotherapy treatments are based on cross-sectional CT and MR information, however more attention is being paid to functional hybrid imaging describing the biological and functional morphology of tumor lesions. 18F-DOPA is an amino acid tracer with high specificity and sensitivity, which may play an important role in the precise definition of target volume in the irradiation process of GBM patients. Our study presents the first experiences with 18F-DOPA based PET/CT/MR 3D irradiation planning process. METHODS: In Hungary the 18F-DOPA radiotracer has been available for clinical use since September 2017. Between September 2017 and January 2018, at the Somogy County Kaposi Mór Teaching Hospital Dr. József Baka Diagnostic, Radiation Oncology, Research and Teaching Center 3 histologically verified glioblastoma multiforme patients received 18F-DOPA based 3D irradiation treatment. In the contouring process the native planning CT scanes were fused with the PET/MR series (T1 contrast enhanced, T2 and 18F-DOPA sequences). We defined 18F-DOPA uptake volume (BTV-F-DOPA), the T1 contrast enhanced MRI volume (GTV-T1CE), and the volume of the area covered by oedema on the T2 weighted MRI scan (CTV-oedema) in all patients. We also registered the BTV-F-DOPA volumes not covered by the conventional MR based target volumes. RESULTS: Examining the 3 cases, the average volume of 18F-DOPA tumor was 22.7 cm3 (range 15.3-30.9; SD = 7.82). The average GTV T1 CE was found to be 8.7 cm3 (range 3.8-13.2; SD = 4.70). The mean CTV oedema volume was 40.3 cm3 (range 27.7-57.7; SD = 15.36). A non-overlapping target volume difference (BTV-F-DOPA not covered by CTV oedema area) was 4.5 cm3 (range 1-10.3; SD = 5.05) for PTV definition. CONCLUSION: Based on our results the tumor area defined by the amino acid tracer is not fully identical with the MRI defined T2 oedema CTV. 18F-DOPA defined BTV can modify the definiton of the PTV, and the radiotherapy treatment.

Covariance statistics and network analysis of brain PET imaging studies.

The analysis of structural and functional neuroimaging data using graph theory has increasingly become a popular approach for visualising and understanding anatomical and functional relationships between different cerebral areas. In this work we applied a network-based approach for brain PET studies using population-based covariance matrices, with the aim to explore topological tracer kinetic differences in cross-sectional investigations. Simulations, test-retest studies and applications to cross-sectional datasets from three different tracers ([18F]FDG, [18F]FDOPA and [11C]SB217045) and more than 400 PET scans were investigated to assess the applicability of the methodology in healthy controls and patients. A validation of statistics, including the assessment of false positive differences in parametric versus permutation testing, was also performed. Results showed good reproducibility and general applicability of the method within the range of experimental settings typical of PET neuroimaging studies, with permutation being the method of choice for the statistical analysis. The use of graph theory for the quantification of [18F]FDG brain PET covariance, including the definition of an entropy metric, proved to be particularly relevant for Alzheimer's disease, showing an association with the progression of the pathology. This study shows that covariance statistics can be applied to PET neuroimaging data to investigate the topological characteristics of the tracer kinetics and its related targets, although sensitivity to experimental variables, group inhomogeneities and image resolution need to be considered when the method is applied to cross-sectional studies.

False-positive findings on 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (18F-FDOPA-PET) performed for imaging of neuroendocrine tumors.

BACKGROUND/AIM: PET with 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) has been shown to be a useful imaging tool with a high sensitivity for the visualization of neuroendocrine tumors (NETs). 18F-FDOPA uptake in tumors other than NETs has been suggested previously, but data on this phenomenon are limited. We therefore studied the non-physiological, false-positive uptake of 18F-FDOPA in a large population of patients with a NET or with a high clinical suspicion of harboring a NET. PATIENTS AND METHODS: Retrospective single-center study among adult patients in whom 18F-FDOPA PET scintigraphy was performed between January 2004 and December 2014. The original scan report was compared with the original pathology report corresponding with the 18F-FDOPA PET-positive lesion. In case this was inconsistent with the diagnosis of a NET, both the scan and the pathology slides were reassessed. Specimens of these non-NET tissues were immunohistochemically stained for AADC. RESULTS: 1070 18F-FDOPA PET scans from 705 patients were evaluated. Focal or multiple 18F-FDOPA-avid lesions were described in 709 18F-FDOPA PET scans (66%). Histology of these 18F-FDOPA PET-positive lesions was present in 508 (72%) cases. In seven cases, the histopathology was not compatible with NET but showed squamous cell carcinoma of the cervix, multiple myeloma (two cases), hepatocellular carcinoma, Schwannoma, adrenocortical carcinoma and a skeletal myxoid chondrosarcoma, with positive immunohistochemical staining for AADC in 67%. CONCLUSIONS: Pathological uptake of 18F-FDOPA does not always indicate the presence of a NET. The possibility of 18F-FDOPA uptake by tumor types other than NETs, although rare, should be considered.

Accuracy of 18F-FDOPA Positron Emission Tomography and 18F-FET Positron Emission Tomography for Differentiating Radiation Necrosis from Brain Tumor Recurrence.

BACKGROUND: Distinguishing radiation necrosis from brain tumor recurrence remains challenging. We performed a meta-analysis to assess the diagnostic accuracy of 2 different amino acid tracers used in positron emission tomography/computed tomography scans: 18F-FDOPA (6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine) and 18F-FET (O-(2-18F-fluoroethyl)-L-tyrosine). METHODS: We searched for studies in 3 databases: PubMed, Embase, and Chinese Biomedical databases. The data were extracted from eligible studies and then processed with heterogeneity test, threshold effect test, and calculations of sensitivity, specificity, and area under the summary receiver operating characteristic curve. Meta-regression and subgroup analyses were performed to explore the source of heterogeneity. RESULTS: A total of 48 studies (18F-FDOPA, n = 21; 18F-FET, n = 27) were included. Quantitative synthesis determined pooled weight values in the 18F-FDOPA and 18F-FET groups: sensitivity, 0.85 versus 0.82; specificity, 0.77 versus 0.80; diagnostic odds ratio, 21.7 versus 23.03; area under the curve (AUC) values, 0.8771 versus 0.8976 (P = 0.46). Moreover, the type of tumor was identified as the possible source of the significant heterogeneity (I2 = 52%; P = 0.003) found in the 18F-FDOPA group. In meta-regression and subgroup analyses, 18F-FDOPA showed better diagnostic accuracy in patients with glioma compared with patients with brain metastases (AUC values, 0.9691 vs. 0.837; P < 0.01). 18F-FDOPA also showed a significant advantage in the diagnosis of glioma recurrence compared with 18F-FET (AUC values, 0.9691 vs. 0.9124; P = 0.015). CONCLUSIONS: Both 18F-FDOPA and 18F-FET exhibit moderate overall accuracy in diagnosing brain tumor recurrence from radiation necrosis. However, 18F-FDOPA is more adept at diagnosing glioma recurrence compared with brain metastases, and it is more effective than 18F-FET in diagnosing glioma recurrence.

Role of positron emission tomography imaging in Multiple Endocrine Neoplasia syndromes.

The aim of this review was to summarize the recent developments on the role of positron emission tomography (PET) imaging using different radiopharmaceuticals in patients with multiple endocrine neoplasia (MEN) syndromes. Although most guidelines do not mention the use of PET imaging in patients with MEN syndromes, recent data seem to suggest a relevant diagnostic role of PET imaging in this setting. In particular, latest evidence has shown that somatostatin receptor PET provides a diagnostic accuracy in detecting MEN syndromes-related neuroendocrine tumours (NETs) higher than that of somatostatin receptor scintigraphy, thus influencing patient management in a significant percentage of cases. 18 F-DOPA PET seems to have a potential role in detecting MEN-2-related NETs, whereas 18 F-FDG PET is potentially useful in identifying aggressive NETs with poorer outcomes. More studies are needed to better define the role of different radiotracer-based PET imaging in patients with MEN syndromes.

A novel injectable formulation of 6-fluoro-l-DOPA imaging agent for diagnosis of neuroendocrine tumors and Parkinson's disease.

Two [19F]F-l-DOPA (F-DOPA) new ß-cyclodextrin (CD)-based dosage forms (FA and FB, respectively) have been studied and their physico-chemical and pharmacological features determined to overcome the administration site reactions showed by the currently used [18F]F-l-DOPA formulation (IASOdopa®) to perform PET-CT diagnosis in oncology (neuroendocrine tumors) and neurological (Parkinson's disease) field. Chemical stability of FA and FB was found to be longer than IASOdopa® by adding the thiol-antioxidant agent, L-Cysteine. 1H and 19F NMR investigations suggest the formation of an inclusion complex of F-DOPA with ß-CD. In vitro experiments on the effects of FA and FB on mouse skeletal muscle fibers and on the human neuroblastoma SH-SY5Y and embryonal kidney tsA201 cell lines viability showed that FA was the most performant formulation compared to F-DOPA solutions. In vivo tolerability tests of FA on adult male rat showed no significant effects on body weight and no change in their dried organs weight. In addition, their metabolic and physiological parameters were not affected. In conclusion, [18F]F-l-DOPA, formulated as FA, constitutes a promising dosage form for PET-CT diagnosis of both neuroendocrine tumors and Parkinson's disease.

Aberrant CpG Methylation Mediates Abnormal Transcription of MAO-A Induced by Acute and Chronic L-3,4-Dihydroxyphenylalanine Administration in SH-SY5Y Neuronal Cells.

L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective drug for therapy of Parkinson's disease (PD); however, long-term use of it causes serious side effects. L-dopa-induced dyskinesia (LID) has consistently been related to L-dopa-derived excessive dopamine release, but the mechanisms have not been addressed very clear. Monoamine oxidase A (MAO-A) is one of the key enzymes in dopamine metabolism and therefore may be involved in L-dopa-induced side effects. And, epigenetic modification controls MAO-A gene transcription. To investigate the effects of L-dopa on MAO-A transcription and its underlying epigenetic mechanism, neuronal SH-SY5Y cells were treated with L-dopa for 24 h (acute) and for 7-21 days (chronic). Results showed that chronic L-dopa administration resulted in a dose-dependent and time-dependent downregulation of MAO-A, whereas acute L-dopa administration induced upregulation of MAO-A transcription and expression. Meanwhile, chronic L-dopa exposure induced CpG hypermethylation in MAO-A promoter, while acute L-dopa administration caused CpG hypomethylation. And, CpG demethylation resulted in reactivation of MAO-A transcription. These results indicated that aberrant CpG methylation might play a key role in MAO-A transcriptional misregulation in L-dopa administration. In addition, results showed that acute L-dopa administration induced downregulation of DNA methyltransferase 3a (DNMT3a). Transcription of ten-eleven translocation 1 (TET1) were significantly downregulated in chronic L-dopa administration. These data indicated that in chronic L-dopa administration, TET1 downregulation might mediate CpG hypermethylation, which is responsible for the downregulation of MAO-A transcription. In contrast, in acute L-dopa administration, DNMT3a downregulation might mediate hypomethylation, contributing to the MAO-A upregulation. In conclusion, our findings suggested that TET1 and DNMTs might mediate aberrant CpG methylation, associated with the misregulation of MAO-A in L-dopa administration, which might contribute to dopamine release abnormally leading to the side effects of L-dopa.

Pharmaceutical development of novel lactate-based 6-fluoro-l-DOPA formulations.

6-[18F]fluoro-l-dihydroxyphenylalanine (18F-DOPA) is a diagnostic positron emission tomography (PET) agent, which has been used for decades in imaging the loss of dopaminergic neurons in Parkinson's disease, and more recently to detect, stage and restage neuroendocrine tumors (NETs) and to search for recurrence of viable glioma tissue. The commercially available 18F-DOPA PET radiopharmaceutical for diagnostic use in European Union countries, is formulated in an aqueous solution of acetic acid (1.05mg/mL) and has the disadvantages that, immediately before injection, the pH must be adjusted to 4.0-5.0 by the addition of a sterile solution of sodium bicarbonate (84mg/mL) causing a light and transient burning sensation at the injection site. To overcome these drawbacks, preformulation studies were accomplished to confirm that F-DOPA degradation was affected by pH. Hence, two formulations of F-DOPA, namely ND1 and ND2, were prepared maintaining the pH=5.0 using 1mM l-(+)-lactate buffer, excluding oxygen, and incorporating in the formula the chelating agent Na2EDTA (1mM). F-DOPA oxygen exposure, the presence of free metal cations in formulation and high pH values seem to promote F-DOPA degradation. The resulting formulations proved to guarantee the chemical stability of F-DOPA in solution at pH5.0, value also compatible with the direct infusion. In vitro cell viability tests on mouse skeletal muscle fibers, renal tsa201 and neuronal SH-SY5Y cell lines, and in vivo studies in rats reported elsewhere, showed cell tolerability to the new F-DOPA formulations providing the basis for their further in vivo evaluation.

Dopamine and Opioid Neurotransmission in Behavioral Addictions: A Comparative PET Study in Pathological Gambling and Binge Eating.

Although behavioral addictions share many clinical features with drug addictions, they show strikingly large variation in their behavioral phenotypes (such as in uncontrollable gambling or eating). Neurotransmitter function in behavioral addictions is poorly understood, but has important implications in understanding its relationship with substance use disorders and underlying mechanisms of therapeutic efficacy. Here, we compare opioid and dopamine function between two behavioral addiction phenotypes: pathological gambling (PG) and binge eating disorder (BED). Thirty-nine participants (15 PG, 7 BED, and 17 controls) were scanned with [11C]carfentanil and [18F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BPND) for [11C]carfentanil and influx rate constant (Ki) values for [18F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [11C]carfentanil BPND in multiple subcortical and cortical brain regions and in striatal [18F]fluorodopa Ki compared with controls. In PG patients, [11C]carfentanil BPND was reduced in the anterior cingulate with no differences in [18F]fluorodopa Ki compared with controls. In the nucleus accumbens, a key region involved in reward processing, [11C]Carfentanil BPND was 30-34% lower and [18F]fluorodopa Ki was 20% lower in BED compared with PG and controls (p<0.002). BED and PG are thus dissociable as a function of dopaminergic and opioidergic neurotransmission. Compared with PG, BED patients show widespread losses of mu-opioid receptor availability together with presynaptic dopaminergic defects. These findings highlight the heterogeneity underlying the subtypes of addiction and indicate differential mechanisms in the expression of pathological behaviors and responses to treatment.

Study of LAT1 Expression in Brain Metastases: Towards a Better Understanding of the Results of Positron Emission Tomography Using Amino Acid Tracers.

Positron emission tomography using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumour and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to determine and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochemistry in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5% and 59.7% of BM respectively and were significantly associated with BM tissue as compared to NT (p<0.001). LAT1 expression in recurrent BM was significantly increased as compared to newly occurring BM. Ten cases investigated by [18F] FDOPA-PET corresponding to recurrent BM displayed significant [18F] FDOPA uptake and LAT1 overexpression whereas three cases corresponding to radionecrosis showed no or low uptake and LAT1 expression. LAT1 expression level and [18F] FDOPA uptake were significantly correlated. In conclusion, we hypothesized that BM may overexpress the AA transporter LAT1. We have shown that LAT1 overexpression was common in BM and was specific for BM as compared to healthy brain. These results could explain the specific BM uptake on PET-AA.

Potential efficacy of dopamine loaded-PVP/PAA nanogel in experimental models of Parkinsonism: possible disease modifying activity.

This study aimed to investigate the ability of dopamine (DA)-loaded polyvinylpyrrolidone-poly(acrylic acid) (PVP/PAAc) nanogel [synthesized by gamma (γ) radiation-induced template polymerization] [Nano-DA] to deliver DA across the blood brain barrier, and to evaluate the efficacy and safety of the acute and subchronic administration of Nano-DA in modulating motor activity and/or the biochemical changes in rat brain; induced by different models of Parkinsonism. In this respect, (PVP/PAAc) nanogel was synthesized by gamma radiation-induced polymerization of acrylic acid (AAc) in an aqueous solution of PVP as a template polymer, and then, it was used as a nano-drug carrier for DA. The PVP/PAAc and (PVP/PAAc loaded-DA nanogel particles were characterized by dynamic light scattering, infrared spectroscopy, and field emission-scanning electron microscopy. The loaded gel was administered in different doses and dosing regimens to Parkinsonian rats, and the catalepsy score and striatal DA levels were assessed. Then, the potential disease-modifying activity of this form of DA was investigated, through the assessment of the improvement in mitochondrial function, following the subchronic administration of Nano-DA to Parkinsonian rats. Significant disease-modifying effects were observed upon the administration of Nano-DA; in addition to normalization in their motor activity.

Influence of O-methylated metabolite penetrating the blood-brain barrier to estimation of dopamine synthesis capacity in human L-[ß-(11)C]DOPA PET.

O-methyl metabolite (L-[ß-(11)C]OMD) of (11)C-labeled L-3,4-dihydroxyphenylalanine (L-[ß-(11)C]DOPA) can penetrate into brain tissue through the blood-brain barrier, and can complicate the estimation of dopamine synthesis capacity by positron emission tomography (PET) study with L-[ß-(11)C]DOPA. We evaluated the impact of L-[ß-(11)C]OMD on the estimation of the dopamine synthesis capacity in a human L-[ß-(11)C]DOPA PET study. The metabolite correction with mathematical modeling of L-[ß-(11)C]OMD kinetics in a reference region without decarboxylation and further metabolism, proposed by a previous [(18)F]FDOPA PET study, were implemented to estimate radioactivity of tissue L-[ß-(11)C]OMD in 10 normal volunteers. The component of L-[ß-(11)C]OMD in tissue time-activity curves (TACs) in 10 regions were subtracted by the estimated radioactivity of L-[ß-(11)C]OMD. To evaluate the influence of omitting blood sampling and metabolite correction, relative dopamine synthesis rate (kref) was estimated by Gjedde-Patlak analysis with reference tissue input function, as well as the net dopamine synthesis rate (Ki) by Gjedde-Patlak analysis with the arterial input function and TAC without and with metabolite correction. Overestimation of Ki was observed without metabolite correction. However, the kref and Ki with metabolite correction were significantly correlated. These data suggest that the influence of L-[ß-(11)C]OMD is minimal for the estimation of kref as dopamine synthesis capacity.

Hybrid microPET imaging for dosimetric applications in mice: improvement of activity quantification in dynamic microPET imaging for accelerated dosimetry applied to 6-[18 F]fluoro-L-DOPA and 2-[18 F]fluoro-L-tyrosine.

PURPOSE: Dynamic microPET imaging has advantages over traditional organ harvesting, but is prone to quantification errors in small volumes. Hybrid imaging, where microPET activities are cross-calibrated using post scan harvested organs, can improve quantification. Organ harvesting, dynamic imaging and hybrid imaging were applied to determine the human and mouse radiation dosimetry of 6-[18 F]fluoro-L-DOPA and 2-[18 F]fluoro-L-tyrosine and compared. PROCEDURES: Two-hour dynamic microPET imaging was performed with both tracers in four separate mice for 18 F-FDOPA and three mice for 18 F-FTYR. Organ harvesting was performed at 2, 5, 10, 30, 60 and 120 min post tracer injection with n = 5 at each time point for 18 F-FDOPA and n = 3 at each time point for 18 F-FTYR. Human radiation dosimetry projected from animal data was calculated for the three different approaches for each tracer using OLINDA/EXM. S-factors for the MOBY phantom were used to calculate the animal dosimetry. RESULTS: Correlations between dose estimates based on organ harvesting and imaging was improved from r = 0.997 to r = 0.999 for 18 F-FDOPA and from r = 0.985 to r = 0.996 (p < 0.0001 for all) for 18 F-FTYR by using hybrid imaging. CONCLUSION: Hybrid imaging yields comparable results to traditional organ harvesting while partially overcoming the limitations of pure imaging. It is an advantageous technique in terms of number of animals needed and labour involved.