11C-Labeling of acyclic retinoid peretinoin by rapid C-[11C]methylation to disclose novel brain permeability and central nervous system activities hidden in antitumor agent.

Recently, retinoid actions on the central nervous system (CNS) have attracted considerable attention from the perspectives of brain disease diagnosis and drug development. Firstly, we successfully synthesized [11C]peretinoin esters (methyl, ethyl, and benzyl) using a Pd(0)-mediated rapid C-[11C]methylation of the corresponding stannyl precursors without geometrical isomerization in 82%, 66%, and 57% radiochemical yields (RCYs). Subsequent hydrolysis of the 11C-labeled ester produced [11C]peretinoin in 13 ± 8% RCY (n = 3). After pharmaceutical formulation, the resulting [11C]benzyl ester and [11C]peretinoin had high radiochemical purity (>99% each) and molar activities of 144 and 118 ± 49 GBq µmol-1 at total synthesis times of 31 min and 40 ± 3 min, respectively. Rat brain PET imaging for the [11C]ester revealed a unique time-radioactivity curve, suggesting the participation of the acid [11C]peretinoin for the brain permeability. However, the curve of the [11C]peretinoin rose steadily after a shorter time lag to reach 1.4 standardized uptake value (SUV) at 60 min. These various phenomena between the ester and acid became more pronounced in the monkey brain (SUV of > 3.0 at 90 min). With the opportunity to identify high brain uptake of [11C]peretinoin, we discovered CNS activities of a drug candidate called peretinoin, such as the induction of a stem-cell to neuronal cell differentiation and the suppression of neuronal damages.

[11C]NCGG401, a novel PET ligand for imaging of colony stimulating factor 1 receptors.

Colony-stimulating factor 1 receptors (CSF1R) are expressed exclusively on microglia in the central nervous system. The receptors regulate immune responses by controlling the survival and activity of microglia and are intricately involved in the pathophysiology of Alzheimer's disease. In this study, we developed [11C]NCGG401, a positron emission tomography (PET) ligand, targeting for CSF1R as an imaging biomarker for microglial pathophysiology in Alzheimer's disease. NCGG401 showed a high potency to inhibit human CSF1R kinase activity and a high binding affinity to human CSF1R. PET imaging with [11C]NCGG401 in healthy rats showed a good brain permeability. Furthermore, the specific binding component was determined by postmortem autoradiography in rat brain and human hippocampal sections. The knowledge of the characteristics of [11C]NCCC401, our initial CSF1R compound, we have obtained may be useful for further development and optimization of CSF1R radioligands for PET imaging of microglia.

A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7.

PURPOSE: Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains. METHODS: Seven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. RESULTS: PET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET. CONCLUSION: We have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.

Transient and chronic seizure-induced inflammation in human focal epilepsy.

In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.

Positron Emission Tomography.

Positron emission tomography (PET) is a minimally invasive imaging procedure with a wide range of clinical and research applications. PET allows for the three-dimensional mapping of administered positron-emitting radiopharmaceuticals such as (18)F-fluorodeoxyglucose (for imaging glucose metabolism). PET enables the study of biologic function in both health and disease, in contrast to magnetic resonance imaging (MRI) and computed tomography (CT), that are more suited to study a body's morphologic changes, although functional MRI can also be used to study certain brain functions by measuring blood flow changes during task performance. This chapter first provides an overview of the basic physics principles and instrumentation behind PET methodology, with an introduction to the merits of merging functional PET imaging with anatomic CT or MRI imaging. We then focus on clinical neurologic disorders, and reference research on relevant PET radiopharmaceuticals when applicable. We then provide an overview of PET scan interpretation and findings in several specific neurologic disorders such as dementias, epilepsy, movement disorders, infection, cerebrovascular disorders, and brain tumors.

[(11)C]TASP457, a novel PET ligand for histamine H3 receptors in human brain.

PURPOSE: The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [(11)C]TASP0410457 ([(11)C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain. METHODS: Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [(11)C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme. RESULTS: [(11)C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 - 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm(3) in the pallidum, 9 - 14 in the basal ganglia, 6 - 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [(11)C]TASP457 was 6.9 µSv/MBq. CONCLUSION: [(11)C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.

Clinical utility of 18F-FDG positron emission tomography in malignant peritoneal mesothelioma.

BACKGROUND: The purpose of this study was to determine the utility of 18F-FDG-PET for evaluating the presence and the extent of malignant peritoneal mesothelioma (MPM), for disease surveillance/recurrence detection and for evaluating response to therapy. METHODS: We retrospectively analyzed clinical and imaging data of 60 MPM patients (34 women and 26 men, mean age 53.6 y, range 18-80 y) who had multiple 18F-FDG-PET/CT or PET scans (18F-FDG scans) at various stages of the disease. RESULTS: Eleven patients had baseline pretreatment scans and all 11 scans showed 18F-FDG avid diffuse, nodular or mixed disease distribution patterns characteristic of MPM. Four patients out of eleven had an early post-treatment 18F-FDG scan (<6 months) and all scans were accurate in determining response to treatment. Forty-nine patients with a history of treated MPM without baseline scans had multiple disease surveillance 18F-FDG scans. Their initial 18F-FDG scans had an accuracy of 82% and positive predictive value of 83% and negative predictive value of 80% for the detection of disease presence and disease-free state, respectively. For fifteen patients with a true negative 18F-FDG scan, a second follow-up scan accurately detected disease recurrence or absence of recurrence in all cases. Metastatic or remote nodal disease was more common in the biphasic histopathologic subtype group while pleural disease was predominantly seen in the epithelial MPM group. No relationship was found between the uptake pattern and the histopathologic subtype. CONCLUSION: 18F-FDG-PET is a valuable imaging modality in the pre-surgical evaluation and management of MPM and further prospective studies are warranted.

A case of immunogammaglobulin 4-related disease.

An 81-year-old woman with history of thyroiditis and a putative diagnosis of retroperitoneal fibrosis presented with abdominal pain, progressive shoulder pain, back pain, and lower extremity weakness. Abdominal and pelvic MRI revealed periaortic inflammation and a left renal mass, which were F-FDG avid on PET/CT. Renal biopsy was compatible with immunogammaglobulin 4 (IgG4)-related disease. Total spine MRI revealed postcontrast meningeal enhancement, correlating with FDG activity. Epidural biopsy showed chronic inflammation and scattered but not abnormal IgG4-positive cells, possibly related to posttreatment changes. This case exemplifies multiorgan involvement in IgG4-related disease.

Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia.

BACKGROUND AND PURPOSE: Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS: A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS: PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient's seizure focus as identified by ictal and interictal 18F-fluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS: PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci.

Vesicular monoamine transporter, type 2 (VMAT2) expression as it compares to insulin and pancreatic polypeptide in the head, body and tail of the human pancreas.

The vesicular monoamine transporter, type 2 (VMAT2) is responsible for sequestering monoamine neurotransmitters into exocytic vesicles in neurons, enterochromaffin-like cells of the stomach and cells arising from the common myeloid progenitor. VMAT2 is also present in the pancreas and is expressed by insulin producing ß cells, but not by glucagon or somatostatin expressing islet cells. Positron emission tomography (PET) targeting of VMAT2 is currently being evaluated as a non-invasive tool to measure ß cell mass (BCM) in living humans. In recent trials, PET measurements of VMAT2 in the pancreas overestimated BCM in type 1 diabetes (T1D) patients predicted to have little to no BCM by metabolic measures. Recently, tissue immunohistochemistry studies suggested that VMAT2 staining may also co-localize with pancreatic polypeptide (PP) staining cells in pancreas tissue, but these studies were not quantitative. In this report, we evaluated VMAT2 specificity for ß cells in sub-regions of the human pancreas using antibodies targeting VMAT2, insulin and PP by double-label immunofluorescence. Immunostaining for VMAT2 and insulin demonstrated 89 ± 8% overlap in the body and tail of the pancreas. However, 44 ± 12% and 53 ± 15% of VMAT2 cells co-stained with PP- and insulin-staining cells, respectively in the pancreatic head. Significant co-staining for VMAT2 and PP cells in the head of the pancreas may partly explain the apparent overestimation of BCM in T1D by PET. Specific targeting of the pancreatic body and tail using VMAT2 PET scanning may reflect BCM more accurately.

PET [11C]DASB imaging of serotonin transporters in patients with alcoholism.

OBJECTIVE: Alcoholism and aggression have each been associated with neurochemical measurements suggestive of decreased serotonin synaptic transmission. We measured densities of the serotonin transporter (SERT) in a moderate-sized sample of alcoholic patients who were assessed for aggressive characteristics. METHODS: Thirty alcoholic inpatients and 18 healthy controls received a PET scan with [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile. The alcoholic inpatients were classified as aggressive or nonaggressive based on a comparison between the top third and bottom third scores on the Buss-Durkee Hostility Index. RESULTS: Using a pixel-wise comparison, no brain region showed significant alterations in SERT binding among the 3 groups of subjects (aggressive alcoholic subjects, nonaggressive alcoholic subjects, and healthy controls) or between the combined alcoholic group and healthy controls. None of the clinical measures (including measures of aggression) correlated with SERT binding in the alcoholic subjects. CONCLUSION: Contrary to prior imaging reports using the nonselective ligand [(123)I]beta-CIT, we found no significant alterations of SERT density in alcoholic patients.

Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease.

The derivation of dopamine neurons is one of the best examples of the clinical potential of embryonic stem (ES) cells, but the long-term function of the grafted neurons has not been established. Here, we show that, after transplantation into an animal model, neurons derived from mouse ES cells survived for over 32 weeks, maintained midbrain markers, and had sustained behavioral effects. Microdialysis in grafted animals showed that dopamine (DA) release was induced by depolarization and pharmacological stimulants. Positron emission tomography measured the expression of presynaptic dopamine transporters in the graft and also showed that the number of postsynaptic DA D(2) receptors was normalized in the host striatum. These data suggest that ES cell-derived neurons show DA release and reuptake and stimulate appropriate postsynaptic responses for long periods after implantation. This work supports continued interest in ES cells as a source of functional DA neurons.

Biodistribution and radiation dosimetry of the serotonin transporter ligand 11C-DASB determined from human whole-body PET.

UNLABELLED: 11C-Labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) is a selective radioligand for the in vivo quantitation of serotonin transporters (SERTs) using PET. The goal of this study was to provide dosimetry estimates for 11C-DASB based on human whole-body PET. METHODS: Dynamic whole-body PET scans were acquired for 7 subjects after the injection of 669 +/- 97 MBq (18.1 +/- 2.6 mCi) of 11C-DASB. The acquisition for each subject was obtained at 14 time points for a total of 115 min after injection of the radioligand. Regions of interest were placed over compressed planar images of source organs that could be visually identified to generate time-activity curves. Radiation burden to the body was calculated from residence times of these source organs using the MIRDOSE3.1 program. RESULTS: The organs with high radiation burden included the lungs, urinary bladder wall, kidneys, gallbladder wall, heart wall, spleen, and liver. The activity peaked within 10 min after the injection of 11C-DASB for all these organs except two--the excretory organs gallbladder and urinary bladder wall, which had peak activities at 32 and 22 min, respectively. Monoexponential fitting of activity overlying the urinary bladder suggested that approximately 12% of activity was excreted via the urine. Simulations in which the urinary voiding interval was decreased from 4.8 to 0.6 h produced only modest effects on the dose to the urinary bladder wall. With a 2.4-h voiding interval, the calculated effective dose was 6.98 microGy/MBq (25.8 mrem/mCi). CONCLUSION: The estimated radiation burden of 11C-DASB is relatively modest and would allow multiple PET examinations of the same research subject per year.

Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease.

This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.