HDAC6 inhibitors sensitize resistant t(11;14) multiple myeloma cells to a combination of bortezomib and BH3 mimetics.

Not available.

[18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

Effects of chronic voluntary alcohol consumption on PDE10A availability: a longitudinal behavioral and [18F]JNJ42259152 PET study in rats.

PURPOSE: Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in dopamine-receptive striatal medium spiny neurons, which are involved in psychiatric disorders such as alcohol use disorders (AUD). Although preclinical studies suggest a correlation of PDE10A mRNA expression in neuronal and behavioral responses to alcohol intake, little is known about the effects of alcohol exposure on in vivo PDE10A activity in relation to apparent risk factors for AUD such as decision-making and anxiety. METHODS: We performed a longitudinal [18F]JNJ42259152 microPET study to evaluate PDE10A changes over a 9-week intermittent access to alcohol model, including 6 weeks of alcohol exposure, 2 weeks of abstinence followed by 1 week relapse. Parametric PDE10A-binding potential (BPND) images were generated using a Logan reference tissue model with cerebellum as reference region and were analyzed using both a volume-of-interest and voxel-based approach. Moreover, individual decision-making and anxiety levels were assessed with the rat Iowa Gambling Task and open-field test over the IAE model. RESULTS: We observed an increased alcohol preference especially in those animals that exhibited poor initial decision-making. The first 2 weeks of alcohol exposure resulted in an increased striatal PDE10A binding (> 10%). Comparing PDE10A-binding potential after 2 versus 4 weeks of exposure showed a significant decreased PDE10A in the caudate-putamen and nucleus accumbens (pFWE-corrected < 0.05). This striatal PDE10A decrease was related to alcohol consumption and preference. Normalization of striatal PDE10A to initial levels was observed after 1 week of relapse, apart from the globus pallidus. CONCLUSION: This study shows that chronic voluntary alcohol consumption induces a reversible increased PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. Thus, PDE10A-mediated signaling plays an important role in modulating the reinforcing effects of alcohol, and the data suggest that PDE10A inhibition may have beneficial behavioral effects on alcohol intake.

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin.

PURPOSE: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. METHODS: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. RESULTS: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 µSv/MBq, with highest absorbed doses for liver (16.9 µGy/MBq), heart wall (15.9 µGy/MBq) and small intestine (15.8 µGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 µSv/MBq with the highest absorbed doses for the gallbladder (26.5 µGy/MBq), small intestine (20.4 µGy/MBq) and liver (19.6 µGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. CONCLUSION: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. TRIAL REGISTRATION: EudraCT number 2020-002129-27. CLINICALTRIALS: gov NCT05224115 (retrospectively registered).

Synthetic Pept-Ins as a Generic Amyloid-Like Aggregation-Based Platform for In Vivo PET Imaging of Intracellular Targets.

Amyloid-like aggregation of proteins is induced by short amyloidogenic sequence segments within a specific protein sequence resulting in self-assembly into ß-sheets. We recently validated a technology platform in which synthetic amyloid peptides ("Pept-ins") containing a specific aggregation-prone region (APR) are used to induce specific functional knockdown of the target protein from which the APR was derived, including bacterial, viral, and mammalian cell proteins. In this work, we investigated if Pept-ins can be used as vector probes for in vivo Positron Emission Tomography (PET) imaging of intracellular targets. The radiolabeled Pept-ins [68Ga]Ga-NODAGA-PEG4-vascin (targeting VEGFR2) and [68Ga]Ga-NODAGA-PEG2-P2 (targeting E. coli) were evaluated as PET probes. The Pept-in based radiotracers were cross-validated in a murine tumor and muscle infection model, respectively, and were found to combine target specificity with favorable in vivo pharmacokinetics. When the amyloidogenicity of the interacting region of the peptide is suppressed by mutation, cellular uptake and in vivo accumulation are abolished, highlighting the importance of the specific design of synthetic Pept-ins. The ubiquity of target-specific amyloidogenic sequence segments in natural proteins, the straightforward sequence-based design of the Pept-in probes, and their spontaneous internalization by cells suggest that Pept-ins may constitute a generic platform for in vivo PET imaging of intracellular targets.

Clinical validation of the novel HDAC6 radiotracer [18F]EKZ-001 in the human brain.

PURPOSE: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [18F]EKZ-001 ([18F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects. METHODS: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (VT) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. VT differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches. RESULTS: The effective dose was 39.1 ± 7.0 µSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA VT were in agreement with 2TCM VT, however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional VT values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher VT than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported. CONCLUSION: [18F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain.

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

Binding of [18F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients.

PURPOSE: In vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP). METHODS: We conducted an in vitro [18F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Alzheimer's disease (AD), and one Pick's disease (PiD)). Binding was compared with two controls without neurodegeneration, two typical AD, one corticobasal syndrome with underlying AD, and one frontotemporal dementia behavioral variant with FTLD-TDP. The effect of blocking with the authentic reference material and with the MAO-B inhibitor deprenyl was assessed. Immunohistochemistry was performed on adjacent cryosections. RESULTS: Absence of specific [18F]AV1451 binding was observed for all three SV PPA FTLD-TDP cases. The absence of binding in controls as well as the successful blocking with authentic AV1451 in cases with tauopathy demonstrated specificity of the [18F]AV1451 signal for tau. The specific [18F]AV1451 binding was highest in AD, followed by PiD. This binding colocalized with the respective tau lesions and could not be blocked by deprenyl. Similar pilot findings were obtained with [18F]THK5351. CONCLUSION: In vitro autoradiography showed no [18F]AV1451 binding in SV PPA due to FTLD-TDP, while specific binding was present in SV PPA due to AD and PiD. The discrepancy between in vitro and in vivo findings remains to be explained. The discordance is not related to [18F]AV1451 idiosyncrasies as [18F]THK5351 findings were similar.

[18F]AlF-NOTA-octreotide PET imaging: biodistribution, dosimetry and first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour patients.

PURPOSE: The widespread use of gallium-68-labelled somatostatin analogue (SSA) PET, the current standard for somatostatin receptor (SSTR) imaging, is limited by practical and economic challenges that could be overcome by a fluorine-18-labelled alternative, such as the recently introduced [18F]AlF-NOTA-octreotide ([18F]AlF-OC). This prospective trial aimed to evaluate safety, dosimetry, biodistribution, pharmacokinetics and lesion targeting of [18F]AlF-OC and perform the first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour (NET) patients. METHODS: Six healthy volunteers and six NET patients with a previous clinical [68Ga]Ga-DOTATATE PET were injected with an IV bolus of 4 MBq/kg [18F]AlF-OC. Healthy volunteers underwent serial whole-body PET scans from time of tracer injection up to 90 min post-injection, with an additional PET/CT at 150 and 300 min post-injection. In patients, a 45-min dynamic PET was acquired and three whole-body PET scans at 60, 90 and 180 min post-injection. Absorbed organ doses and effective doses were calculated using OLINDA/EXM. Normal organ uptake (SUVmean) and tumour lesion uptake (SUVmax and tumour-to-background ratio (TBR)) were measured. A lesion-by-lesion analysis was performed and the detection ratio (DR), defined as the fraction of detected lesions was determined for each tracer. RESULTS: [18F]AlF-OC administration was safe and well tolerated. The highest dose was received by the spleen (0.159 ± 0.062 mGy/MBq), followed by the urinary bladder wall (0.135 ± 0.046 mGy/mBq) and the kidneys (0.070 ± 0.018 mGy/MBq), in accordance with the expected SSTR-specific uptake in the spleen and renal excretion of the tracer. The effective dose was 22.4 ± 4.4 µSv/MBq. The physiologic uptake pattern of [18F]AlF-OC was comparable to [68Ga]Ga-DOTATATE. Mean tumour SUVmax was lower for [18F]AlF-OC (12.3 ± 6.5 at 2 h post-injection vs. 18.3 ± 9.5; p = 0.03). However, no significant differences were found in TBR (9.8 ± 6.7 at 2 h post-injection vs. 13.6 ± 11.8; p = 0.35). DR was high and comparable for both tracers (86.0% for [68Ga]Ga-DOTATATE vs. 90.1% for [18F]AlF-OC at 2 h post-injection; p = 0.68). CONCLUSION: [18F]AlF-OC shows favourable kinetic and imaging characteristics in patients that warrant further head-to-head comparison to validate [18F]AlF-OC as a fluorine-18-labelled alternative for gallium-68-labelled SSA clinical PET. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03883776, EudraCT: 2018-002827-40.

Molecular imaging of norepinephrine transporter-expressing tumors: current status and future prospects.

The human norepinephrine transporter (hNET) is a transmembrane protein responsible for reuptake of norepinephrine in presynaptic sympathetic nerve terminals and adrenal chromaffin cells. Neural crest tumors, such as neuroblastoma, paraganglioma and pheochromocytoma often show high hNET expression. Molecular imaging of these tumors can be done using radiolabeled norepinephrine analogs that target hNET. Currently, the most commonly used radiopharmaceutical for hNET imaging is meta-[123I]iodobenzylguanidine ([123I]MIBG) and this has been the case since its development several decades ago. The γ-emitter, iodine-123 only allows for planar scintigraphy and single photon emission computed tomography imaging. These modalities typically have a poorer spatial resolution and lower sensitivity than positron emission tomography (PET). Additional practical disadvantages include the fact that a two-day imaging protocol is required and the need for thyroid blockade. Therefore, several PET alternatives for hNET imaging are actively being explored. This review gives an in-depth overview of the current status and recent developments in clinical trials leading to the next generation of clinical PET ligands for imaging of hNET-expressing tumors.

Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging.

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [18F]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [18F]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE-/- mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET/CT images and ex vivo data showed specific uptake of [18F]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the ß-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology.

[11C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson's disease and healthy volunteers.

PURPOSE: The P2X7 receptor (P2X7R) is an ATP-gated ion channel predominantly expressed on activated microglia and is important in neurodegenerative diseases including Parkinson's disease (PD). In this first-in-human study, we investigated [11C]JNJ54173717 ([11C]JNJ717), a selective P2X7R tracer, in healthy volunteers (HV) and PD patients. Biodistribution, dosimetry, kinetic modelling and short-term test-retest variation (TRV), as well as possible genotype effects, were investigated. METHODS: Biodistribution and radiation dosimetry studies were performed in three HV (mean age 30 ± 2 years, two women) using whole-body PET/CT. The most appropriate kinetic model was determined in 11 HV (mean age 62 ± 10 years, six women) and 10 PD patients (mean age 64 ± 8 years, three women; mean UPDRS motor score 21 ± 8) using 90-min dynamic simultaneous PET/MR scans. The total volume of distribution (VT) was calculated using a one-tissue and a two-tissue compartment model (1TCM, 2TCM) and Logan graphical analysis, and its time stability was assessed. Seven subjects underwent retest scans (mean age 60 ± 13 years, four HV, one woman). A group analysis was performed to compare PD patients and HV. Finally, 13 exons of P2X7R were genotyped in all subjects included in the second part of the study. RESULTS: The mean effective dose was 4.47 ± 0.32 µSv/MBq, with the highest absorbed doses to the gallbladder, liver and small intestine. A reversible 2TCM was the most appropriate kinetic model with relatively homogeneous VT values in the grey and white matter. Average VT values were 3.4 ± 0.8 in HV and 3.3 ± 0.7 in PD patients, with no significant difference between the groups, but a possible genotype effect (rs3751143) was identified which can affect VT. Average TRV was 10-15%. The stability of VT over time allowed a reduction in scan time to 70 min. CONCLUSION: [11C]JNJ717 is safe and suitable for quantifying P2X7R expression in human brain. In this pilot study, no significant differences in P2X7R binding were found between HV and PD patients. The results also suggest that genotype effects need to be incorporated in future P2X7R PET analyses.

Effects of alcohol exposure on the glutamatergic system: a combined longitudinal 18 F-FPEB and 1 H-MRS study in rats.

In a longitudinal rat model of alcohol consumption, we showed that exposure to alcohol decreased the concentration of glutamate in the prefrontal cortex, whereas a normalization occurred during abstinence. 18F-FPEB PET scans revealed that pre-exposure mGluR5 availability in the nucleus accumbens was associated with future alcohol preference. Finally, alcohol exposure induced a decrease in mGluR5 availability in the bilateral hippocampus and amygdala compared with baseline, and in the hippocampus and striatum compared with saccharin (Figure).

The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI-microangiography-histopathology in rats.

To better inform the next clinical trials of vascular disrupting agent combretastatin-A4-phosphate (CA4P) in patients with hepatic malignancies, this preclinical study aimed at evaluating CA4P therapeutic efficacy in rats with primary hepatocellular carcinomas (HCCs) of a full spectrum of differentiation and vascularity by magnetic resonance imaging (MRI), microangiography and histopathology. Ninety-six HCCs were raised in 25 rats by diethylnitrosamine gavage. Tumor growth was monitored by T2-/T1-weighted-MRI (T2WI, T1WI) using a 3.0 T scanner. Early vascular response and later intratumoral necrosis were detected by dynamic-contrast-enhanced (DCE) MRI and diffusion-weighted-imaging (DWI) before, 1 and 12 hr after CA4P iv-administration. In vivo MRI-findings were validated by postmortem-techniques. Multi-parametric MRI revealed rapid CA4P-induced tumor vascular shutdown within 1 hr, followed by variable intratumoral necrosis at 12 hr. Tumor volumes decreased by 10% at 1 hr (p < 0.05), but resumed at 12 hr. Correlations of semi-quantitative DCE parameter initial-area-under-the-gadolinium-curve (IAUGC30) with histopathology proved partial vascular closure and compensational reopening (p < 0.05). The higher grades of vascularity prevented those residual tumor tissues from CA4P-caused ischemic necrosis. By histopathology using a 4-scale cellular-differentiation criteria and a 4-grade tumor-vascularity classification, percentage of CA4P-induced necrosis negatively correlated with HCC differentiation (r = -0.404, p < 0.001) and tumor vascularity (r = -0.370, p < 0.001). Ordinal-logistic-regression helped to predict early tumor responses to CA4P in terms of tumoral differentiation and vascularity. Our study demonstrated that CA4P could induce vascular shutdown in primary HCCs within 1 hr, resulting in various degrees of tumor necrosis at 12 hr. MRI as a real-time imaging biomarker may help to define tumor vascularity and differentiation and further to predict CA4P therapeutic outcomes.

Distinct [18F]THK5351 binding patterns in primary progressive aphasia variants.

PURPOSE: To assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology. METHODS: The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction. RESULTS: Patients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results. CONCLUSION: [18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment.

Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study.

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18 F]fallypride and [18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect.

Pretargeted PET Imaging Using a Bioorthogonal 18F-Labeled trans-Cyclooctene in an Ovarian Carcinoma Model.

In cancer research, pretargeted positron emission tomography (PET) imaging has emerged as an effective two-step approach that combines the excellent target affinity and selectivity of antibodies with the advantages of using short-lived radionuclides such as fluorine-18. One possible approach is based on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between tetrazines and trans-cyclooctene (TCO) derivatives. Here, we report the first successful use of an 18F-labeled small TCO compound, [18F]1 recently developed in our laboratory, to perform pretargeted immuno-PET imaging. The study was performed in an ovarian carcinoma mouse model, using a trastuzumab-tetrazine conjugate.

cGMP production of the radiopharmaceutical [18 F]MK-6240 for PET imaging of human neurofibrillary tangles.

Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18 F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [18 F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FXFN . Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [18 F]fluoride (K[18 F]/K222 ) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170-250 mCi) of [18 F]MK-6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [18 F]fluoride) with a specific activity of 222 ± 67 GBq/µmol (6.0 ± 1.8 Ci/µmol) at the end of synthesis (90 minutes; n = 3). [18 F]MK-6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.

[18F]JNJ42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic AMP.

Phosphodiesterase 10A (PDE10A) is a key regulator of medium spiny neuron excitability. Therefore, it plays an important role in the regulation of motor, reward, and cognitive processes. Despite the interest in PDE10A as a drug and positron emission tomography (PET) imaging target, little is known about the regulation of PDE10A enzymatic activity. This study aimed to further investigate the role of cAMP in the regulation of PDE10A activity and PDE10A PET imaging. Using [18 F]JNJ42259152 as radioligand, we investigated alterations in PDE10A binding secondary to changes in cAMP levels. An in vitro striatum homogenate binding assay was developed to determine KD and Bmax of [18 F]JNJ42259152. Homogenate binding was assessed after addition of increasing concentrations of exogenous cAMP (1, 10, and 100 µM). Rats were treated using JNJ49137530 and rolipram to induce in vivo alterations of cAMP. The effect of the induced cAMP alterations on PDE10A binding was assessed by comparing [18 F]JNJ42259152 microPET studies after treatment to microPET studies acquired at baseline conditions prior to treatment. In vitro binding affinity of [18 F]JNJ42259152 was higher in the presence of cAMP compared to baseline conditions (KD  = 3.17 ± 0.91 nM with 10 µM cAMP vs. KD  = 6.62 ± 0.7 nM at baseline). Inhibition of PDE4 using rolipram significantly increased [18 F]JNJ42259152 binding (BPND  = 2.61 ± 0.50 vs. 1.91 ± 0.36 at baseline). Administration of the PDE2 inhibitor JNJ49137530 significantly increased PDE10A binding potential (BPND  = 2.74 ± 0.22 vs. 2.05 ± 0.16 at baseline). Our data indicate an important role for cAMP in the regulation of PDE10A activity. Additionally, our data show a profound interaction between several PDEs in striatum.