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Background: Visual association memory test (VAMT) is a brief 6-point cognition test that has been shown to be effective in differentiating Alzheimer's disease (AD) from other types of dementia. This study aimed to investigate the correlation of the VAMT performance with amyloid plaque burden and hippocampal atrophy. Methods: Fourteen patients with AD, 29 with amnestic mild cognitive impairment (aMCI), and 11 normal cognition (NC) subjects were recruited. Brain magnetic resonance imaging (MRI) and [18F]AV-45 positron emission tomography (PET) were performed to evaluate hippocampal atrophy and amyloid plaque burden. Results: The VAMT median score and interquartile range of the NC, aMCI and AD groups were 6 (6-6), 2 (0–4), and 0 (0–1), respectively (p

Background The aim of this study is to investigate the associations between post-stroke cognitive impairment (PSCI) severity and reactive astrogliosis (RA) extent on normalized 18F-THK-5351 positron-emission tomography (PET) imaging in amyloid-negative patients with first-ever stroke. Methods We prospectively enrolled 63 amyloid-negative patients with first-ever stroke. Neurocognitive evaluation, MRI, 18F-THK-5351, and 18F-florbetapir PET were performed around 3 months after stroke. The 18F-THK-5351 uptake intensity was normalized using a signal distribution template to obtain the Z-SUM scores as the RA extent in the whole brain and cerebral hemisphere ipsilateral to stroke lesion. We evaluated stroke volume, leukoaraiosis, and brain atrophy on MRI. We used a comprehensive neurocognitive battery to obtain composite cognitive scores, and defined PSCI as a general cognitive function score < − 1. We analyzed the influence of Z-SUM scores on PSCI severity after adjusting for demographic, vascular, and neurodegenerative variables. Results Twenty-five of 63 stroke patients had PSCI. Patients with PSCI had older age, lower education, and more severe cortical atrophy and total Z-SUM scores. Total Z-SUM scores were significantly associated with general cognitive and executive functions at multiple regression models. Path analyses showed that stroke can exert cognitive influence directly by stroke itself as well as indirectly through RA, including total and ipsilateral Z-SUM scores, in patients with either right or left hemisphere stroke. Conclusion The patterns and intensity of 18F-THK-5351 uptake in amyloid-negative patients with first-ever stroke were associated with PSCI manifestations, which suggests that RA presents a modulating effect in PSCI development.

Background The 18F-THK-5351 radiotracer has been used to detect the in vivo tau protein distribution in patients with tauopathy, such as Alzheimer’s disease and corticobasal syndrome. In addition, 18F-THK-5351 can also monitor neuroinflammatory process due to high affinity to astrogliosis. We aimed to explore 18F-THK-5351 distribution patterns and characteristics in patients with recent ischemic stroke. Results Fifteen patients received 18F-THK-5351 positron emission tomography (PET) and diffusion tensor imaging (DTI) approximately 3 months after ischemic stroke. A region of interest (ROI) was placed in the peri-ischemic area and was mirrored on the contralateral side as the control, and a proportional value was derived from the ratio of the peri-ischemic ROI value over the mirrored ROI value. Increased 18F-THK-5351 retention was observed in the areas around and remote from the stroke location. The proportional 18F-THK-5351 values were negatively correlated with the proportional fractional anisotropy values (r = − 0.39, P = 0.04). Conclusion 18F-THK-5351 PET imaging provides a potential tool for in vivo visualization of the widespread ischemia-related changes associated with a microstructural disruption in recent ischemic stroke patients. Electronic supplementary material The online version of this article (10.1186/s13550-018-0417-1) contains supplementary material, which is available to authorized users.

Purpose: One of the promising radiosensitizers is the ultrasmall gold nanoparticle (GNP) with a hydrodynamic diameter vβ3) in the murine ALTS1C1 glioma cell line. Materials and methods: We investigated the uptake, toxicity and radiosensitivity of GNP–PEG–cRGDfKs in ALTS1C1 cells exposed to protons, kilovoltage photons and megavoltage photons. The in vitro uptake and toxicity of GNPs in the hepatocytes and Kupffer cells were assessed for murine AML12 hepatocyte and RAW 264.7 macrophage cell lines. The in vivo biodistribution of GNPs in the ALTS1C1 tumor model was tested using the inductively coupled plasma mass spectrometry. Results: Results indicated GNPs accumulated in the cytoplasm with negligible toxicity for a moderate concentration of GNPs. Observed sensitizer enhancement ratios and dose enhancement factors are 1.21–1.66 and 1.14–1.33, respectively, for all radiations. Conclusion: Ultrasmall GNP–PEG–cRGD can be considered as a radiosensitizer. For radiotherapy applications, the delivery method should be developed to increase the GNP uptake in the tumor and decrease the uptakes in undesirable organs.

Without conjunctive administration of an anticoagulant, endothelial injury-induced thrombosis is resistant to thrombolysis and prone to re-thrombosis. We hypothesized that co-delivery of recombinant tissue plasminogen activator (rtPA) with annexin V–containing anticoagulants that specifically target the injured endothelium may passivate the thrombogenic elements of the vascular injury site and enhance rtPA-induced thrombolysis. In this study, the effects of conjunctive administration of Kinexins (Kunitz inhibitor–annexin V fusion proteins) with rtPA on thrombolysis were determined in vitro and in vivo. Thromboelastometry showed that both TAP-A (tick anticoagulant peptide–annexin V fusion protein; an inhibitor of factor Xa [FXa] and prothrombinase) and A-6L15 (annexin V-6L15 fusion protein; an inhibitor of tissue factor/FVIIa) exerted concentration-dependent (10–100 nM) effects on clot formation, with TAP-A being several folds more potent than A-6L15 in whole blood. Combination of TAP-A or A-6L15 with rtPA (1 μg/mL) led to decrease in lysis index, suggesting conjunctive enhancement of thrombolysis by combined use of rtPA with TAP-A or A-6L15. In a rat cremaster muscle preparation subjected to photochemical injury, conjunctive administration of rtPA and TAP-A significantly restored tissue perfusion to 56%, which is approximately two fold of that by rtPA or TAP-A alone. Near-infrared fluorescence images demonstrated local retention of a fluorescent A-6L15-S288 at the injury site, suggesting a targeting effect of the fusion protein. Pharmacokinetic analysis showed that 123I-labelled TAP-A and A-6L15 had initial distribution half-lives (T1/2α) of approximately 6 minutes and elimination half-lives (T1/2β) of approximately 2.3 hours. In conclusion, Kinexins were potentially useful adjunctive agents with rtPA thrombolytic therapy especially for thrombosis induced by endothelial injury.

Nuclear reactions of high-energy protons with treatment equipment, air, and patient tissue during proton therapy generate residual radioactivity and secondary particles including protons, deuterons, alphas, and neutrons. The most up-to-date versions of INCL++ (v5.2.9), TALYS (v1.8), EMPIRE (v3.2.2 Malta), and ALICE/ASH were used in this study to calculate the excitation functions of proton-induced reactions with carbon, nitrogen, oxygen, aluminum, calcium, iron, nickel, copper, zinc, tin, tungsten, and lead nuclei. The cross sections of different nuclear reaction mechanisms, gamma particles, and residual radionuclides were calculated. The obtained results were compared with available experimental data and the ENDF/B-VII.1.

Lactacystin has been used to establish rodent models of Parkinson disease (PD), with cerebral α-synuclein inclusions. This study evaluated the uptake of [18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ), a vesicular monoamine transporter type 2 (VMAT2)-targeting radiotracer, through positron emission tomography (PET) in lactacystin-treated rat brains. Adult male Sprague–Dawley rats were randomly treated with a single intracranial dose of lactacystin (2 or 5 μg) or saline (served as the sham control) into the left medial forebrain bundle. A 30-min static [18F]FP-(+)-DTBZ brain PET scan was performed following an intravenous [18F]FP-(+)-DTBZ dose (approximately 22 MBq) in each animal at 2 and 3 weeks after lactacystin treatment. Upon completing the last PET scans, the animals were killed, and their brains were dissected for ex vivo autoradiography (ARG) and immunohistochemical (IHC) staining of tyrosine hydroxylase (TH) as well as VMAT2. Both the 2- and 5-μg lactacystin-treated groups exhibited significantly decreased specific [18F]FP-(+)-DTBZ uptake in the ipsilateral striata (I-ST) at 2 weeks (1.51 and 1.16, respectively) and 3 weeks (1.36 and 1.00, respectively) after lactacystin treatment, compared with the uptake in the corresponding contralateral striata (C-ST) (3.48 and 3.08 for the 2- and 5-μg lactacystin-treated groups, respectively, at 2 weeks; 3.36 and 3.11 for the 2- and 5-μg lactacystin-treated groups, respectively, at 3 weeks) and the sham controls (3.34–3.53). Lactacystin-induced decline in I-ST [18F]FP-(+)-DTBZ uptake was also demonstrated through ex vivo ARG, and the corresponding dopaminergic neuron damage was confirmed by the results of TH- and VMAT2-IHC studies. In this PD model, lactacystin-induced dopaminergic terminal damage in the ipsilateral striatum could be clearly visualized through in vivo [18F]FP-(+)-DTBZ PET imaging. This may serve as a useful approach for evaluating the effectiveness of new treatments for PD.

18F-THK-5351 is a novel radiotracer that demonstrates high binding selectivity and affinity for tau pathology and exhibits better pharmacokinetics in the living brain than previous THK tau probes. The aim of the present study was to estimate the radiation dose of 18F-THK-5351 in humans and to compare the clinical radiation dosimetry results to estimations published previously with preclinical data. Methods: Serial whole-body PET/CT imaging was performed for 240 min on 12 healthy volunteers after injecting 18F-THK-5351 (mean administered activity, 377.8 ± 14.0 MBq; range, 340-397 MBq). The bladder and gallbladder were delineated on PET images, and the other organs were delineated on CT images. Voided urine activity was recorded. The decay-corrected and normalized 18F-THK-5351 activity of 15 source-organ regions as a function of time was entered into the OLINDA/EXM software to calculate the effective dose for each subject following the medical internal radiation dosimetry schema. Results: Overall, the 18F-THK-5351 injection was well tolerated. The highest mean initial uptake at 10 min after injection was in the liver (11.4% ± 2.0%), lung (5.7% ± 2.1%), intestine (3.4% ± 0.8%), and kidney (1.4% ± 0.3%). The highest mean absorbed dose of radiation was in the gallbladder wall (242.2 ± 105.2 μGy/MBq), upper large intestine (90.0 ± 15.8 μGy/MBq), small intestine (79.5 ± 13.8 μGy/MBq), and liver (55.8 ± 6.1 μGy/MBq). The resultant whole-body effective dose was 22.7 ± 1.3 μSv/MBq. Conclusion: Our results suggest that a routine injection of 370 MBq of 18F-THK-5351 would lead to an estimated effective dose of 8.4 mSv; hence, 18F-THK-5351 has a radiation burden similar to that of other commonly used clinical tracers. Our findings in humans were compatible with recently published preclinical dosimetry data extrapolated from mice.

Additional file 9: Supplementary Table 8. Correlations of contralateral Z-SUM scores with cognitive performance in patients with left and right hemisphere stroke

Additional file 2: Supplementary Figure 1. The illustration of path analyses models. We used path analyses to evaluate whether Z-SUM scores of 18F-THK-5351 uptake intensity mediated the associations between stroke volume and cognitive performance. We selected cognitive functions showing significant correlations with both stroke volume and Z-sum scores as the endogenous variables. Further, we adjusted for age, education, and depressive symptoms (a) and anxiety (b) co-variables.

Additional file 14: Supplementary Table 12. Clinical characteristics of patients with hemorrhagic and ischemic stroke

Additional file 6: Supplementary Table 5. Associations of total Z-SUM scores of 18F-THK-5351 uptake intensity with cognitive function in model II

Additional file 8: Supplementary Table 7. Demographic data, imaging findings and cognitive results between patients with left and right hemisphere stroke

Additional file 7: Supplementary Table 6. Associations of total Z-SUM scores of 18F-THK-5351 uptake intensity with cognitive function in model III

Additional file 3: Supplementary Table 2. The comparisons of total Z-SUM scores between the presence and absence of vascular risk factors in stroke patients and healthy subjects

We investigated dual-phase (18)F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs).A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase (18)F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion (18)F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid (18)F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and (18)F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses.HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P 0.0001). (18)F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and (18)F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when (18)F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced MCI.Our results indicate that brain perfusion deficits and beta-amyloid deposition in AD follow different trajectories that can be successfully traced using dual-phase (18)F-AV-45 PET imaging.

Parkinson's disease (PD) is a profound neurodegenerative disorder with gradual loss of dopamine nigrostriatal neurons linked to serious behavioral symptoms. While the current treatment strategies present limitations on halting the progression of PD, this study aimed to investigate the therapeutic potential of honokiol, as a partial peroxisome proliferator-activated receptor-gamma (PPARγ) mimic, on the proceeding behavioral and biochemical alterations in hemiparkinsonian mice. Results showed that unilateral striatal 6-hydroxydopamine (6-OHDA)-lesioned mice exhibited motor impairment, reflecting the contralateral rotation induced by apomorphine at 1-3 weeks post-lesion. Subchronic honokiol administration for 1-2 weeks, beginning 7 days after 6-OHDA-lesion, dose-dependently ameliorated motor dysfunction in hemiparkinsonian mice. Recovery of motor function was correlated with reversal of nigrostriatal dopaminergic neuronal loss, accompanied by higher tyrosine hydroxylase (TH) density, dopamine transporter (DAT) expression and vesicular monoamine transporter-2 (VMAT2) levels. Furthermore, honokiol attenuated oxidative stress and reactive astrocyte induction via decreasing NADPH-oxidase and glial fibrillary acidic protein (GFAP) expressions in 6-OHDA-lesioned striatum. The reversal effects of honokiol on behavioral impairment and striatal PPARγ expression were impeded by PPARγ antagonist GW9662. Notably, subchronic honokiol treatment extended the lifespan of these hemiparkinsonian mice. The present findings demonstrate the therapeutic activities of honokiol in ameliorating motor impairment and progressive dopaminergic damage that could be associated with regulating PPARγ signaling. Therefore, honokiol may potentially exert as a novel therapeutic candidate through PPARγ activation for management of motor symptoms and progressive neurodegeneration in PD.

Successful oral delivery of therapeutic proteins such as insulin can greatly improve the quality of life of patients. This study develops a bubble carrier system by loading diethylene triamine pentaacetic acid (DTPA) dianhydride, a foaming agent (sodium bicarbonate; SBC), a surfactant (sodium dodecyl sulfate; SDS), and a protein drug (insulin) in an enteric-coated gelatin capsule. Following oral administration to diabetic rats, the intestinal fluid that has passed through the gelatin capsule saturates the mixture; concomitantly, DTPA dianhydride produces an acidic environment, while SBC decomposes to form CO2 bubbles at acidic pH. The gas bubbles grow among the surfactant molecules (SDS) owing to the expansion of the generated CO2. The walls of the CO2 bubbles consist of a self-assembled film of water that is in nanoscale and may serve as a colloidal carrier to transport insulin and DTPA. The grown gas bubbles continue to expand until they bump into the wall and burst, releasing their transported insulin, DTPA, and SDS into the mucosal layer. The released DTPA and SDS function as protease inhibitors to protect the insulin molecules as well as absorption enhancers to augment their epithelial permeability and eventual absorption into systemic circulation, exerting their hypoglycemic effects.

Table S1. The standardized uptake value ratios (SUVRs) of 18F-THK-5351 PET and diffusion tensor imaging parameters in the bilateral cerebral hemispheres. (DOCX 45Â kb)

Background Carotid artery stenosis (CAS) may induce cerebral hypoperfusion. Early-phase 18F-Florbetapir (AV-45/Amyvid, 18F-AV-45) positron emission tomography (PET) imaging can provide perfusion-like property (pAV-45) for the estimation of cerebral blood flow (CBF). Supra-tentorial lesions may cause decreased blood flow and metabolism in the contralateral cerebellum known as crossed cerebellar diaschisis (CCD). Objective The aim was to study the occurrence of CCD after CAS using pAV-45 PET. Methods Eleven healthy controls and 21 patients with unilateral CAS were studied. All subjects underwent 18F-AV-45 PET imaging and arterial spin labeling (ASL) CBF magnetic resonance perfusion imaging. The pAV-45 and ASL CBF values were first correlated. Then, cerebral and cerebellar hypoperfusion volume was analyzed. The cerebral and cerebellar perfusion asymmetry indices (AIs) were calculated from the pAV-45 standard uptake value ratios (SUVRs) of bilateral cerebral and cerebellar cortices, respectively. Results We found that pAV-45 SUVR was significantly correlated to ASL CBF (pl0.0001, r=0.5731). The AI of cerebellar perfusion was negatively correlated to that of cerebral perfusion (pl0.0001, r=-0.8751). Multiple linear regression showed the cerebral AI (pl0.0001) and hypoperfusion volume (p=0.02) but not the infarction severity and CAS degree significantly correlated to cerebellar AI. If the lower limit of 95% confidence interval of cerebellar AI in healthy controls was set as cut-off for positive CCD, the occurrence of CCD correlated to infarction severity in CAS patients (p=0.03). Conclusion Our results suggest pAV-45 is reliable to study CBF change. Under unilateral CAS, cerebral AI and hypoperfusion severity may determine the occurrence of CCD.

To use graphene oxide nanoribbons (GONRs) in combination with chemo-photothermal therapy, we modified GONRs with phospholipid-polyethylene glycol (PL-PEG) to prepare PEGylated GONRs (PL-PEG-GONRs), followed by investigation of the short-term in vivo biodistribution of 99m Tc-labeled PL-PEG-GONRs and their excretion in mice. The 99m Tc-labeled PL-PEG-GONRs demonstrated a unique biodistribution pattern of rapid accumulation in and excretion from the liver. Moreover, we determined that the PL-PEG-GNORs were excreted from the body through the renal route in urine, and we used hematological analysis to show that the PL-PEG-GNORs were not toxic in vivo . Furthermore, doxorubicin-loaded PL-PEG-GONRs had IC 50 values for chemo-photothermal therapy toward U87 glioma cells that were 6.7-fold lower than the IC 50 values in traditional chemotherapy. With these advantages, PL-PEG-GONRs could be used as drug nanocarriers to develop an efficient cancer-therapy strategy that would not only improve the efficacy of the therapy, but would also reduce the risk of side effects of the nanocarrier in the body.

The biodegradation of steroids is a crucial biochemical process mediated exclusively by bacteria. So far, information concerning the anoxic catabolic pathways of androgens is largely unknown, which has prevented many environmental investigations. In this work, we show that Sterolibacterium denitrificans DSMZ 13999 can anaerobically mineralize testosterone and some C 19 androgens. By using a 13 C-metabolomics approach and monitoring the sequential appearance of the intermediates, we demonstrated that S. denitrificans uses the 2,3- seco pathway to degrade testosterone under anoxic conditions. Furthermore, based on the identification of a C 17 intermediate, we propose that the A-ring cleavage may be followed by the removal of a C 2 side chain at C-5 of 17-hydroxy-1-oxo-2,3- seco -androstan-3-oic acid (the A-ring cleavage product) via retro-aldol reaction. The androgenic activities of the bacterial culture and the identified intermediates were assessed using the lacZ -based yeast androgen assay. The androgenic activity in the testosterone-grown S. denitrificans culture decreased significantly over time, indicating its ability to eliminate androgens. The A-ring cleavage intermediate (≤500 μM) did not exhibit androgenic activity, whereas the sterane-containing intermediates did. So far, only two androgen-degrading anaerobes ( Sterolibacterium denitrificans DSMZ 13999 [a betaproteobacterium] and Steroidobacter denitrificans DSMZ 18526 [a gammaproteobacterium]) have been isolated and characterized, and both of them use the 2,3- seco pathway to anaerobically degrade androgens. The key intermediate 2,3- seco -androstan-3-oic acid can be used as a signature intermediate for culture-independent environmental investigations of anaerobic degradation of C 19 androgens.

As is widely suspected, lysolipid dissociation from liposomes contributes to the intravenous instability of ThermoDox (lysolipid liposomes), thereby impeding its antitumor efficacy. This work evaluates the feasibility of a thermoresponsive bubble-generating liposomal system without lysolipids for tumor-specific chemotherapy. The key component in this liposomal formulation is its encapsulated ammonium bicarbonate (ABC), which is used to actively load doxorubicin (DOX) into liposomes and trigger a drug release when heated locally. Incubating ABC liposomes with whole blood results in a significantly smaller decrease in the retention of encapsulated DOX than that by lysolipid liposomes, indicating superior plasma stability. Biodistribution analysis results indicate that the ABC formulation circulates longer than its lysolipid counterpart. Following the injection of ABC liposome suspension into mice with tumors heated locally, decomposition of the ABC encapsulated in liposomes facilitates the immediate thermal activation of CO2 bubble generation, subsequently increasing the intratumoral DOX accumulation. Consequently, the antitumor efficacy of the ABC liposomes is superior to that of their lysolipid counterparts. Results of this study demonstrate that this thermoresponsive bubble-generating liposomal system is a highly promising carrier for tumor-specific chemotherapy, especially for local drug delivery mediated at hyperthermic temperatures.

(99m)Tc-TRODAT-1 is the first clinical routine (99m)Tc radiopharmaceutical to evaluate dopamine neurons loss in Parkinson's disease (PD). (18)F-AV-133 is a novel PET radiotracer targeting the vesicular monoamine transporter type 2 (VMAT2) to detect monoaminergic terminal reduction in PD patients. The aim of this study is to compare both images in the same health control (HC) and PD subjects.Eighteen subjects (8 HC and 10 PD) were recruited for (99m)Tc-TRODAT-1 SPECT, (18)F-AV-133 PET and MRI scans within two weeks. The SPECT images were performed at 4-h post-injection for 45 min, and the PET images were performed at 90 min post-injection for 10 min. Each PET and SPECT image was normalized into Montreal Neurological Institute template aided from individual MRI for comparison. For regional analysis, volume of interest (VOIs) of bilateral caudate nuclei, anterior, posterior putamen and occipital cortex (as reference region) were delineated from the normalized MRI. The specific uptake ratio (SUR) was calculated as (regional mean counts/reference mean counts-1). The nonparametric Mann-Whitney U test was used to evaluate the power of differentiating control from PD subjects for both image modalities. The correlations of the SURs to the clinical parameters were examined. For voxelwise analysis, two-sample t-test for group comparison between HC and PD was computed in both image modalities.The SURs of caudate nucleus and putamen correlated well between two image modalities (r = 0.81, p0.001), and showed significant different between HC and PD subjects. Of note, the (18)F-AV-133 SUR displayed a better correlation to PD clinical laterality index as compared to (99m)Tc-TRODAT-1 (r = 0.73 vs. r = 0.33). Voxelwise analysis showed more lesions for PD subjects from (18)F-AV-133 image as compared to (99m)Tc-TRODAT-1 especially at the substantia nigra region.(18)F-AV-133 PET demonstrated similar performance in differentiation PD from control, and a better correlation to clinical characteristics than that of (99m)Tc-TRODAT-1 SPECT. (18)F-AV-133 PET also showed additional information in substantia nigra integrity in PD subjects by voxelwise analysis. Collectively, (18)F-AV-133 could be a promising and better tracer for clinical use to detect monoaminergic terminal reduction in PD patients.

PET with 18F-9-fluoropropyl-(+)-dihydrotetrabenzazine (18F-DTBZ), a novel radiotracer targeting vesicular monoamine transporter type 2 (VMAT2), has been proven as a useful imaging marker to measure dopaminergic integrity. Methods: The aim of this study was to evaluate the capability of 18F-DTBZ PET in detecting the monoaminergic degeneration in early Parkinson disease (PD) in vivo. Seventeen age-matched healthy subjects and 30 PD patients at early stage of disease (duration of disease ≤ 5 y) with mild and unilateral motor symptoms underwent 18F-DTBZ PET scans. The severity of disease, including Unified Parkinson Disease Rating Scale and modified Hoehn and Yahr Stage (mHY), were recorded at off-medication states. The standardized volumes of interest were applied to the spatial normalized image for quantification analysis. The specific uptake ratios (SURs) were calculated according to the formula (specific volumes-of-interest counts/occipital cortex counts) − 1. SUR measurements were summarized for each brain region. Results: The mean duration of disease in the PD group was 3.2 ± 2.1 y (range, 0.5–5 y). The mean mHY was 1.0 ± 0.1 (range, 1–1.5). The SURs of bilateral caudate, anterior putamen, posterior putamen, substantia nigra, and nucleus accumbens were significantly lower in PD patients than those of healthy subjects. The reduction of SURs was most severe in the contralateral (the brain regions that are located opposite to the symptomatic side) posterior putamen (−81%), followed by the ipsilateral posterior putamen (−67%). Receiver-operating-characteristic curve analysis showed that the SURs of the bilateral posterior putamen and contralateral anterior putamen had a sensitivity of 100% and specificity of 100% in differentiating PD patients from healthy subjects. Conclusion:18F-DTBZ PET was as an excellent tool for the early diagnosis of PD. The obvious decline of 18F-DTBZ uptake in the ipsilateral (asymptomatic) striatum suggested that 18F-DTBZ PET might serve as an in vivo biomarker to detect the monoaminergic degeneration in the premotor phase of PD.

Low accumulation of chemotherapeutic agent in tumor tissue and multidrug resistance (MDR) present a major obstacle to curing cancer treatment. Therefore, how to combine several therapeutics in one system is a key issue to overcome the problem. Here, we demonstrate epidermal growth factor receptor (EGFR) antibody-conjugated PEGylated nanographene oxide (PEG-NGO) to carry epirubicin (EPI) for tumor targeting and triple-therapeutics (growth signal blocking, chemotherapy, photothermal therapy) in tumor treatment. This synergistic targeted treatment simultaneously enhances the local drug concentration (6.3-fold) and performs the ultra-efficient tumor suppression to significantly prolong the mice survival (over the course of 50 days).

Amyloid positron emission tomography (PET) is an important noninvasive method for detecting amyloid burden in Alzheimer's disease (AD) patients. As amyloid PET images have limited anatomical information, magnetic resonance (MR) imaging is usually acquired to perform reliable spatial normalization needed for large-scale analysis. This work proposed and evaluated the performance of new MR-free spatial normalization methods using a perfusion-like template for amyloid PET imaging.Amyloid PET and MR images were collected in 35 subjects (cohort 1: 8 AD patients and 6 controls; cohort 2: 15 AD patients and 6 controls). Three ligand-related templates (AD, control, mixed group) and a perfusion-like template (pAV-45) from early time frames of amyloid PET images were constructed from cohort 1. The variations of (18)F-AV-45 standardized uptake value ratios (SUVRs) among AD patients, controls, and all subjects were tested with repeated two-way (template × brain region) analysis of variance (ANOVA) in cohort 2. (18)F-AV-45 SUVRs by region of interest analysis and voxelwise analysis between MR-based and MR-free approaches were compared and correlated to clinical and image parameters. Effect size (group mean SUVR difference between AD and control/standard deviation) was also evaluated for each template method.Significantly different (18)F-AV-45 SUVRs between MR-free spatial normalization and MR-based reference images were found among AD patients, controls, and all subjects by the effect of template and brain regions. The highest correlation (r=0.991) of (18)F-AV-45 SUVR to MR-based reference was found in the pAV-45 group. The SUVR percentage difference to MR-based reference showed the least variation and bias (control: -1.31±3.47 %; AD: -0.36±2.50 %) in the pAV-45 group as well. The voxelwise analysis showed the smallest t statistic value in pAV-45 followed by mixed, control, and AD groups when compared to MR-based reference images. Moreover, an overall larger effect size but compatible to that of MR-based reference result was observed in the pAV-45 group as compared to those of the other MR-free template.The novel MR-free template based on the early-phase perfusion images pAV-45 approach for amyloid imaging showed significantly better performance in quantitation accuracy, effect size, and stability when compared with other MR-free PET templates and thus has potential for large-scale clinical applications.

Purpose: One of the promising radiosensitizers is the ultrasmall gold nanoparticle (GNP) with a hydrodynamic diameter vβ3) in the murine ALTS1C1 glioma cell line. Materials and methods: We investigated the uptake, toxicity and radiosensitivity of GNP-PEG-cRGDfKs in ALTS1C1 cells exposed to protons, kilovoltage photons and megavoltage photons. The in vitro uptake and toxicity of GNPs in the hepatocytes and Kupffer cells were assessed for murine AML12 hepatocyte and RAW 264.7 macrophage cell lines. The in vivo biodistribution of GNPs in the ALTS1C1 tumor model was tested using the inductively coupled plasma mass spectrometry. Results: Results indicated GNPs accumulated in the cytoplasm with negligible toxicity for a moderate concentration of GNPs. Observed sensitizer enhancement ratios and dose enhancement factors are 1.21-1.66 and 1.14-1.33, respectively, for all radiations. Conclusion: Ultrasmall GNP-PEG-cRGD can be considered as a radiosensitizer. For radiotherapy applications, the delivery method should be developed to increase the GNP uptake in the tumor and decrease the uptakes in undesirable organs.

18F-9-Fluoropropyl-(+)-dihydrotetrabenazine [18F-FP-(+)-DTBZ] positron emission tomography (PET) has been shown to detect dopaminergic neuron loss associated with Parkinson's disease (PD) in human and neurotoxin-induced animal models. A polyphenol compound, magnolol, was recently proposed as having a potentially restorative effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 6-hydroxydopamine-treated animal models. In this study, 18F-FP-(+)-DTBZ PET was used to determine the therapeutic efficacy of magnolol in an MPTP-PD mouse model that was prepared by giving an intraperitoneally (i.p.) daily dose of 25 mg/kg MPTP to male C57BL/6 mice for 5 consecutive days. Twenty-minute static 18F-FP-(+)-DTBZ PET scans were performed before MPTP treatment and 5 days after the termination of MPTP treatment to set up the baseline control. Half of the MPTP-treated mice then received a daily dose of magnolol (10 mg/kg dissolved in corn oil, i.p.) for 6 days. 18F-FP-(+)-DTBZ PET imaging was performed the day after the final treatment. All 18F-FP-(+)-DTBZ PET images were analysed and the specific uptake ratio (SUr) was calculated. Ex vivo autoradiography (ARG) and corresponding immunohistochemistry (IHC) studies were conducted to confirm the distribution of dopaminergic terminals in the striatum. The striatal SUr ratios of 18F-FP-(+)-DTBZ PET images for the Sham, the MPTP, and the MPTP + Magnolol-treated groups were 1.25 ± 0.05, 0.75 ± 0.06, and 1.00 ± 0.11, respectively (n = 4 for each group). The ex vivo 18F-FP-(+)-DTBZ ARG and IHC results correlated favourably with the PET imaging results. 18F-FP-(+)-DTBZ PET imaging suggested that magnolol post-treatment may reverse the neuronal damage in the MPTP-lesioned PD mice. In vivo imaging of the striatal vesicular monoamine transporter type 2 (VMAT2) distribution using 18F-FP-(+)-DTBZ animal PET is a useful method to evaluate the efficacy of therapeutic drugs i.e., magnolol, for the management of PD.

Animal studies have shown that cerebral hypoperfusion may be associated with amyloid plaque accumulation. Amyloid plaque is known to be associated with dementia and [(18)F]AV-45 is a positron emission tomography (PET) ligand that binds to extracelluar plaques. We hypothesized that demented patients with cerebral hypoperfusion may have increased [(18)F]AV-45 uptake. Five demented patients with cerebral hypoperfusion due to unilateral carotid artery stenosis (CAS) were examined with [(18)F]AV-45 PET, and the results were compared with six elderly controls. The standard uptake value ratio (SUVR) of each region of interest (ROI) was created using whole cerebellum as the reference region. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information. Patients with dementia and unilateral CAS had a higher global [(18)F]AV-45 SUVR (1.34 ± 0.06) as compared with controls (1.10 ± 0.04, p=0.0043), especially over the frontal, temporal, precuneus, anterior cingulate and occipital regions. The statistical distribution maps revealed a significantly increased [(18)F]AV-45 SUVR in the medial frontal, caudate, thalamus, posterior cingulate, occipital and middle and superior temporal regions ipsilateral to the side of CAS (p

[18F]AV-133 is a novel PET tracer for targeting the vesicular monoamine transporter 2 (VMAT2). The aim of this study is to characterize and quantify the loss of monoamine neurons with [18F]AV-133 in the MPTP-lesioned PD mouse model using animal PET imaging and ex vivo quantitative autoradiography (QARG). Methods: Optimal imaging time window of [18F]AV-133 was first determined in normal C57BL/6 mice (n = 3) with a 90-min dynamic scan. The reproducibility of [18F]AV-133 PET imaging was evaluated by performing a test–retest study within 1 week for the normal group (n = 6). For MPTP-lesioned studies, normal, and MPTP-treated [25 mg mg/kg once (Group A) and twice (Group B), respectively, daily for 5 days, i.p., groups of four normal and MPTP-treated] mice were used. PET imaging studies at baseline and at Day 4 post-MPTP injections were performed at the optimal time window after injection of 11.1 MBq [18F]AV-133. Specific uptake ratio (SUr) of [18F]AV-133 was calculated by [(target uptake–cerebellar uptake)/cerebellar uptake] with cerebellum as the reference region. Ex vitro QARG and immunohistochemistry (IHC) studies with tyrosine hydroxylase antibody were carried out to confirm the abundance of dopaminergic neurons. Results: The variability between [18F]AV-133 test–retest striatal SUr was 6.60 ± 3.61% with less than 5% standard deviation between animals (intervariability). The percentages of MPTP lesions were Group A 0.94 ± 0.29, −42.1% and Group B 0.65 ± 0.09, −60.4%. By QARG, specific binding of [18F]AV-133 was reduced relative to the control groups by 50.6% and 60.7% in striatum and by 30.6% and 46.4% in substantia nigra (Groups A and B, respectively). Relatively small [18F]AV-133 SUr decline was noted in the serotonin and norepinephrine-enriched regions (7.9% and 9.4% in mid-brain). Results obtained from IHC consistently confirmed the sensitivity and selectivity of dopaminergic neuron loss after MPTP treatment. Conclusions: [18F]AV-133 PET SUr displayed a high test–retest stability. The SUr significantly declined in the caudate putamen but not in the hypothalamus and midbrain regions after MPTP treatment in the mouse brain. The results obtained for QARG and IHC were consistent and correlated well with the PET imaging studies. On the basis of these concordant results, we find that [18F]AV-133 should serve as a useful and reliable PET tracer for evaluating nigrostriatal degeneration. Synapse 66:823–831, 2012. © 2012 Wiley Periodicals, Inc.

Complexing agents such as diethylene triamine pentaacetic acid (DTPA) are known to disrupt intestinal tight junctions and inhibit intestinal proteases by chelating divalent metal ions. This study attempts to incorporate these benefits of DTPA in functional nanoparticles (NPs) for oral insulin delivery. To maintain the complexing agent concentrated on the intestinal mucosal surface, where the paracellular permeation enhancement and enzyme inhibition are required, DTPA was covalently conjugated on poly(γ-glutamic acid) (γPGA). The functional NPs were prepared by mixing cationic chitosan (CS) with anionic γPGA-DTPA conjugate. The γPGA-DTPA conjugate inhibited the intestinal proteases substantially, and produced a transient and reversible enhancement of paracellular permeability. The prepared NPs were pH-responsive; with an increasing pH, CS/γPGA-DTPA NPs swelled gradually and disintegrated at a pH value above 7.0. Additionally, the biodistribution of insulin orally delivered by CS/γPGA-DTPA NPs in rats was examined by confocal microscopy and scintigraphy. Experimental results indicate that CS/γPGA-DTPA NPs can promote the insulin absorption throughout the entire small intestine; the absorbed insulin was clearly identified in the kidney and bladder. In addition to producing a prolonged reduction in blood glucose levels, the oral intake of the enteric-coated capsule containing CS/γPGA-DTPA NPs showed a maximum insulin concentration at 4 h after treatment. The relative oral bioavailability of insulin was approximately 20%. Results of this study demonstrate the potential role for the proposed formulation in delivering therapeutic proteins by oral route.

18 F-9-fluoropropyl-(+)-dihydrotetrabenazine ( 18 F-AV-133) is a novel positron emission tomography tracer for imaging the vesicular monoamine transporter II in dopaminergic neuron degeneration, which might be indicative for Parkinson's disease (PD) and other parkinsonism. Studies were performed to optimize the imaging time window for calculating standardized uptake value ratio (SUVR) with correlation to distribution volume ratio (DVR) and in differentiating PD from normal controls (NCs). Methods Thirteen 18 F-AV-133 positron emission tomography studies were conducted on four NCs (age, 62.3±4.9 years) and nine PD patients (age, 60.8±6.0 years) with Hoehn and Yahr stages 2 to 3. Dynamic images were acquired within 180 min (0–30, 50–140 and 160–180 min) and were rearranged into 14 of 10-min scans. The contralateral striatum was defined as the opposite striatum to the predominantly affected limbs. Volumes of interest (VOIs) of bilateral putamen, caudate nuclei and occipital cortex (OC; as the reference region) were delineated from individual magnetic resonance imaging. SUVRs of striatum to OC were computed from 14 dynamic image sets. The DVRs were computed from Logan graphic analysis by using OC as the input. The performance of SUVR was evaluated based on the correlation of SUVR at each time window to DVR, as well as the Cohen effect size (group mean SUVR difference between PD and NC/standard deviation). Results 18 F-AV-133 uptake decreased in PD subjects at bilateral striatum especially at contralateral side with posterior putamen predominant as compared with NC. Consistent higher correlations of SUVRs to DVR for all VOIs were observed at later time window and reached to its maximal value of 0.9917 at 90–100 min. The group mean SUVR differences between NC and PD subjects increased and reached relatively stable values after 90 min. The effect sizes for all VOIs were stable across different time window and with the largest value around 90~120 min. Conclusion The scanning time of 90–100 min for 18 F-AV-133 is considered as the optimal time window for summed uptake measurements in terms of SUVRs' correlation to DVRs, differential power, stability and clinical feasibility across and between NC and PD patients.

The vesicular monoamine transporter type II (VMAT2) is highly expressed in pancreatic β-cells and thus has been proposed to be a potential target for measuring β-cell mass (BCM) by molecular imaging. Several tracers based on the TBZ backbone, including 9-fluoropropyl-(+)-dihydrotetrabenazine ([ 18 F]AV-133), have shown some promising results as potential biomarkers for BCM despite a relatively high background signal in the pancreas. In the present study, we explore the background binding characteristics of [ 18 F]AV-133 in rat pancreas. Methods Pancreatic exocrine cells and islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum regions, were used for in vitro binding studies of [ 18 F]AV-133 under a selective masking condition. 1,3-Di- o -tolylguanidine (DTG), displaying high and roughly equal affinity for both sigma-1 and sigma-2 receptors, was chosen at 5 μM concentration for the masking/blocking studies. Results [ 18 F]AV-133 binding to rat striatum homogenates was not significantly altered by the presence of DTG. In contrast, [ 18 F]AV-133 showed significant competition with DTG for binding sites in rat pancreatic exocrine homogenates as well as in rat islet cell homogenates. Importantly, in the presence of DTG, [ 18 F]AV-133 showed a single high-affinity binding site on islet cell homogenates with a K d value of 3.8 nM which is consistent with the affinity reported previously for VMAT2 sites in rat pancreas. Conclusions [ 18 F]AV-133, in addition to a high-affinity VMAT2 binding site, binds with low affinity (but high capacity) to sigma components that are present in the rat pancreas. Identification of the cause of background binding of [ 18 F]AV-133 to rat pancreatic tissue may lead to improved methods for quantification.

Exendin-4 is a potent insulinotropic agent in diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. In this study, an orally available exendin-4 formulation, using an enteric-coated capsule containing pH-responsive NPs, was developed. Following oral administration of 123I-labeled-exendin-4 loaded NPs in rats, the biodistribution of the administered drug was investigated using a dual isotope dynamic SPECT/CT scanner. The results showed that the radioactivity of 123I-exendin-4 propagated from the esophagus, stomach, and small intestine and then was absorbed into the systemic circulation; with time progressing, 123I-exendin-4 was metabolized and excreted into the urinary bladder. In the in vivo dissolution study, it was found that the enteric-coated capsule remained intact while in the stomach; the capsule was completely dissolved in the proximal segment of the small intestine and the loaded contents were then released. Oral administration of the capsule containing exendin-4 loaded NPs showed a maximum plasma concentration at 5 h after treatment; the bioavailability, relative to its subcutaneous counterpart, was found to be 14.0 ± 1.8%. The absorbed exendin-4 could then stimulate the insulin secretion and provide a prolonged glucose-lowering effect. The aforementioned results suggest that the orally available exendin-4 formulation developed warrants further exploration as a potential therapy for diabetic patients.

to investigate the effects cannabidiol (CBD) on delayed-type hypersensitivity (DTH) reactions and antigen-induced T-cell cytokine expression.DTH was induced by subcutaneous ovalbumin (OVA) challenge to the footpads of mice sensitized with OVA. Inflammatory reactions were measured by footpad swelling and histological analysis. Antigen-induced cytokine expression by OVA-primed splenocytes was measured using ELISA and RT-PCR.CBD (1-10 mg/kg) administration, in a dose-dependent fashion, significantly attenuated inflammatory reactions associated with DTH in the footpads of mice sensitized and challenged with OVA. Histological examination revealed that CBD suppressed the infiltration of T cells and macrophages, and the expression of interferon (IFN)-γ and tumor necrosis factor-α, two pro-inflammatory cytokines implicated in DTH in the inflammatory site. In contrast, the expression of interleukin (IL)-10 in the footpads was enhanced by CBD administration. In addition, CBD at concentrations devoid of cytotoxic effects (1-4 micromol/L) attenuated OVA-induced IFN-γ production by OVA-primed splenocytes, whereas IL-4 was unaffected.CBD curbs DTH reactions via suppressing the infiltration and functional activity of T cells and macrophages in the inflammatory site, suggesting a therapeutic potential for CBD for the treatment of type IV hypersensitivity.

In this study, we report the biodistribution of aspart-insulin, a rapid-acting insulin analogue, following oral or subcutaneous (SC) administration to rats using the single-photon emission computed tomography (SPECT)/computed tomography (CT). Oral delivery of aspart-insulin was achieved using a pH-responsive nanoparticle (NP) system composed of chitosan (CS) and poly(gamma-glutamic acid). The results obtained in the SPECT/CT study indicate that the orally administered aspart-insulin was absorbed into the systemic circulation, while the drug carrier (CS) was mainly retained in the gastrointestinal tract.Via the SC route, the peak aspart-insulin concentration in the peripheral tissue/plasma was observed at 20 min after injection. Within 3 h, half of the initial dose (ID) of aspart-insulin was degraded and excreted into the urinary bladder. In contrast, via oral delivery, there was constantly circulating aspart-insulin in the peripheral tissue/plasma during the course of the study, while 20% of the ID of aspart-insulin was metabolized and excreted into the urinary bladder. In the pharmacodynamic (PD) and pharmacokinetic (PK) evaluation in a diabetic rat model, the orally administered aspart-insulin loaded NPs produced a slower hypoglycemic response for a prolonged period of time, whereas the SC injection of aspart-insulin produced a more pronounced hypoglycemic effect for a relatively shorter duration. Finally, comparison of the PD/PK profiles of the orally administered aspart-insulin with those of the SC injection of NPH-insulin, an intermediate-acting insulin preparation, suggests the suitability of our NP system to be used as a non-invasive alternative for the basal insulin therapy.

Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-(18)F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-FP-(+)-dihydrotetrabenazine [DTBZ] or (18)F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use.Nine healthy human subjects (mean age +/- SD, 58.6 +/- 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 +/- 22.9 MBq of (18)F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs.The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% +/- 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 +/- 23.8 microGy/MBq, was the pancreas. The effective dose equivalent and effective dose for (18)F-AV-133 were 36.5 +/- 2.8 and 27.8 +/- 2.5 microSv/MBq, respectively. These values are comparable to those reported for any other (18)F-labeled radiopharmaceutical.(18)F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.

Areca-nut chewing has been linked to oral cancer and many other diseases, in which immune deterioration and tissue inflammation are plausibly involved. Recent studies reported that areca-nut extract (ANE) affected the functionality of lymphocytes and neutrophils in vitro. In the present study, we investigated the immunomodulatory effect of ANE in vivo. Ovalbumin (OVA)-sensitized mice were daily administered with ANE (5-50 mg/kg) for 10 doses by intraperitoneal injection from days 1 to 5 and from 8 to 12. The mice were systemically sensitized with OVA on day 3, and their footpads were challenged with OVA to induce delayed-type hypersensitivity (DTH) reactions on day 13. The serum level of OVA-specific IgM and IgG(1) was significantly attenuated by 5 and 25 mg/kg of ANE, whereas OVA-specific IgG(2a) was markedly enhanced by 50 mg/kg of ANE. The production of interferon (IFN)-γ by splenocytes reexposed to OVA in culture was markedly augmented by ANE (25 and 50 mg/kg). In addition, ANE (25 and 50 mg/kg) demonstrated an enhancing effect on DTH reactions, including the tissue swelling, the infiltration of CD3(+) and F4/80(+) cells, and the expression of IFN-γ and tumor necrosis factor (TNF)-α in the footpads challenged with OVA. The phagocytic activity and TNF-α production by the splenic CD11b(+) cells were also enhanced in ANE-treated groups. Taken together, these results demonstrated that ANE modulated antigen-specific immune responses and promoted inflammatory reactions in vivo, which may contribute to immune deregulation associated with areca-related diseases.

The vesicular monoamine transporter type 2 (VMAT2) is highly expressed in pancreatic β-cells and thus has been proposed to be a potential target for measuring β-cell mass (BCM) by molecular imaging. C-11- and F-18-labeled tetrabenazine derivatives targeting VMAT2 have shown some promising results as potential biomarkers for BCM. In the present study, we examined the binding characteristics of 9-fluoropropyl-(+)-dihydrotetrabenzazine ([ 18 F]AV-133), a potential PET tracer for BCM imaging, in rat pancreas and rat brain. Methods Pancreatic exocrine cells and pancreatic islet cells were isolated and purified from Sprague-Dawley rats. Membrane homogenates, prepared from both pancreatic exocrine and islet cells as well as from brain striatum and hypothalamus regions, were used for in vitro binding studies. In vitro and ex vivo autoradiography studies with [ 18 F]AV-133 were performed on rat brain and rat pancreas sections. Immunohistochemistry studies were performed to confirm the distribution of VMAT2 on islet β-cells. Results Excellent binding affinities of [ 18 F]AV-133 were observed in rat striatum and hypothalamus homogenates with K d values of 0.19 and 0.25 nM, respectively. In contrast to single-site binding observed in rat striatum homogenates, rat islet cell homogenates showed two saturable binding sites (site A: K d =6.76 nM, B max =60 fmol/mg protein; site B: K d =241 nM, B max =1500 fmol/mg protein). Rat exocrine pancreas homogenates showed only a single low-affinity binding site ( K d =209 nM), which was similar to site B in islet cells. In vitro autoradiography of [ 18 F]AV-133 using frozen sections of rat pancreas showed specific labeling of islets, as evidenced by co-localization with anti-insulin antibody. Ex vivo VMAT2 pancreatic autoradiography in the rat, however, was not successful, in contrast to the excellent ex vivo autoradiography of VMAT2 binding sites in the brain. In vivo/ex vivo islet labeling may be complicated by the presence of the low-affinity/high-capacity site B binding in rat pancreas. Conclusions [ 18 F]AV-133 is an excellent imaging agent for mapping VMAT2 sites in rat brain and specifically binds rat islet cells in vitro and postmortem. Additional optimization may be required to achieve ex vivo islet β-cell labeling in rats.