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Introduction Vesicular monoamine transporter 2 (VMAT2) has been associated with the risk of PD. Genetic reduction of VMAT2 level is reported to increase the vulnerability for dopaminergic neurodegeneration. In this study, by using in vivo microPET imaging with a VMAT2 radioligand [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ), we investigated the enhanced role of inhibiting VMAT2 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons. Methods The (+)-α-dihydrotetrabenazine ((+)-DTBZ, an inhibitor of VMAT2, 5 mg/kg), or MPTP (low dose (ld): 10 mg/kg, high dose (hd): 30 mg/kg) or both of them were intraperitoneally injected into C57BL/6 mice for 5 or 10 consecutive days. MicroPET imaging with [18F]FP-(+)-DTBZ was performed to test the dopaminergic neuronal integrity. [18F]FP-(+)-DTBZ uptake in striatum was quantified as standardized uptake value (SUV). The pathological changes in the striata and substantia nigra were confirmed by measuring the DA contents and immunohistochemical staining of tyrosine hydroxylase (TH). Results In vivo imaging results showed that the striatal SUVs of both DTBZ&MPTPld and MPTPhd groups were substantially declined compared to the baseline. Moreover, the striatal uptakes of [18F]FP-(+)-DTBZ in DTBZ&MPTPld and MPTPhd groups were obviously lower than the control, DTBZ group and MPTPld group. Notably, the decrease of the striatal uptake in the DTBZ&MPTPld/10d group was more serious than the DTBZ&MPTPld/5d group and comparable to the MPTPhd group. Consistently, the ratios of DA metabolites to DA in DTBZ&MPTPld/10d and MPTPhd mice were significantly increased. The correlation analysis showed that SUVs were highly correlated to the striatal dopaminergic fiber density and TH-positive dopaminergic neuron number in the substantia nigra. Conclusions MicroPET brain imaging with [18F]FP-(+)-DTBZ noninvasively revealed that (+)-DTBZ co-administration significantly aggravated the neurotoxicity of MPTP to dopaminergic neurons, suggesting that inhibition of VMAT2 may be related to the pathogenesis of PD and tracing VMAT2 activity with PET imaging is of potential value in monitoring PD progression.

Objective The deficit of dopaminergic neurons in the nigrostriatal pathway is one of the pathological features of Parkinson's disease (PD). The decline of vesicular monoamine transporter type 2 (VMAT2) has been verified to relate with the severity of PD. The purpose of this study was to evaluate the ability of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) to detect dopaminergic neuron dysfunction in a standard rat model of PD using PET imaging. Specifically, two different doses of 6-hydroxydopamine (6-OHDA) were injected unilaterally into the medial forebrain bundle (MFB) to create the models with two different severities. Methods Male Sprague-Dawley rats were intracranially injected with 8 μg 6-OHDA (partial lesion group), 16 μg 6-OHDA (full lesion group) and vehicle (sham group) into MFB, respectively. Thirty minutes static [18F]FP-(+)-DTBZ microPET scanning was performed to determine the dopaminergic neuron integrity on the 28th day post-injection and the behavioral tests were carried out in the next two days. Then, the rats were decapitated, and the brains were collected for biogenic amines content analysis or dissected for autoradiography and immunohistochemical (IHC) staining. The correlations of PET results to the behavioral, biological, histological, autoradiography results were analyzed, respectively. Results The standardized uptake value ratio (ST to CB) of [18F]FP-(+)-DTBZ in the ipsilateral striata decreased significantly in partial lesion group and full lesion group. Compared with the sham group, the ratio of the standardized uptake value in ipsilateral striatum to that in contralateral striatum decreased by 57.09 ± 2.30% (full lesion group) and 25.31 ± 5.70% (partial lesion group), respectively. The dopaminergic neuronal dysfunction was corroborated by in vitro autoradiography, IHC, and quantitative analysis of DA as well as its metabolites concentration tests. The motor function impairments of 6-OHDA-treated animals were manifested by a series of behavioral tests. The results of microPET imaging were linearly correlated with behavioral, biological, histological, and autoradiography results, respectively. Conclusion Our data suggest that [18F]FP-(+)-DTBZ may be useful for detecting different degrees of dopaminergic neuronal lesions by PET imaging in PD models induced by 6-OHDA.

Immune thrombocytopenia (ITP) is one of the most common acquired immune-mediated bleeding disorders found in children. Prednisone is usually considered a first-line therapeutic agent for ITP in children. Yet, prolonged exposure to prednisone has been associated with certain side effects. This prospective randomized study comparatively assessed the efficacy and safety of short-course high-dose dexamethasone (HDD) and standard prednisone (PDN) as a first-line treatment for children with previously untreated primary ITP. Two hundred eleven children were randomized into the HDD (n = 110) and PDN (n = 101) groups. There was no difference in baseline characteristics between the two groups (p > 0.05). Early response rates were 92.7% and 93% (p = 0.923); initial response rates were 93.6% and 95% (p = 0.658) and durable response rates were 90% and 91% (p = 0.787) in the HDD and PDN groups, respectively. More remission patients in the HDD group compared with the PDN group (86.3% vs. 80.1%) at 12th month after treatment, yet no statistical difference was observed (p = 0.703). Bleeding events were 10.9% and 14.8% (p = 0.105), and bleeding score improvement rates were 78.2% and 76.2% (p = 0.284) in the HDD and PDN groups, respectively. Cushing’s disease, weight gain and infection rates were higher in the PDN group compared to the HDD group (80% vs. 10%, p = 0.001; 74.2% vs. 13.6%, p = 0.001; and 26% vs. 11.8%, p = 0.012) 1 month after treatment. HDD showed non-inferior efficacy and fewer glucocorticoid-related adverse effects compared with PDN. These findings indicated that HDD could be considered as a first-line treatment in children with previously untreated primary ITP, thus replacing standard PDN.

To study the pharmacokinetics, biodistribution, and injection doses of 99mTc-TRODAT-1 in healthy adults. Thirty healthy individuals comprising 15 females and 15 males were randomly divided into three groups and the injection doses of 99mTc-TRODAT-1 of group 1, 2, and 3 were 370 MBq, 740 MBq, and 1110 MBq, respectively. Assessments of subjective symptoms and tests were performed before and after injection. Blood and urine collections and whole-body planar imaging were analyzed at various time points. Bilateral brain striatal SPECT images obtained at 3.5 h PI were assessed visually and semiquantitatively. No serious adverse events or deaths were observed in our study. The pharmacokinetic analysis showed that 99mTc-TRODAT-1 was eliminated rapidly from the circulation, with just about 4% of the injected dose remaining in blood at 1 h post-injection. The mean cumulative urinary excretion over 24 h was just 2.96 ± 0.96%ID. The time-activity curve demonstrated that the radioactivity was mainly in liver and abdomen. The highest absorbed dose was in the dose-limiting organ, liver (20.88 ± 4.45 × 10−3 mSv/MBq). The average effective dose was 5.22 ± 1.05 × 10−3 mSv/MBq. The clarity of striatal images assessed visually in group 1 was worse than that in group 2 and 3. The semiquantitative analysis showed that there were no differences in striatum/cerebellum between the three groups (group 1: 1.77 ± 0.11, group 2: 1.62 ± 0.14, and group 3: 1.75 ± 0.20; P = 0.088). 99mTc-TRODAT-1 was safe to use in humans and showed the status of dopaminergic neurons specifically and clearly. The injection dose we suggested was 740 MBq.

Objective To analyze the effects of escalating treatment strategy in children with severe chronic immune thrombocytopenia (SCITP). Methods This was a single-center, retrospective cohort study. Data from children with SCITP who received escalating treatment strategy in our center were collected between June 2017 and August 2019. The escalating strategy included three steps: Step I (six courses of high-dose dexamethasone [HDD]), Step II (HDD combined with low-dose rituximab), and Step III (eltrombopag). Results A total of 30 cases (18 males and 12 females) were included, with duration of immune thrombocytopenia (ITP) of 20.5 (12.0-96.0) months. After treatment, the remission rate was 36.7% (11/30) and the sustained response (SR) rate was 68.2% (15/22). The distribution (remission rates) from Step I to III was as follows: nine of 30 (33.3%, 3/9); four of 30 (50%, 2/4); 17/30 (29.4%, 5/17), respectively. In eltrombopag (Step III) cases, 47.5% (8/17) maintained a platelet count of ≥50 × 109 /L, 37.5% (3/8) had dose tapering, and 25% (2/8) have successfully discontinued the medication. The number of patients at 12, 24, and 36 months were 30, seven, and two, with a total response and remission rates of 80% (36.7%), 57.1% (28.6%), and 50% (50%), respectively. The total relapse rate was 26.7% (8/30), and three cases from Step II and five cases from Step III. Conclusion The escalating strategy for children SCITP showed an effective improvement rate with 36.7% remission and 68.2% SR, and 30% could benefit and retain SR from HDD treatment. Combined treatment with eltrombopag can reduce the relapse rate of low-dose rituximab.

A new radioiodinated tetrabenazine (TBZ) derivative containing an iodovinyl group at 9-position of TBZ (131I-IV-TBZ, 11a) and the corresponding cold compound IV-TBZ (11b) were synthesized and characterized. Analysis of in vitro autoradiography with rat brain slices showed 11a has a high uptake in the striatum and the uptake could be blocked by known vesicular monoamine transporter 2 (VMAT2) inhibitor. Furthermore, 11b has a competitive binding to VMAT2. These results suggest that 11a has ability to bind to VMAT2 and the binding is specific. Further studies are warranted to assess this radioiodinated TBZ derivative for VMAT2 imaging in vivo.

We studied on the structural requirement of C11b chirality of tetrabenazine (TBZ) analogs as vesicular monoamine transporter 2 (VMAT2) ligands. TBZ analogs (2, 6a, 6b) and 18F-radiolabeled [18F]6a and [18F]6b with eliminated C11b chirality were synthesized and characterized. Competition studies demonstrated that 2, 6a and 6b displayed much lower in vivo VMAT2 bindings than TBZ. MicroPET imaging studies of [18F]6a and [18F]6b showed negligible accumulation in VMAT2-enriched regions as compared with the known VMAT2 ligand 18F-FP-(+)-DTBZ. These results suggest that C11b chirality of TBZ analogs is essential for in vivo VMAT2 binding bioactivity.

Objectives The in vivo binding analysis of vesicular monoamine transporter type 2 (VMAT2) to radioligand has provided a means of investigating related disorders. Anesthesia is often inevitable when the investigations are performed in animals. In the present study, we tested effects of four commonly-used anesthetics: isoflurane, pentobarbital, chloral hydrate and ketamine, on in vivo VMAT2 binding to 18 F-FP-(+)-DTBZ, a specific VMAT2 radioligand, in rat brain. Methods The transient equilibrium time window for in vivo binding of 18 F-FP-(+)-DTBZ after a bolus injection was firstly determined. The brain biodistribution studies under anesthetized and awake rats were then performed at the equilibrium time. Standard uptake values (SUVs) of the interest brain regions: the striatum (ST), hippocampus (HP), cortex (CX) and cerebellum (CB) were obtained; and ratios of tissue to cerebellum were calculated. Results Isoflurane and pentobarbital did not alter distribution of 18 F-FP-(+)-DTBZ in the brain relative to the awake group; neither SUVs nor ratios of ST/CB and HP/CB were altered significantly. Chloral hydrate significantly increased SUVs of all the brain regions, but did not significantly alter ratios of ST/CB and HP/CB. Ketamine significantly increased SUVs of the striatum, hippocampus and cortex, and insignificantly increased the SUV of the cerebellum; consequently, ketamine significantly increased ratios of ST/CB and HP/CB. Conclusions It is concluded that in vivo VMAT2 binding to 18 F-FP-(+)-DTBZ are not altered by isoflurane and pentobarbital, but altered by chloral hydrate and ketamine. Isoflurane and pentobarbital may be promising anesthetic compounds for investigating in vivo VMAT2 binding. Further studies are warranted to investigate the interactions of anesthetics with VMAT2 binding potential with in vivo PET studies.

(68)Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: (68)Ga-1, using DOTA-monoamide as the chelating agent; (68)Ga-2, containing the macrocyclic chelating agent p-SCN-Bn-NOTA; and (68)Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). (68)Ga-2 demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to (68)Ga-1 at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. (68)Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation (68)Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging.