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Longitudinal, non-invasive, in vivo monitoring of therapeutic gene expression is an unmet need for gene therapy (GT). Positron emission tomography (PET) radiotracers designed to bind to therapeutic proteins may provide a sensitive imaging platform to guide treatment response and dose optimization in GT. Herein, we evaluate a novel PET tracer ([ 18 F]AGAL) for targeting α-galactosidase A (GLA), an enzyme deficient in Fabry disease. Gla knockout mice were subjected to either GT with an adeno-associated virus encoding the human GLA (AAV GLA ) or recombinant GLA for enzyme replacement studies. PET imaging, ex vivo autoradiography, biochemical analyses and radiation dosimetry were performed. [ 18 F]AGAL exhibited pH-dependent binding to GLA, suggesting recognition of the active enzyme residing within the acidified lysosomes. Imaging studies in the Fabry mouse model showed quick renal clearance with high radioactive uptake in the heart at 6 weeks that was sustained for 26 weeks after a single administration of AAV GLA , indicating effective and durable transgene expression from GT. Good concordance was achieved between in vivo PET imaging and ex vivo quantification of GLA levels in biofluids and tissues. Biodistribution and dosimetry in non-human primate showed acceptable radiation exposure for multiple injections, demonstrating its potential for translation to clinical trial use., Competing Interests: Declaration of interests C.K., T.T., A.K., Y.P., P.S., L.C., W.R., S.M., S.N., M.D., R.I., S.Y., P.McQ., C.T.W., and T.G.L. were employees of Takeda Pharmaceutical Company Inc. and had ownership of Takeda stock during the execution of the reported studies. W.R. and R.I. are current employees of Crosswalk Therapeutics and may have stock ownership. M.D. is a current employee of Dyno Therapeutics and may have stock ownership. The study was funded by Takeda Pharmaceutical Company Inc. A US patent application titled “PET Trace Compounds and Reaction Intermediates, and Method of Use”; USPTO Application no. 63/502,761″ was submitted. C.C.C. and A.L.A. were employees of Invicro. S.H.A., A.P.B., L.M.C., and Q.-D.N. have declared that no competing interest exists., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [ 18 F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders., (© 2024. The Author(s).)

While automated modules for F-18 and C-11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi-preparative HPLC, labeling and processing of compounds with radiometals such as Zr-89, Lu-177 and Ac-225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F-18 or C-11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high-throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT-2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177 Lu-PSMA-617 and 225 Ac-PSMA-617 on the system. The OT-2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist., (© 2024 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

The overexpression of fibroblast activation protein-α (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative N -(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI). In this study, the diagnostic and therapeutic (theranostic) potential of N -(pyridine-4-carbonyl)-d-Ala-boroPro-based metal-chelating DOTA-FAPIs was evaluated. Methods: Three DOTA - FAPIs, PNT6555, PNT6952, and PNT6522, were synthesized and characterized with respect to potency and selectivity toward soluble and cell membrane FAP; cellular uptake of the Lu-chelated analogs; biodistribution and pharmacokinetics in mice xenografted with human embryonic kidney cell-derived tumors expressing mouse FAP; the diagnostic potential of 68 Ga-chelated DOTA-FAPIs by direct organ assay and small-animal PET; the antitumor activity of 177 Lu-, 225 Ac-, or 161 Tb-chelated analogs using human embryonic kidney cell-derived tumors expressing mouse FAP; and the tumor-selective delivery of 177 Lu-chelated DOTA-FAPIs via direct organ assay and SPECT. Results: DOTA-FAPIs and their nat Ga and nat Lu chelates exhibited potent inhibition of human and mouse sources of FAP and greatly reduced activity toward closely related prolyl endopeptidase and dipeptidyl peptidase 4. 68 Ga-PNT6555 and 68 Ga-PNT6952 showed rapid renal clearance and continuous accumulation in tumors, resulting in tumor-selective exposure at 60 min after administration. 177 Lu-PNT6555 was distinguished from 177 Lu-PNT6952 and 177 Lu-PNT6522 by significantly higher tumor accumulation over 168 h. In therapeutic studies, all 3 177 Lu-DOTA-FAPIs exhibited significant antitumor activity at well-tolerated doses, with 177 Lu-PNT6555 producing the greatest tumor growth delay and animal survival. 225 Ac-PNT6555 and 161 Tb-PNT6555 were similarly efficacious, producing 80% and 100% survival at optimal doses, respectively. Conclusion: PNT6555 has potential for clinical translation as a theranostic agent in FAP-positive cancer., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer [ 18 F]AGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. [ 18 F]AGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with IC 50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo [ 18 F]AGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.

Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15-20% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with 18 F-fluciclovine uptake on positron emission tomography imaging. While PSMA is regulated by AR, we identified a subset of AR-negative CRPC with high PSMA. HOXB13 and AR co-occupancy at the PSMA enhancer and knockout models point to HOXB13 as an upstream regulator of PSMA in AR-positive and AR-negative prostate cancer. These data demonstrate how PSMA expression is differentially regulated across metastatic lesions and in the context of the AR, which may inform selection for PSMA-targeted therapies and development of complementary biomarkers., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The serine/threonine kinase B-Raf is an essential regulator of cellular growth, differentiation, and survival. B-Raf protein expression is elevated throughout melanoma progression, making it an attractive target for noninvasive imaging using positron-emission tomography. Encorafenib is a potent and highly selective inhibitor of B-Raf used in the clinical management of melanoma. In this study, the radiosynthesis of a 11 C-isotopologue of encorafenib was developed using an in-loop [ 11 C]CO 2 fixation reaction. Optimization of reaction conditions reduced the formation of a radiolabeled side product and improved the isolated yields of [ 11 C]encorafenib (14.5 ± 2.4% radiochemical yield). The process was fully automated using a commercial radiosynthesizer for the production of 6845 ± 888 MBq of [ 11 C]encorafenib in high molar activity (177 ± 5 GBq μmol -1 ), in high radiochemical purity (99%), and in a formulation suitable for animal injection. An in vitro cellular binding experiment demonstrated saturable binding of the radiotracer to A375 melanoma cells., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Space travel will expose people to high-energy, heavy particle radiation, and the cognitive deficits induced by this exposure are not well understood. To investigate the short-term effects of space radiation, we irradiated 4-month-old Alzheimer's disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates with a single, whole-body dose of 10 or 50 cGy 56 Fe ions (1 GeV/u) at Brookhaven National Laboratory. At ~1.5 months post irradiation, behavioural testing showed sex-, genotype-, and dose-dependent changes in locomotor activity, contextual fear conditioning, grip strength, and motor learning, mainly in Tg but not WT mice. There was little change in general health, depression, or anxiety. Two months post irradiation, microPET imaging of the stable binding of a translocator protein ligand suggested no radiation-specific change in neuroinflammation, although initial uptake was reduced in female mice independently of cerebral blood flow. Biochemical and immunohistochemical analyses revealed that radiation reduced cerebral amyloid-β levels and microglia activation in female Tg mice, modestly increased microhemorrhages in 50 cGy irradiated male WT mice, and did not affect synaptic marker levels compared to sham controls. Taken together, we show specific short-term changes in neuropathology and behaviour induced by 56 Fe irradiation, possibly having implications for long-term space travel.

The ability of heart and skeletal muscle (SM) to switch between fat and carbohydrate oxidation is of high interest in the study of metabolic diseases and exercise physiology. Positron emission tomography (PET) imaging with the glucose analog 2-[ 18 F]fluoro-2-deoxy-glucose ( 18 F-FDG) provides a noninvasive means to quantitate glucose metabolic rates. However, evaluation of fatty acid oxidation (FAO) rates by PET has been limited by the lack of a suitable FAO probe. We have developed a metabolically trapped oleate analog, ( Z)-18-[ 18 F]fluoro-4-thia-octadec-9-enoate ( 18 F-FTO), and investigated the feasibility of using 18 F-FTO and 18 F-FDG to measure FAO and glucose uptake, respectively, in heart and SM of rats in vivo. To enhance the metabolic rates in SM, the vastus lateralis (VL) muscle was electrically stimulated in fasted rats for 30 min before and 30 min following radiotracer injection. The responses of radiotracer uptake patterns to pharmacological inhibition of FAO were assessed by pretreatment of the rats with the carnitine palmitoyl-transferase-1 (CPT-1) inhibitor sodium 2-[5-(4-chlorophenyl)-pentyl]oxirane-2-carboxylate (POCA). Small-animal PET images and biodistribution data with 18 F-FTO and 18 F-FDG demonstrated profound metabolic switching for energy provision in the myocardium from exogenous fatty acids to glucose in control and CPT-1-inhibited rats, respectively. Uptake of both radiotracers was low in unstimulated SM. In stimulated VL muscle, 18 F-FTO and 18 F-FDG uptakes were increased 4.4- and 28-fold, respectively, and CPT-1 inhibition only affected 18 F-FTO uptake (66% decrease). 18 F-FTO is a FAO-dependent PET probe that may allow assessment of energy substrate metabolic switching in conjunction with 18 F-FDG and other metabolic probes.

Objective: In MRI of patients with recurrent glioblastoma, bevacizumab-induced normalization of tumor vascularity can be difficult to differentiate from antitumor effects. The aim of this study was to assess the utility of 18 F-fluoroethyl-L-tyrosine (FET) PET in the evaluation of recurrent glioblastoma treated with bevacizumab., Subjects and Methods: MRI and FET PET were performed before and after administration of two doses of bevacizumab to 11 patients with recurrent glioblastoma. The ratio between normalized FET uptake at follow-up and baseline of the entire (volume of T2 FLAIR abnormality) and enhancing tumor were assessed for prediction of progression-free survival (PFS) and overall survival (OS). Voxel-wise Spearman correlation between normalized FET uptake and contrast-enhanced T1 signal intensity was assessed and tested as a predictor of PFS and OS., Results: Mean Spearman correlation between FET uptake and contrast-enhanced T1 signal intensity before therapy was 0.65 and after therapy was 0.61 (p = 0.256). The median PFS after initiation of bevacizumab therapy was 111 days, and the OS was 223 days. A post-treatment to pretreatment PET uptake ratio (mean and 90th percentile) greater than 0.7 for both entire and enhancing tumor was associated with lower PFS and OS (p < 0.001-0.049). The increase in correlation between PET uptake and contrast-enhanced T1 intensity after treatment was associated with lower PFS (p < 0.001) and OS (p = 0.049)., Conclusion: There is only a moderate correlation between FET PET uptake and contrast-enhanced T1 signal intensity. High posttreatment-to-pretreatment FET PET uptake ratio and increase in correlation between PET uptake and contrast-enhanced T1 signal intensity after bevacizumab treatment are associated with poor PFS and OS.

Background and Purpose: F-PBR06 and C-PBR28 are second-generation PET radioligands targeting the 18-kd translocator protein to assess microglial activation. We directly compared F-PBR06 and C-PBR28 for detecting brain translocator protein binding in multiple sclerosis (MS)., Methods: Six patients with MS (4 women; mean age ± SD, 32.1 ± 4.9 [range, 23.5-37.4 years]; Expanded Disability Status Scale score 2.3 ± 1.2 [range, 1.0-4.0]) underwent brain PET with both ligands, along with 3-T MRI. MRI was coregistered to the summed 60- to 90-minute PET images. SUV ratios (SUVRs), derived by normalization to global brain radioactivity, were obtained for whole-brain white matter (WM), supratentorial WM, normal-appearing WM (NAWM), and T2 (fluid-attenuated inversion recovery) hyperintense and T1 hypointense MS WM lesions. The highest mean SUVR for the fluid-attenuated inversion-recovery lesional slices was defined as SUVRmax., Results: F-PBR06 and C-PBR28 were moderately intercorrelated for whole-brain WM SUVR (r = 0.83, P = 0.04) and supratentorial WM SUVR (r = 0.81, P = 0.05) but not for SUVRs of NAWM, T1 lesions, T2 lesions, or SUVRmax. Both tracers demonstrated that SUVR was higher in NAWM than in T1 and T2 lesions (all P < 0.05). F-PBR06 (but not C-PBR28) demonstrated a higher SUVR in T1 versus T2 lesions (0.85 ± 0.07 vs 0.78 ± 0.03, P = 0.03). F-PBR06-derived (but not C-PBR28) SUVRmax correlated with both Expanded Disability Status Scale score (r = 0.82, P = 0.04) and timed 25-ft walking speed (r = 0.89, P = 0.01)., Conclusions: Our preliminary results suggest an association between microglial activation and physical disability in MS. Microglial detection in lesions was not interchangeable between the tracers, with a higher clinical relevance suggested for F-PBR06.

Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer (18)F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of (18)F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of (18)F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the (18)F-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of (18)F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice. (18)F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined (18)F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ∼90% was due to parent (18)F-GE180. In conclusion, (18)F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment., Significance Statement: Microglial activation, a player in Alzheimer's disease (AD) pathogenesis, is thought to reflect neuroinflammation. Using in vivo microPET imaging with a novel TSPO radioligand, (18)F-GE180, we detected significantly enhanced neuroinflammation during normal aging in WT mice and in response to AD-associated pathology in APP/PS1dE9 Tg mice, an AD mouse model. Increased uptake and specific binding of (18)F-GE180 in whole brain and hippocampus were confirmed by ex vivo PET and autoradiography. The binding specificity and stability of (18)F-GE180 was further confirmed by a cold tracer competition study and a metabolite study, respectively. Therefore, (18)F-GE180 PET imaging may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment and may also be useful for other neurodegenerative diseases., (Copyright © 2015 the authors 0270-6474/15/3515717-15$15.00/0.)

Rationale: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention., Objective: To explore (18)F-FLT positron emission tomography-computed tomography imaging of cell proliferation in atherosclerosis., Methods and Results: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed in atherosclerotic lesions, spleen, and bone marrow (standardized uptake values wild-type versus apolipoprotein E knock out mice, 0.05 ± 0.01 versus 0.17 ± 0.01, P<0.05 in aorta; 0.13 ± 0.01 versus 0.28 ± 0.02, P<0.05 in bone marrow; 0.06 ± 0.01 versus 0.22 ± 0.01, P<0.05 in spleen), corroborated by ex vivo scintillation counting and autoradiography. Flow cytometry confirmed significantly higher proliferation of macrophages in aortic lesions and hematopoietic stem and progenitor cells in the spleen and bone marrow in these mice. In addition, (18)F-FLT plaque signal correlated with the duration of high cholesterol diet (r(2)=0.33, P<0.05). Aortic (18)F-FLT uptake was reduced when cell proliferation was suppressed with fluorouracil in apolipoprotein E knock out mice (P<0.05). In rabbits, inflamed atherosclerotic vasculature with the highest (18)F-fluorodeoxyglucose uptake enriched (18)F-FLT. In patients with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta., Conclusions: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis., (© 2015 American Heart Association, Inc.)

In vivo imaging of regional fatty acid oxidation (FAO) rates would have considerable potential for evaluation of mammalian diseases. We have synthesized and evaluated 18F-labeled thia fatty acid analogues as metabolically trapped FAO probes to understand the effect of chain length, degree of unsaturation, and placement of the thia substituent on myocardial uptake and retention. 18-[18F]Fluoro-4-thia-(9Z)-octadec-9-enoic acid (3) showed excellent heart/background radioactivity concentration ratios along with highest retention in heart and liver. Pretreatment of rats with the CPT-1 inhibitor, POCA, caused >80% reduction in myocardial uptake of 16-[18F]fluoro-4-thiahexadecanoic acid (2) and 3, indicating high specificity for FAO. In contrast, 18-[18F]fluoro-4-thiaoctadecanoic acid (4) showed dramatically reduced myocardial uptake and blunted response to POCA. 18-[18F]Fluoro-6-thiaoctadecanoic acid (5) showed moderate myocardial uptake and no sensitivity of myocardial uptake to POCA. The results demonstrate relationships between structures of 18F-labeled thia fatty acid and uptake and their utility as FAO probes in various tissues.

Unlabelled: Microwave reactors remain largely underutilized in the field of positron emission tomography (PET) chemistry. This is particularly unfortunate since microwave synthesis elegantly addresses two of the most critical issues of PET radiochemistry with short-lived radionuclides: reaction rate and side-product formation. In this study, we investigate the efficiency of synthesis of terminally [(18)F]fluorinated fatty acid analogs using a commercial microwave reactor in comparison with conventional heating (CH)., Methods: The labeling precursors were methyl esters of terminally substituted alkyl bromides and iodides. Duration and temperatures of the [(18)F]fluorination reaction were varied. Chemical and radiochemical purities, and radiochemical yields were investigated for conventional (CH) and microwave-assisted (MW) radiosyntheses., Results: The results demonstrate that microwave heating enhanced [(18)F]fluoride incorporation to >95% (up to 55% improvement), while reducing reaction times to 2 min (∼ 10-fold reduction) or temperatures to 55-60 °C (20 °C reduction). Overall decay-corrected radiochemical yields of purified [(18)F]fluoro fatty acids were higher (MW = 49.0 ± 4.5%, CH = 23.6 ± 3.5%, P < .05) with microwave heating and side-products were notably fewer., Conclusion: For routine synthesis of [(18)F]fluoro fatty acid analogs, microwave heating is faster, milder, cleaner, less variable and higher yielding than CH and therefore the preferred reaction method., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Oxidative cyclization of 1,1'-binaphthyl (1) to perylene (2) can be achieved in essentially quantitative yield by the action of three or more equivalents of potassium metal in hot tetrahydrofuran. An overall reaction mechanism is proposed that accounts for all of the experimental observations reported by previous investigators and those from the present studies. The trans-6a,6b-dihydroperylene dianion (6(2-)) is believed to be the pivotal intermediate from which H(2) is lost. A radical chain reaction involving free hydrogen atoms (H(•)) in the two-step propagation cycle is proposed to explain the formation of H(2) from 6(2-). Anionic cyclodehydrogenations of this sort are complementary to those performed under strongly acidic/oxidizing conditions, photochemically, or thermally (flash vacuum pyrolysis), and a better understanding of how they occur, together with the optimized synthetic protocol reported here, should encourage their wider use in organic synthesis.

Unlabelled: Fatty acid oxidation (FAO) is a major energy-providing process with important implications in cardiovascular, oncologic, neurologic, and metabolic diseases. A novel 4-thia oleate analog, 18-(18)F-fluoro-4-thia-oleate ((18)F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-(18)F-fluoro-4-thia-palmitate ((18)F-FTP) as an FAO probe., Methods: (18)F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with (18)F-FTO and (18)F-FTP in rats., Results: A practical synthesis of (18)F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of (18)F-FTO (0.70 +/- 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of (18)F-FTP at 30 min after injection. At 2 h, myocardial uptake of (18)F-FTO was maintained, whereas (18)F-FTP uptake in the heart was 82% reduced. Similar to (18)F-FTP, (18)F-FTO uptake by the heart was approximately 80% reduced at 30 min by pretreatment of rats with the CPT-I inhibitor etomoxir. Folch-type extraction analyses showed 70-90% protein-bound fractions in the heart, liver, and skeletal muscle, consistent with efficient trafficking of (18)F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of (18)F-FTO and of (18)F-FTP into the heart and liver. Images of (18)F-FTO accumulation in the rat myocardium were clearly superior to those of (18)F-FTP., Conclusion: (18)F-FTO is shown to be a promising metabolically trapped FAO probe that warrants further evaluation.

The bubble point test is the de facto standard for postproduction filter membrane integrity test in the radiopharmaceutical community. However, the bubble point test depends on a subjective visual assessment of bubbling rate that can be obscured by significant diffusive gas flows below the manufacturer's prescribed bubble point. To provide a more objective means to assess filter membrane integrity, this study evaluates the pressure-hold test as an alternative to the bubble point test. In our application of the pressure-hold test, the nonsterile side of the sterilizing filter is pressurized to 85% of the predetermined bubble point with nitrogen, the filter system is closed off from the pressurizing gas and the pressure is monitored over a prescribed time interval. The drop in pressure, which has a known relationship with diffusive gas flow, is used as a quantitative measure of membrane integrity. Characterization of the gas flow vs. pressure relationship of each filter/solution combination provides an objective and quantitative means for defining a critical value of pressure drop over which the membrane is indicated to be nonintegral. The method is applied to sterilizing filter integrity testing associated with the commonly produced radiopharmaceuticals, [(18)F]FDG and [(11)C]PIB. The method is shown to be robust, practical and amenable to automation in radiopharmaceutical manufacturing environments (e.g., hot cells).

[structure: see text] The reduction of several annelated corannulene derivatives was undertaken using lithium and potassium metals. It was found that annelation affects the annulenic character of corannulene by changing its charge distribution; the dianions of derivatives that are annelated with six-membered rings have less annulenic character and are less paratropic than corannulene dianion. This effect is even more pronounced in corannulenes that are peri-annelated with five-membered rings. The alkali metal used in the reduction process has a great influence on the outcome, especially on the degree of reduction. Most derivatives get reduced to tetraanions only with potassium, and not with lithium, the exception being systems that can stabilize the tetraanion with lithium by special means, such as aggregation or dimerization. One such system is cyclopenta[bc]corannulene (acecorannulylene), which gives a coordinative dimer that consists of two cyclopentacorannulene tetraanions, bound together in a convex-convex fashion by lithium cations. The points of contact in this dimer are two rehybridized carbons from each cyclopentacorannulene unit, which are bridged together by two lithium cations.