Association between Striatal Subregions and Extrastriatal Regions in Dopamine D1 Receptor Expression: A Positron Emission Tomography Study

The mesencephalic dopamine (DA) system is the main DA system related to affective and cognitive functions. The system consists of two different cell groups, A9 and A10, which originate from different regions of the midbrain. The striatum is the main input from the midbrain, and is functionally organized into associative, sensorimotor and limbic subdivisions. At present, there have been few studies investigating the associations of DA functions between striatal subdivisions and extrastriatal regions. The aim of this study was to investigate the relationship of DA D₁ receptor (D₁R) expression between striatal subdivisions and extrastriatal regions in humans using positron emission tomography (PET) with voxel-by-voxel whole brain analysis. The PET study was performed on 30 healthy subjects using [¹¹C]{"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 to measure D₁R expression. Parametric images of binding potentials (BP _ND) were created using the simplified reference tissue model. Regions of interest were defined for striatal subdivisions. Multiple regression analysis was undertaken to determine extrastriatal regions that were associated with each striatal subdivision in BP _ND using statistical parametric mapping 5. The BP _ND values of associative, sensorimotor and limbic subdivisions were similarly correlated with those of multiple brain regions. Regarding the interrelationships among striatal subdivisions, mutual correlations were found among associative, sensorimotor and limbic subdivisions in BP _ND as well. The relationships in BP _ND between striatal subdivisions and extra-striatal regions suggest that differential striatal subdivisions and extrastriatal regions have a similar biological basis of D₁R expression. Different DA projections from the midbrain did not explain the associations between striatal subdivisions and extrastriatal regions in D₁R expression, and the DA-related neural networks among the midbrain, striatum and the other regions would contribute to a similar D₁R expression pattern throughout the whole brain.     

Radiology: Positron Emission Tomography in Clinical Oncology

The Council on Scientific Affairs of the California Medical Association presents the following inventory of items of progress in radiology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of these items of progress in radiology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Radiology of the California Medical Association, and the summaries were prepared under its direction.     

Relation between Dopamine Synthesis Capacity and Cell-Level Structure in Human Striatum: A Multi-Modal Study with Positron Emission Tomography and Diffusion Tensor Imaging

Positron emission tomography (PET) study has shown that dopamine synthesis capacity varied among healthy individuals. This interindividual difference might be due to a difference in the cell-level structure of presynaptic dopaminergic neurons, i.e., cellular density and/or number. In this study, the relations between the dopamine synthesis capacity measured by PET and the parameter estimates in diffusion tensor imaging (DTI) in striatal subregions were investigated in healthy human subjects. DTI and PET studies with carbon-11 labeled L-DOPA were performed in ten healthy subjects. Age-related changes in the above parameters were also considered. Fractional anisotropy showed a significant positive correlation with age in the posterior caudate. There was significant negative correlation between dopamine synthesis capacity and mean diffusivity in the posterior caudate and putamen. Assuming that mean diffusivity reflects the density of wide-spreading axonal terminals in the striatum, the result suggests that dopamine synthesis may be related to the density of dopaminergic neuronal fibers. It is evident that PET/DTI combined measurements can contribute to investigations of the pathophysiology of neuropsychiatric diseases involving malfunction of dopaminergic neurons.     

Prognostic Value of SUVmax Measured by Pretreatment Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients with Ewing Sarcoma

AimThe aim of this retrospective study was to determine whether glucose metabolism assessed by using Fluorine-18 (F-18) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) provides prognostic information independent of established prognostic factors in patients with Ewing sarcoma.MethodsWe retrospectively reviewed the medical records of 34 patients (men, 19; women, 15; mean age, 14.5 ± 9.7 years) with pathologically proven Ewing sarcoma. They had undergone F-18 FDG PET/CT as part of a pretreatment workup between September 2006 and April 2012. In this analysis, patients were classified by age, sex, initial location, size, and maximum standardized uptake value (SUVmax). The relationship between FDG uptake and survival was analyzed using the Kaplan-Meier method with the log-rank test and Cox’s proportional hazards regression model.ResultsThe median survival time for all 34 subjects was 999 days and the median SUV by using PET/CT was 5.8 (range, 2–18.1). Patients with a SUVmax ≤ 5.8 survived significantly longer than those with a SUVmax > 5.8 (median survival time, 1265 vs. 656 days; p = 0.002). Survival was also found to be significantly related to age (p = 0.024), size (p = 0.03), and initial tumor location (p = 0.036). Multivariate analysis revealed that a higher SUVmax (p = 0.003; confidence interval [CI], 3.63–508.26; hazard ratio [HR], 42.98), older age (p = 0.023; CI, 1.34–54.80; HR, 8.59), and higher stage (p = 0.03; CI, 1.21–43.95; HR, 7.3) were associated with worse overall survival.ConclusionsSUVmax measured by pretreatment F-18-FDG PET/CT can predict overall survival in patients with Ewing sarcoma.     

Non-invasive Imaging and Analysis of Cerebral Ischemia in Living Rats Using Positron Emission Tomography with 18F-FDG

Stroke is the third leading cause of death among Americans 65 years of age or older¹. The quality of life for patients who suffer from a stroke fails to return to normal in a large majority of patients², which is mainly due to current lack of clinical treatment for acute stroke. This necessitates understanding the physiological effects of cerebral ischemia on brain tissue over time and is a major area of active research. Towards this end, experimental progress has been made using rats as a preclinical model for stroke, particularly, using non-invasive methods such as ¹⁸F-fluorodeoxyglucose (FDG) coupled with Positron Emission Tomography (PET) imaging^3,10,17. Here we present a strategy for inducing cerebral ischemia in rats by middle cerebral artery occlusion (MCAO) that mimics focal cerebral ischemia in humans, and imaging its effects over 24 hr using FDG-PET coupled with X-ray computed tomography (CT) with an Albira PET-CT instrument. A VOI template atlas was subsequently fused to the cerebral rat data to enable a unbiased analysis of the brain and its sub-regions⁴. In addition, a method for 3D visualization of the FDG-PET-CT time course is presented. In summary, we present a detailed protocol for initiating, quantifying, and visualizing an induced ischemic stroke event in a living Sprague-Dawley rat in three dimensions using FDG-PET.     

18F-Fluorodeoxyglucose Positron Emission Tomography in Elderly Patients with an Elevated Erythrocyte Sedimentation Rate of Unknown Origin

Patients with an elevated erythrocyte sedimentation rate (ESR) and non-specific symptoms often pose a diagnostic dilemma. PET/CT visualises infection, inflammation and malignancy, all of which may cause elevated ESR. The objective of this study was to determine the contribution of 18F-fluorodeoxglucose positron emission tomography (PET/CT) in the diagnostic work-up of referred patients with an elevated ESR, in whom initial routine evaluation did not reveal a diagnosis. We conducted a combined retrospective (A) and prospective (B) study in elderly (>50 years) patients with a significantly elevated ESR of≥50 mm/h and non-specific complaints. In study A, 30 patients were included. Malignancy (8 patients), auto-inflammatory disease (8 patients, including 5 with large-vessel vasculitis) and infection (3 patients) were suggested by PET/CT. Two scans showed non-specific abnormalities and 9 scans were normal. Of the 21 abnormal PET/CT results, 12 diagnoses were independently confirmed and two alternative diagnosis were made. Two diagnoses were established in patients with a normal scan. In study B, 58 patients in whom a prior protocolised work-up was non-diagnostic, were included. Of these, 25 PET/CT-scans showed suspected auto-inflammatory disease, particularly large-vessel vasculitis (14 cases). Infection and malignancy was suspected in 5 and 3 cases, respectively. Seven scans demonstrated non-specific abnormalities, 20 were normal. Of the 40 abnormal PET/CT results, 22 diagnoses were confirmed, 3 alternative diagnoses were established. Only one diagnosis was established in the 20 patients with a normal scan. In both studies, the final diagnosis was based on histology, clinical follow-up, response to therapy or additional imaging. In conclusion, PET/CT may be of potential value in the diagnostic work-up of patients with elevated ESR if routine evaluation reveals no diagnosis. In particular, large-vessel vasculitis appears to be a common finding. A normal PET/CT scan in these patients suggests that it is safe to follow a wait-and-see policy.     

In Vivo High Intrinsic Efficacy of Triazolam: A Positron Emission Tomography Study in Nonhuman Primates

Abstract: The triazolobenzodiazepine triazolam is a central-type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of γ-aminobutyric acid-mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [¹¹C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist [¹¹C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half-life of 202 min). Triazolam is very potent in displacing [¹¹C]flumazenil (ID₅₀= 28 ± 6 μg/kg). Hill analysis of the displacement curve does not show obvious binding-site heterogeneity. Triazolam is 20 times more potent in displacing [¹¹C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol-induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam-positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.     

Localized Fetomaternal Hyperglycemia: Spatial and Kinetic Definition by Positron Emission Tomography

Background

Complex but common maternal diseases such as diabetes and obesity contribute to adverse fetal outcomes. Understanding of the mechanisms involved is hampered by difficulty in isolating individual elements of complex maternal states in vivo. We approached this problem in the context of maternal diabetes and sought an approach to expose the developing fetus in vivo to isolated hyperglycemia in the pregnant rat.

Methodology and Principal Findings

We hypothesized that glucose infused into the arterial supply of one uterine horn would more highly expose fetuses in the ipsilateral versus contralateral uterine horn. To test this, the glucose tracer [¹⁸F]fluorodeoxyglucose (FDG) was infused via the left uterine artery. Regional glucose uptake into maternal tissues and fetuses was quantified using positron emission tomography (PET). Upon infusion, FDG accumulation began in the left-sided placentae, subsequently spreading to the fetuses. Over two hours after completion of the infusion, FDG accumulation was significantly greater in left compared to right uterine horn fetuses, favoring the left by 1.9±0.1 and 2.8±0.3 fold under fasted and hyperinsulinemic conditions (p<10⁻¹¹ n = 32-35 and p<10⁻¹² n = 27–45) respectively. By contrast, centrally administered [³H]-2-deoxyglucose accumulated equally between the fetuses of the two uterine horns. Induction of significant hyperglycemia (10³ mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained.

Conclusions and Significance

This approach exposes selected fetuses to localized hyperglycemia in vivo, minimizing exposure of the mother and thus secondary effects. Additionally, a set of less exposed internal control fetuses are maintained for comparison, allowing direct study of the in vivo fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health.     

4-[18F]Fluoro-L-m-Tyrosine: An L-3,4-Dihydroxyphenylalanine Analog for Probing Presynaptic Dopaminergic Function with Positron Emission Tomography

4-[18F]Fluoro-L-m-tyrosine (FMT), a biochemical probe of striatal dopaminergic function, has been synthesized as an L-3,4-dihydroxyphenylalanine analog for positron emission tomography. Biochemical characterization of this compound in the rat 30 min after intrajugular administration indicated that in the brain, selective decarboxylation occurred in the striatum, with the formation of 4-fluoro-3-hydroxyphenylethylamine and its metabolites. Positron emission tomography analysis of brain tissue in monkeys (Macaca nemestrina) after intravenous injection of FMT revealed a true time-dependent, specific accumulation of radioactivity in striatum, with a striatum/cerebellum (nonspecific) ratio of 4 at 180 min. Peripheral metabolism accounted for less than 40% of the total radioactivity in arterial blood samples after 120 min. The amino acid remained as the major component throughout the period of investigation (n = 3; 5 min, 95%; 10 min, 85%; 30 min, 67%; 60 min, 62%; 120 min, 60%), with a plasma clearance t 1/2 of 112 min. 3-O-Methylated metabolites were not observed. The substrate specificity of FMT, coupled with its limited in vivo peripheral metabolism, makes it a useful, new biochemical probe for in vivo, noninvasive evaluation of central dopaminergic mechanisms.     

Detection of Cancer Metastases with a Dual-labeled Near-Infrared/Positron Emission Tomography Imaging Agent

By dual labeling a targeting moiety with both nuclear and optical probes, the ability for noninvasive imaging and intraoperative guidance may be possible. Herein, the ability to detect metastasis in an immunocompetent animal model of human epidermal growth factor receptor 2 (HER-2)-positive cancer metastases using positron emission tomography (PET) and near-infrared (NIR) fluorescence imaging is demonstrated. METHODS: (⁶⁴Cu-DOTA)_n-trastuzumab-(IRDye800)_m was synthesized, characterized, and administered to female Balb/c mice subcutaneously inoculated with highly metastatic 4T1.2neu/R breast cancer cells. (⁶⁴Cu-DOTA)_n-trastuzumab-(IRDye800)_m (150 µg, 150 µCi, m = 2, n = 2) was administered through the tail vein at weeks 2 and 6 after implantation, and PET/computed tomography and NIR fluorescence imaging were performed 24 hours later. Results were compared with the detection capabilities of F-18 fluorodeoxyglucose (¹⁸FDG-PET). RESULTS: Primary tumors were visualized with ¹⁸FDG and (⁶⁴Cu-DOTA)_n-trastuzumab-(IRDye800)_m, but resulting metastases were identified only with the dual-labeled imaging agent. ⁶⁴Cu-PET imaging detected lung metastases, whereas ex vivo NIR fluorescence showed uptake in regions of lung, skin, skeletal muscle, and lymph nodes, which corresponded with the presence of cancer cells as confirmed by histologic hematoxylin and eosin stains. In addition to detecting the agent in lymph nodes, the high signal-to-noise ratio from NIR fluorescence imaging enabled visualization of channels between the primary tumor and the axillary lymph nodes, suggesting a lymphatic route for trafficking cancer cells. Because antibody clearance occurs through the liver, we could not distinguish between nonspecific uptake and liver metastases. CONCLUSION: (⁶⁴Cu-DOTA)_n-trastuzumab-(IRDye800)_m may be an effective diagnostic imaging agent for staging HER-2-positive breast cancer patients and intraoperative resection.     

臂丛神经撕脱伤后慢性疼痛患者脑区葡萄糖代谢的研究

臂丛神经撕脱伤后慢性疼痛是一种临床上顽固性神经病理性疼痛.然而,对于其潜在的中枢机制还知之甚少.为了进一步探讨臂丛神经撕脱伤后慢性疼痛的相关脑区活动,利用18F-脱氧葡萄糖(FDG)正电子断层扫描(PET)技术观察臂丛神经撕脱后慢性疼痛患者的脑葡萄糖代谢.选择左侧臂丛神经撕脱伤后慢性疼痛行脊髓后根入髓区(DREZ)切开术后疼痛减轻>75%的患者,共5例,分别在术前和术后14天行PET扫描采集数据,同时行视觉模拟评分(VAS),汉密尔顿(Hamilton)抑郁和焦虑评分.用统计参数图(SPM2)软件分析数据.与术前疼痛状态下相比,术后葡萄糖代谢明显减低的脑区有双侧尾状核,眶额回(OFC)(BA11),对侧扣带下回(BA25)和同侧前额叶背外侧区域(DLPFC)(BA46/47).葡萄糖代谢明显增高的脑区有对侧丘脑,枕核和同侧项叶(BA7).研究结果提示,涉及情绪、注意和疼痛内在调节的脑区在臂丛神经撕脱伤后慢性疼痛的调制中发挥重要作用.     

[18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments

Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [¹⁸F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [¹⁸F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [¹⁸F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [¹⁸F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm³*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [¹⁸F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models.     

Effect of Aspartame-Derived Phenylalanine on Neutral Amino Acid Uptake in Human Brain: A Positron Emission Tomography Study

The possible effects of elevation of the plasma phenylalanine level secondary to the ingestion of aspartame on brain amino acid uptake in human subjects have been investigated by means of positron emission tomography (PET). 1-[11C]Aminocyclohexanecarboxylate [( 11C]ACHC) is a poorly metabolized synthetic amino acid that crosses the blood-brain barrier by the same carrier that transports naturally occurring large neutral amino acids. Quantitative test-retest PET studies were performed on 15 individuals. Seven received two identical baseline scans, whereas eight received a baseline scan followed by a scan performed approximately 40-45 min following ingestion of an orange-flavored beverage containing 34 mg/kg of body weight of the low-calorie sweetener aspartame, a dose equivalent to the amount in 5 L of diet soft drink consumed all at once by the study subjects, weighing an average of 76 kg. The 40-45-min interval was selected to maximize the detection of possible decreases in ACHC uptake resulting from increased competition for the carrier, because the plasma phenylalanine level is known to peak at this time. We observed an 11.5% decrease in the amino acid transport rate constant K1 and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET.     

Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using Positron Emission Tomography in rat and non-human primate

Several quinazoline derivatives were made as mitochondrial complex 1 inhibitors. Compound 4 showed an IC(50) of 11.3 nM and was the most potent compound of this series. The (18)F analog of 4, [(18)F] 4, was injected in the rat and showed high and rapid heart uptake, fast liver clearance, and low blood uptake. Images obtained using a microPET showed clear delineation of the myocardium in normal rats and perfusion deficit in ischemic rats. In the non-human primate, [(18)F] 4 showed rapid uptake and clearance from the myocardium and high liver uptake.     

Thyroid Carcinoma Detected by 18f-Fluorodeoxyglucose Positron Emission Tomography Among Individuals without Prior Evidence of Thyroid Disease: Relevance and Clinicopathologic Features

ObjectiveThe expanding use of ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) has contributed to an increasing number of thyroid incidentalomas. The present study aimed to estimate the prevalence of ¹⁸F-FDG-PET thyroid incidentalomas and evaluate the clinicopathologic features of thyroid malignancies detected by ¹⁸F-FDG-PET.MethodsWe reviewed all ¹⁸F-FDG-PET exams performed at the Portuguese Institute of Oncology, Lisbon, between 2007 and 2012 (n = 9,374). The inclusion criteria were focal thyroid uptake and absence of known thyroid disease.ResultsFocal thyroid uptake was observed in 60 out of 9,374 ¹⁸F-FDG-PET exams (prevalence of 0.64%). Fineneedle aspiration cytology (FNAC) was performed in 23 patients and reported as malignant in 14 cases (56.5% primary thyroid carcinoma; 4.3% secondary malignancy), as benign in 7 cases (30.5%) and as follicular lesion of undetermined significance in 2 cases (8.7%). Fourteen patients had surgery. A final histologic diagnosis of papillary thyroid carcinoma was established in 12 cases (52.2%). Three were multifocal (25.0%); 8 had extrathyroidal extension (66.7%); 5 had angioinvasion (41.7%); 3 had lymph nodes metastases (25.0%) and 2 showed lung metastases (16.7%). Overall, 91.7% were classified as intermediate or high risk. All patients had radioiodine therapy. At the last observation (mean follow-up was 29.9 months), persistent or recurrent disease was identified in 4 patients (33.3%) and none died from thyroid malignancy.ConclusionsThyroid carcinomas disclosed by ¹⁸F-FDG-PET are associated with aggressive histological criteria likely to carry a worse prognosis. (Endocr Pract. 2014;20:1129-1136)     

Comparison of Three 18F-Labeled Butyrophenone Neuroleptic Drugs in the Baboon Using Positron Emission Tomography

The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.     

Evaluation of 89Zr-Labeled Human Anti-CD147 Monoclonal Antibody as a Positron Emission Tomography Probe in a Mouse Model of Pancreatic Cancer

Introduction

Pancreatic cancer is an aggressive cancer and its prognosis remains poor. Therefore, additional effective therapy is required to augment and/or complement current therapy. CD147, high expression in pancreatic cancer, is involved in the metastatic process and is considered a good candidate for targeted therapy. CD147-specfic imaging could be useful for selection of appropriate patients. Therefore, we evaluated the potential of a fully human anti-CD147 monoclonal antibody 059-053 as a new positron emission tomography (PET) probe for pancreatic cancer.

Methods

CD147 expression was evaluated in four pancreatic cancer cell lines (MIA Paca-2, PANC-1, BxPC-3, and AsPC-1) and a mouse cell line A4 as a negative control. Cell binding, competitive inhibition and internalization assays were conducted with ¹²⁵I-, ⁶⁷Ga-, or ⁸⁹Zr-labeled 059-053. In vivo biodistribution of ¹²⁵I- or ⁸⁹Zr-labeled 059-053 was conducted in mice bearing MIA Paca-2 and A4 tumors. PET imaging with [⁸⁹Zr]059-053 was conducted in subcutaneous and orthotopic tumor mouse models.

Results

Among four pancreatic cancer cell lines, MIA Paca-2 cells showed the highest expression of CD147, while A4 cells had no expression. Immunohistochemical staining showed that MIA Paca-2 xenografts also highly expressed CD147 in vivo. Radiolabeled 059-053 specifically bound to MIA Paca-2 cells with high affinity, but not to A4. [⁸⁹Zr]059-053 uptake in MIA Paca-2 tumors increased with time from 11.0±1.3% injected dose per gram (ID/g) at day 1 to 16.9±3.2% ID/g at day 6, while [¹²⁵I]059-053 uptake was relatively low and decreased with time, suggesting that 059-053 was internalized into tumor cells in vivo and ¹²⁵I was released from the cells. PET with [⁸⁹Zr]059-053 clearly visualized subcutaneous and orthotopic tumors.

Conclusion

[⁸⁹Zr]059-053 is a promising PET probe for imaging CD147 expression in pancreatic cancer and has the potential to select appropriate patients with CD147-expressing tumors who could gain benefit from anti-CD147 therapy.     

[11C]MADAM Used as a Model for Understanding the Radiometabolism of Diphenyl Sulfide Radioligands for Positron Emission Tomography (PET)

In quantitative PET measurements, the analysis of radiometabolites in plasma is essential for determining the exact arterial input function. Diphenyl sulfide compounds are promising PET and SPECT radioligands for in vivo quantification of the serotonin transporter (SERT) and it is therefore important to investigate their radiometabolism. We have chosen to explore the radiometabolic profile of [¹¹C]MADAM, one of these radioligands widely used for in vivo PET-SERT studies. The metabolism of [¹¹C]MADAM/MADAM was investigated using rat and human liver microsomes (RLM and HLM) in combination with radio-HPLC or UHPLC/Q-ToF-MS for their identification. The effect of carrier on the radiometabolic rate of the radioligand [¹¹C]MADAM in vitro and in vivo was examined by radio-HPLC. RLM and HLM incubations were carried out at two different carrier concentrations of 1 and 10 μM. Urine samples after perfusion of [¹¹C]MADAM/MADAM in rats were also analysed by radio-HPLC. Analysis by UHPLC/Q-ToF-MS identified the metabolites produced in vitro to be results of N-demethylation, S-oxidation and benzylic hydroxylation. The presence of carrier greatly affected the radiometabolism rate of [¹¹C]MADAM in both RLM/HLM experiments and in vivo rat studies. The good concordance between the results predicted by RLM and HLM experiments and the in vivo data obtained in rat studies indicate that the kinetics of the radiometabolism of the radioligand [¹¹C]MADAM is dose-dependent. This issue needs to be addressed when the diarylsulfide class of compounds are used in PET quantifications of SERT.     

Design,Synthesis, Lipophilic Properties,and Binding Affinities of Potential Ligands in Positron Emission Tomography (PET) for Visualization of Brain Dopamine D4 Receptors

We report the synthesis of compounds structurally related to the high‐affinity dopamine D₄ receptor ligand N‐{2‐[4‐(3‐cyanopyridin‐2‐yl)piperazin‐1‐yl]ethyl}‐3‐methoxybenzamide ( 1e ). All compounds were specifically designed as potential PET radioligands for brain D₄ receptor visualization, having lipophilicity within a range for brain uptake and weak non‐specific binding (0.75<cLogP<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope ¹¹C or ¹⁸F. The best compound of the series, N‐{2‐[4‐(4‐chlorophenyl)piperazin‐1‐yl]ethyl}‐6‐fluoropyridine‐3‐carboxamide ( 7a ), displayed excellent selectivity over D₂ and D₃ receptors (>100‐fold), but its D₄ receptor affinity was suboptimal for imaging of brain D₄ receptors (K_i=30 nM ).