Talakad Lohith

Pathophysiologic Correlation Between 62Cu-ATSM and 18F-FDG in Lung Cancer

The purpose of this study was to delineate the differences in intratumoral uptake and tracer distribution of 62Cu-diacetyl-bis(N4-methylthiosemicarbazone) (62Cu-ATSM), a well-known hypoxic imaging tracer, and 18F-FDG in patients with lung cancer of pathohistologically different types. Methods: Eight patients with squamous cell carcinoma (SCC) and 5 with adenocarcinoma underwent 62Cu-ATSM and 18F-FDG PET within a 1-wk interval. For 62Cu-ATSM PET, 10-min static data acquisition was started at 10 min after a 370- to 740-MBq tracer injection. After image reconstruction, 62Cu-ATSM and 18F-FDG images were coregistered, and multiple small regions of interest were drawn on tumor lesions of the 2 images to obtain standardized uptake values (SUVs). The regression lines were determined between SUVs for 62Cu-ATSM and 18F-FDG in each tumor. The slope values were compared between SCC and adenocarcinoma to observe pathohistologic differences in intratumoral distribution of the tracers. Results: SUVs for 62Cu-ATSM were lower than those for 18F-FDG in both SCC and adenocarcinoma. SCC tumors showed high 62Cu-ATSM and low 18F-FDG uptakes in the peripheral region of tumors but low 62Cu-ATSM and high 18F-FDG uptakes toward the center (spatial mismatching). The relationship of SUVs for the 2 tracers was negatively correlated with a mean regression slope of −0.07 ± 0.05. On the other hand, adenocarcinoma tumors had a spatially similar distribution of 62Cu-ATSM and 18F-FDG, with positive regression slopes averaging 0.24 ± 0.13. The regression slopes for 62Cu-ATSM and 18F-FDG differed significantly between SCC and adenocarcinoma (P < 0.001). Conclusion: The intratumoral distribution patterns of 62Cu-ATSM and 18F-FDG were different between SCC and adenocarcinoma in lung cancers, indicating that intratumoral regions of high glucose metabolism and hypoxia could differ with the pathohistologic type of lung cancer. The identification of regional biologic characteristics in tumors such as hypoxia, energy metabolism, and proliferation could play a significant role in the clinical diagnosis and therapy planning for non–small cell lung cancer patients.

Brain and Whole-Body Imaging of Nociceptin/Orphanin FQ Peptide Receptor in Humans Using the PET Ligand 11C-NOP-1A

Nociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, 11C-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of 11C-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile. Methods: After intravenous injection of 11C-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (VT; a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichises bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose). Results: After 11C-NOP-1A injection, the peak concentration of radioactivity in brain was high (∼5–7 standardized uptake values), occurred early (∼10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent VT identifiability (∼1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional VT values (mL·cm−3) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. VT was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent radioligand, as supported by the fact that all plasma radiometabolites of 11C-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 VT values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. 11C-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 μSv/MBq), and the effective dose was 4.3 μSv/MBq. Conclusion: 11C-NOP-1A is a promising radioligand that reliably quantifies NOP receptors in human brain. The effective dose in humans is low and similar to that of other 11C-labeled radioligands, allowing multiple scans in 1 subject.

Discovery of 6-(Fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimers disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.

11C-ER176, a radioligand for 18-kDa translocator protein (TSPO), has adequate sensitivity to robustly image all three affinity genotypes in human brain

For PET imaging of 18-kDa translocator protein (TSPO), a biomarker of neuroinflammation, most second-generation radioligands are sensitive to the single nucleotide polymorphism rs6971; however, this is probably not the case for the prototypical agent 11C-PK11195 (11C-labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide), which has a relatively lower signal-to-noise ratio. We recently found that 11C-ER176 (11C-(R)-N-sec-butyl-4-(2-chlorophenyl)-N-methylquinazoline-2-carboxamide), a new analog of 11C-(R)-PK11195, showed little sensitivity to rs6971 when tested in vitro and had high specific binding in monkey brain. This study sought, first, to determine whether the sensitivity of 11C-ER176 in humans is similar to the low sensitivity measured in vitro and, second, to measure the nondisplaceable binding potential (BPND, or the ratio of specific-to-nondisplaceable uptake) of 11C-ER176 in human brain. Methods: Nine healthy volunteers—3 high-affinity binders (HABs), 3 mixed-affinity binders (MABs), and 3 low-affinity binders (LABs)—were studied with whole-body 11C-ER176 PET imaging. SUVs from 60 to 120 min after injection derived from each organ were compared between genotypes. Eight separate healthy volunteers—3 HABs, 3 MABs, and 2 LABs—underwent brain PET imaging. The 3 HABs underwent a repeated brain scan after TSPO blockade with XBD173 (N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenylpurin-9-yl)acetamide) to determine nondisplaceable distribution volume (VND) via Lassen occupancy plotting and thereby estimate BPND in brain. Results: Regional SUV averaged from 60 to 120 min after injection in brain and peripheral organs with high TSPO densities such as lung and spleen were greater in HABs than in LABs. On the basis of VND determined via the occupancy plot, the whole-brain BPND for LABs was estimated to be 1.4 ± 0.8, which was much lower than that for HABs (4.2 ± 1.3) but about the same as that for HABs with 11C-PBR28 ([methyl-11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine)) (∼1.2). Conclusion: Obvious in vivo sensitivity to rs6971 was observed in 11C-ER176 that had not been expected from in vitro studies, suggesting that the future development of any improved radioligand for TSPO should consider the possibility that in vitro properties will not be reflected in vivo. We also found that 11C-ER176 has adequately high BPND for all rs6971 genotypes. Thus, the new radioligand would likely have greater sensitivity in detecting abnormalities in patients.

Brain and Whole-Body Imaging in Rhesus Monkeys of 11C-NOP-1A, a Promising PET Radioligand for Nociceptin/Orphanin FQ Peptide Receptors

Our laboratory developed (S)-3-(2′-fluoro-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran]-1-yl)-2-(2-fluorobenzyl)-N-methylpropanamide (11C-NOP-1A), a new radioligand for the nociceptin/orphanin FQ peptide (NOP) receptor, with high affinity (Ki, 0.15 nM) and appropriate lipophilicity (measured logD, 3.4) for PET brain imaging. Here, we assessed the utility of 11C-NOP-1A for quantifying NOP receptors in the monkey brain and estimated the radiation safety profile of this radioligand based on its biodistribution in monkeys. Methods: Baseline and blocking PET scans were acquired from head to thigh for 3 rhesus monkeys for approximately 120 min after 11C-NOP-1A injection. These 6 PET scans were used to quantify NOP receptors in the brain and to estimate radiation exposure to organs of the body. In the blocked scans, a selective nonradioactive NOP receptor antagonist (SB-612111; 1 mg/kg intravenously) was administered before 11C-NOP-1A. In all scans, arterial blood was sampled to measure the parent radioligand 11C-NOP-1A. Distribution volume (VT; a measure of receptor density) was calculated with a compartment model using brain and arterial plasma data. Radiation-absorbed doses were calculated using the MIRD Committee scheme. Results: After 11C-NOP-1A injection, peak uptake of radioactivity in the brain had a high concentration (∼5 standardized uptake value), occurred early (∼12 min), and thereafter washed out quickly. VT (mL · cm−3) was highest in the neocortex (∼20) and lowest in hypothalamus and cerebellum (∼13). SB-612111 blocked approximately 50%–70% of uptake and reduced VT in all brain regions to approximately 7 mL · cm−3. Distribution was well identified within 60 min of injection and stable for the remaining 60 min, consistent with only parent radioligand and not radiometabolites entering the brain. Whole-body scans confirmed that the brain had specific (i.e., displaceable) binding but could not detect specific binding in peripheral organs. The effective dose for humans estimated from the baseline scans in monkeys was 5.0 μSv/MBq. Conclusion: 11C-NOP-1A is a useful radioligand for quantifying NOP receptors in the monkey brain, and its radiation dose is similar to that of other 11C-labeled ligands for neuroreceptors. 11C-NOP-1A appears to be a promising candidate for measuring NOP receptors in the human brain.

Development of microwave-based automated nucleophilic [18F]fluorination system and its application to the production of [18F]flumazenil

INTRODUCTION This study presents the development of an automated radiosynthesis system integrating a microwave reactor and its subsequent application in the synthesis of [(18)F]flumazenil, a potentially useful compound in the evaluation of central benzodiazepine receptor density. METHODS Preparation of dry [K/K(222)](+18)F(-) complex and radiofluorination of the nitro-flumazenil precursor were achieved using the developed microwave-based radiosynthesis system. The crude product was prepurified in a C18 cartridge followed by reversed-phase preparative high-performance liquid chromatography. The isolated [(18)F]flumazenil was evaporated in vacuo and reconstituted in an ethanol-free solution. RESULTS Optimum incorporation of (18)F(-) in the nitro-precursor was achieved in 5 min time utilizing 2 mg of precursor in N,N-dimethylformamide reacted at 160 degrees C which gave an incorporation yield of 40+/-5%. The radiochemical yield obtained at the end of synthesis was 26+/-4% (EOB) with a radiochemical purity of >99% and a total synthesis time of about 55-60 min. The produced [(18)F]flumazenil was observed to be stable for at least 8 h. CONCLUSION The developed [(18)F]flumazenil radiosynthesis system offers shorter reaction time, simplicity in operation and applicability for use in routine clinical practice.

Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans.

[(11)C]NOP-1A is a novel high-affinity PET ligand for imaging nociceptin/orphanin FQ peptide (NOP) receptors. Here, we report reproducibility and reliability measures of binding parameter estimates for [(11)C]NOP-1A binding in the brain of healthy humans. After intravenous injection of [(11)C]NOP-1A, PET scans were conducted twice on eleven healthy volunteers on the same (10/11 subjects) or different (1/11 subjects) days. Subjects underwent serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (VT; a measure of receptor density) was determined by compartmental (one- and two-tissue) modeling in large regions and by simpler regression methods (graphical Logan and bilinear MA1) in both large regions and voxel data. Retest variability and intraclass correlation coefficient (ICC) of VT were determined as measures of reproducibility and reliability respectively. Regional [(11)C]NOP-1A uptake in the brain was high, with a peak radioactivity concentration of 4-7 SUV (standardized uptake value) and a rank order of putamen>cingulate cortex>cerebellum. Brain time-activity curves fitted well in 10 of 11 subjects by unconstrained two-tissue compartmental model. The retest variability of VT was moderately good across brain regions except cerebellum, and was similar across different modeling methods, averaging 12% for large regions and 14% for voxel-based methods. The retest reliability of VT was also moderately good in most brain regions, except thalamus and cerebellum, and was similar across different modeling methods averaging 0.46 for large regions and 0.48 for voxels having gray matter probability >20%. The lowest retest variability and highest retest reliability of VT were achieved by compartmental modeling for large regions, and by the parametric Logan method for voxel-based methods. Moderately good reproducibility and reliability measures of VT for [(11)C]NOP-1A make it a useful PET ligand for comparing NOP receptor binding between different subject groups or under different conditions in the same subject.

Improved models for plasma radiometabolite correction and their impact on kinetic quantification in PET studies.

The quantification of dynamic positron emission tomography studies performed with arterial sampling usually requires correcting the input function for the presence of radiometabolites by using a model of the plasma parent fraction (PPf). Here, we show how to include the duration of radioligand injection in the PPf model formulations to achieve a more physiologic description of the plasma measurements. This formulation (here called convoluted model) was tested on simulated data and on three datasets with different parent kinetics: [11C]NOP-1A, [11C]MePPEP, and [11C](R)-rolipram. Results showed that convoluted PPf models better described the fraction of unchanged parent in the plasma compared with standard models for all three datasets (weighted residuals sum of squares up to 25% lower). When considering the effect on tissue quantification, the overall impact on the total volume of distribution (VT) was low. However, the impact was significant and radioligand-dependent on the binding potential (BP) and the microparameters (K1, k2, k3, and k4). Simulated data confirmed that quantification is sensitive to different degrees to PPf model misspecification. Including the injection duration allows obtaining a more accurate correction of the input function for the presence of radiometabolites and this yields a more reliable quantification of the tissue parameters.

Basic Evaluation of FES-hERL PET Tracer-Reporter Gene System for In Vivo Monitoring of Adenoviral-Mediated Gene Therapy

PurposeThe purpose of the study is to evaluate the feasibility of human estrogen receptor α ligand binding domain (hERL) as a reporter gene in combination with positron emission tomography (PET) probe, 16α-[18F]fluoro-17β-estradiol (FES), in an adenovirus gene delivery system.MethodsAn adenoviral vector (test), carrying hERL gene and a model angiogenesis therapeutic gene (human thymidine phosphorylase, hTP) was constructed along with a control vector. In vitro radioligand binding and expression studies were performed on various cell lines. The control and test viruses were injected into contralateral adductor muscles of a rat followed by FES-PET imaging and immunohistochemical staining of resected muscle samples.ResultsA high FES uptake accompanied by hERL and hTP expression was obtained both in vitro and in vivo by the test adenovirus infection.ConclusionConsidering the versatile tissue permeability of the probe, highly efficient gene expression, and safeness for human use, we expect our reporter gene system to have favorable characteristics for clinical application.

Comparison of two PET radioligands, [11C]FPEB and [11C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain

Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake (BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume (VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.