Tae Joo Jeon

Effective microPET imaging of brain 5-HT(1A) receptors in rats with [(18) F]MeFWAY by suppression of radioligand defluorination.

Introduction: [18F]MeFWAY has been developed for imaging the serotonin 1A receptors in the brain. The purpose of this study were to verify the metabolic stability of [18F]MeFWAY, to measure the degree of defluorination of [18F]MeFWAY in vivo, to investigate methods of inhibition of defluorination of [18F]MeFWAY, and to assess the efficacy of [18F]MeFWAY in rat brains in vivo. Methods: MicroPET experiments in rats were conducted to confirm the distribution of radioactivity in the brain. Nondisplaceable binding potential (BPND) in the hippocampus and frontal cortex were also analyzed. Miconazole and fluconazole were tested for the ability to suppress defluorination of [18F]MeFWAY. We conducted a blockade and displacement experiment by treating with WAY‐100635. Results: In vitro stability tests showed that MeFWAY was very stable in serum for 6 h, but PET revealed that authentic [18F]MeFWAY underwent significant defluorination in vivo. In vitro inhibition study against decreasing parent activity in liver microsomes, miconazole and fluconazole suppressed metabolic elimination of MeFWAY. However, in the PET study, fluconazole showed more potent inhibitory activity than miconazole. In the suppression of metabolizing enzymes using fluconazole, radioactivity in skull was dramatically decreased by 81% (compared with 69% with miconazole) and it was coupled with an increase in brain uptake. Moreover, BPND in hippocampus was 5.53 and 2.66 in frontal cortex. The blockade and displacement study showed the specificity of [18F]MeFWAY to 5‐HT1A receptors. Conclusion: In the rat brain, [18F]MeFWAY microPET showed skull uptake due to defluorination in vivo. We can effectively overcome this drawback with fluconazole. Synapse, 2012.

Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system

Depression frequently accompanies in Parkinsons disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6‐hydroxydopamine (6‐OHDA) lesioned and sham operated rats: [18F]FP‐CIT for DA transporters and [18F]Mefway for serotonin 1A (5‐HT1A) receptors. Here, 6‐OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region‐of‐interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5‐HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6‐OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R2 = 0.79, P = 0.003). In 6‐OHDA lesioned rats, binding values for 5‐HT1A receptors was 22% lower than the sham operated group. This decrement of 5‐HT1A receptor binding was also correlated with the severity of depression (R2 = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. Synapse 69:453–460, 2015.

Evaluation of dopamine transporters and D2 receptors in hemiparkinsonian rat brains in vivo using consecutive PET scans of [18F]FPCIT and [18F]fallypride.

The aim of this study was to investigate dopaminergic function in unilaterally lesioned 6-OHDA rats by dual PET radioligands: [(18)F]FPCIT (a dopamine transporter imaging radioligand) and [(18)F]fallypride (a dopamine D2 receptors imaging radioligand). As a result, the brain uptake of [(18)F]FPCIT was significantly reduced and that of [(18)F]fallypride was increased in the ipsilateral striatum (lesion side) of the 6-OHDA rats. These findings implicated that dopamine transporter is down-regulated and dopamine D2 receptor is up-regulated in this hemiparkinsonian rat model.

[18F]-fluorodeoxyglucose positron emission tomography can contribute to discriminate patients with poor prognosis in hormone receptor-positive breast cancer.

Background Patients with hormone receptor-positive breast cancer typically show favorable survival. However, identifying individuals at high risk of recurrence among these patients is a crucial issue. We tested the hypothesis that [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans can help predict prognosis in patients with hormone receptor-positive breast cancer. Methods Between April 2004 and December 2008, 305 patients with hormone receptor-positive breast cancer who underwent FGD-PET were enrolled. Patients with luminal B subtype were identified by positivity for human epidermal growth factor receptor-2 (HER2) or high Ki67 (≥14%) according to criteria recently recommended by the St. Gallen panelists. The cut-off value of SUVmax was defined using the time-dependent receiver operator characteristic curve for recurrence-free survival (RFS). Results At a median follow up of 6.23 years, continuous SUVmax was a significant prognostic factor with a hazard ratio (HR) of 1.21 (p = 0.021). The cut-off value of SUVmax was defined as 4. Patients with luminal B subtype (n = 82) or high SUVmax (n = 107) showed a reduced RFS (p = 0.031 and 0.002, respectively). In multivariate analysis for RFS, SUVmax carried independent prognostic significance (p = 0.012) whereas classification with immunohistochemical markers did not (p = 0.274). The Harell c-index was 0.729. High SUVmax was significantly associated with larger tumor size, positive nodes, HER2 positivity, high Ki67 (≥14%), high tumor grade, and luminal B subtype. Conclusions Among patients with hormone receptor-positive breast cancer, FDG-PET can help discriminate patients at high risk of tumor relapse.

Acute physical stress induces the alteration of the serotonin 1A receptor density in the hippocampus

Stress affects the serotonergic system, which is associated with depression. Previous research has showed that chronic stress causes the deactivation of the limbic system. However, the influence of the acute physical stress on the serotonergic system in vivo was primarily unclear. The purpose of this research is to elucidate the effects of the acute physical stress in vivo using PET. For quantification of the 5‐HT1A receptors in the brain, we measured [18F]Mefway uptake in the two experiment groups (control and despair rats). The despair group was subjected to the external stressful situation (i.e., forced swimming) and total duration time of immobility, refers to the despair severity, and was analyzed. In the intercomparison experiment, the resulting PET images of [18F]Mefway in the despair rat displayed a significant reduction of radioactivity in the hippocampus (HP) compared with the control. The nondisplaceable binding potential (BPND) refers to the ratio of the concentration of radioligand in the receptor‐rich region (i.e., HP) to the concentration of that in the receptor‐free region (i.e., cerebellum). The hippocampal uptake and the BPND in the despair group were respectively about 25 and 18% lower than those of the control group. The ratio of specific binding to nonspecific binding in the despair group was 18% lower than that of the control. In the intracomparison experiments, the BPND and immobility in the despair group showed a strong negative correlation. Taken together, the data illustrates that an acute physical stress induces the change in the serotonergic system that correlates with the behavioral despair. Synapse 68:363–368, 2014.

A survival benefit of major hepatectomy for hepatocellular carcinoma identified by preoperative [18F] fluorodeoxyglucose positron emission tomography in patients with well-preserved hepatic function

AIMS Hepatic resection can cure hepatocellular carcinoma (HCC). However, the optimal extent of resection remains controversial. Major hepatectomy could minimize a tumor recurrence, but it is harmful due to decreased hepatic functional reserve. [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) scans are known as their reflection tumor differentiation and biological activity in HCC. To evaluate a benefit of major hepatectomy for HCC, we performed this retrospective analysis in patients with well-preserved hepatic function, and further analyzed in the subset identified by preoperative FDG-PET. METHODS We reviewed the medical records of 189 patients with HCC who underwent curative resection between August 2004 and December 2010 at two institutes. All patients underwent anatomical resection, either by major or minor hepatectomy. RESULTS Median overall survival did not differ significantly between the major and minor hepatectomy groups (29.4 versus 26.3 months, p = 0.269). However, the major hepatectomy group had a better recurrence-free survival (24.5 versus 19.9 months, p = 0.004). On multivariate analysis, the presence of intrahepatic metastasis independently predicted overall survival (p = 0.009), but other examined variables did not. Overall survival and recurrence-free survival were significantly better following major hepatectomy rather than minor hepatectomy in patients whose preoperative FDG-PET indicated that the maximum standardized uptake value of the tumor (SUVtumor) was ≥4 and the tumor-to-nontumor SUV ratio (TNR) was ≥1.5. CONCLUSIONS Our findings suggest that preoperative FDG-PET may be useful in identifying patients with favorable hepatic reserve who are most likely to benefit from major rather than minor hepatectomy.

Optimization of the radiosynthesis of [18F]MEFWAY for imaging brain serotonin 1A receptors by using the GE TracerLab FXFN-Pro module

The aim of this study was to develop a highly reliable radiofluorination method for the preparation of N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-(18) F-fluoromethylcyclohexane)carboxamide ([(18) F]Mefway) by using a fully automated system. The optimal condition is composed of two parts. The extraction system of the trapped F-18 in the anion exchange resin (i.e., quaternary methylamine cartridge) is a complex of Kryptofix 2.2.2. (K222, 4 mg/0.9 mL methanol) and K2 CO3 (1 mg/0.1 mL H2 O). After removing the solvents, the trans-tosylated Mefway precursor (1 mg/0.5 mL acetonitrile) was reacted with dried K222-K[(18) F] at 100°C for 5 min. After purification and formulation, [(18) F]Mefway was obtained with 38 ± 2.4% (decay corrected, n = 34) radiochemical yield, a total synthesis time of 52 ± 3.4 min, specific activity was 120.6 ± 8.7 GBq/µmol at the end of synthesis and a radiochemical purity of 99%. According to the quality control tests, formulated [(18) F]Mefway is suitable to apply parenteral clinical application.

Low iodine diet for one week is sufficient for adequate preparation of high dose radioactive iodine ablation therapy of differentiated thyroid cancer patients in iodine-rich areas

BACKGROUND Most current guidelines suggest one or two weeks of low iodine diet (LID) before radioactive iodine ablation therapy (RAIT) to increase its efficacy in differentiated thyroid cancer (DTC) patients after total thyroidectomy. LID duration is particularly important for patients living in iodine excess areas. However, there is no standardized LID protocol and there are limited reports regarding the relationship between LID and ablation outcome. Therefore, we aimed to evaluate the optimal LID duration and define clinical features that affect ablation outcome. METHODS A total of 202 papillary thyroid cancer patients with total thyroidectomy preparing for RAIT were enrolled. All patients had undergone two weeks of LID before (131)I administration. Morning spot urine specimens were obtained twice (one week or two weeks after LID, respectively) from each patient. Urine iodine excretion (UIE) values were used to evaluate LID efficacy. Successful ablation was defined using two definitions: (i) no visible uptake on a follow-up diagnostic (131)I scans, and (ii) no visible uptake on a follow-up diagnostic (131)I scans and stimulated serum thyroglobulin (Tg) levels <1 ng/mL. RESULTS The UIE median values after LID for one and two weeks were lower than 50 μg/L, and the median UIE values were not significantly different according to the LID duration. Based on the first criterion for successful ablation, 175 of the 195 patients were successfully ablated. There were no significant differences in mean and median UIE levels between the ablated and non-ablated groups after LID for two weeks. The rate of ablation did not differ between the mild and moderate iodine deficient groups. Based on the second criterion for successful ablation, 149 of 188 patients were successfully ablated. The ablation success rate did not differ between UIE levels. When we analyzed clinical factors that affect ablation outcome, serum Tg level at the time of ablation was the only significant variable in multivariate logistic analysis. CONCLUSION Strict LID for one week was sufficient to achieve target UIE values for RAIT preparation, even in iodine-rich areas.

Dopaminergic neuron destruction reduces hippocampal serotonin 1A receptor uptake of trans-[(18)F]Mefway.

The purpose of the present study is to investigate the relationship between dopaminergic neuron destruction and 5-HT system changes in a hemiparkinsonian rat model. We performed PET imaging studies with trans-[(18)F]Mefway in a hemiparkinsonian model of unilateral 6-hydroxydopamine (6-OHDA) rats. Region-of-interests (ROIs) were drawn in the hippocampus (HP) and cerebellum (CB). HP uptake, the ratios of specific binding to non-specific binding in the HP, and non-displaceable binding potential (BPND) in the HP were compared between 6-OHDA and control rats. As a result, unilateral 6-OHDA-lesioned rats exhibited significant bilateral reduction of HP uptake and trans-[(18)F]Mefway BPND compared to the intact control group. Therefore, the results demonstrate that destruction of the dopaminergic system causes the reduction of the serotonergic system.

Evaluation of diethylnitrosamine- or hepatitis B virus X gene-induced hepatocellular carcinoma with 18F-FDG PET/CT: a preclinical study.

The aim of this study was to evaluate whether the development of hepatocellular carcinoma (HCC) in murine models resembles tumor progression in humans, using non‑invasive molecular imaging methods. Murine HCC models were generated by treating mice with diethylnitrosamine (DEN) or by the transgenic expression of hepatitis B virus X (HBx) protein (HBx-Tg model). Tumor development was detected using 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological changes and expression of glucose transporter 1 (Glut1) and hexokinase 2 (HK2) were evaluated using hematoxylin and eosin and immunohistochemical staining, respectively. Tumor lesions as small as 1 mm in diameter were detected by MRI. Tumor development was monitored using 18F-FDG PET/CT at 6.5‑10 months after DEN treatment or 11‑20 months after birth of the HBx-Tg model mice. A correlation study between the 18F-FDG uptake levels and expression levels of HK2 and Glut1 in developed HCC showed a high 18F-FDG uptake in poorly differentiated HCCs that expressed high levels of HK2, in contrast to that in well-differentiated tumors. The progression of primary HCCs resembling human HCC in murine models was detected and monitored by 18F-FDG PET/CT. The correlation between tumor size and SUVmax was verified in the two HCC models. To the best of our knowledge, this is the first study to demonstrate that in vivo 18F-FDG uptake varies in HCCs according to differentiation grade in a preclinical study.