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Oxime antidotes regenerate organophosphate‐inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [18F]‐VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [18F]‐VXS was evaluated after an LD50 dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [18F]‐VXS tracer alone had significantly higher radioactivity (two‐ to threefold) in the heart and lung than rats given LD50 POX at 20 or 60 min prior to [18F]‐VXS. When rats were given LD50 POX followed by 2‐PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI‐6 or MMB‐4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX‐treated rats. This new in vivo dynamic platform using [18F]‐VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats. [ABSTRACT FROM AUTHOR]

PURPOSE: Detection of bacteria‐specific metabolism via positron emission tomography (PET) is an emerging strategy to image human pathogens, with dramatic implications for clinical practice. In silico and in vitro screening tools have recently been applied to this problem, with several monosaccharides including l‐arabinose showing rapid accumulation in Escherichia coli and other organisms. Our goal for this study was to evaluate several synthetically viable arabinofuranose‐derived 18F analogs for their incorporation into pathogenic bacteria. PROCEDURES: We synthesized four radiolabeled arabinofuranose‐derived sugars: 2‐deoxy‐2‐[18F]fluoro‐arabinofuranoses (d‐2‐18F‐AF and l‐2‐18F‐AF) and 5‐deoxy‐5‐[18F]fluoro‐arabinofuranoses (d‐5‐18F‐AF and l‐5‐18F‐AF). The arabinofuranoses were synthesized from 18F‐ via triflated, peracetylated precursors analogous to the most common radiosynthesis of 2‐deoxy‐2‐[18F]fluoro‐d‐glucose ([18F]FDG). These radiotracers were screened for their uptake into E. coli and Staphylococcus aureus. Subsequently, the sensitivity of d‐2‐18F‐AF and l‐2‐18F‐AF to key human pathogens was investigated in vitro. RESULTS: All 18F radiotracer targets were synthesized in high radiochemical purity. In the screening study, d‐2‐18F‐AF and l‐2‐18F‐AF showed greater accumulation in E. coli than in S. aureus. When evaluated in a panel of pathologic microorganisms, both d‐2‐18F‐AF and l‐2‐18F‐AF demonstrated sensitivity to most gram‐positive and gram‐negative bacteria. CONCLUSIONS: Arabinofuranose‐derived 18F PET radiotracers can be synthesized with high radiochemical purity. Our study showed absence of bacterial accumulation for 5‐substitued analogs, a finding that may have mechanistic implications for related tracers. Both d‐2‐18F‐AF and l‐2‐18F‐AF showed sensitivity to most gram‐negative and gram‐positive organisms. Future in vivo studies will evaluate the diagnostic accuracy of these radiotracers in animal models of infection. [ABSTRACT FROM AUTHOR]

Purpose: Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice.Procedures: CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats.Results: [89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6 % (n = 5) and specific activities ranging from 74 to 185 MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97 %. [89Zr]DFO-CZP retained high immunoreactivity with more than 95 % of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP.Conclusion: The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA. [ABSTRACT FROM AUTHOR]

Radiolabeled 1-[11C]ethyl, 4-nitrophenyl methylphosphonate (VX surrogate) and 2-[11C]-propanyl, 4-nitrophenyl methylphosphonate (sarin surrogate) were developed as organophosphate (OP) tracers. The [11C]ethyl- and [11C]isopropyl-iodide radiolabeled synthons were obtained by temperature controlled, in loop reactions of [11C]CO 2 with MeMgBr followed by reduction with LiAlH 4 , then reaction with HI. Distillation of the [11C]alkyl iodides into a solution of hydrogen (4-nitrophenyl)methylphosphonate and cesium carbonate afforded the desired tracers in >95% radiochemical purity, yields from [11C]CO 2 of 1–3% and 1.7–15.1 GBq/mmol molar activities. • Loop preparation of [11C]Et–I and [11C]iPr-I from [11C]CO 2 and common reagents was developed. • Increase in Grignard temperature/time shifted the intermediate from [11C]EtI to [11C]iPrI. • [11C]alkyl iodide reaction with (4-NO 2 PhO) (Me)P(O)O–Cs+ affords VX and sarin OP surrogates. [ABSTRACT FROM AUTHOR]

O‐(1‐Fluoropropan‐2‐yl)‐O‐(4‐nitrophenyl) methylphosphonate is a reactive organophosphate ester (OP) developed as a surrogate of the chemical warfare agent sarin that forms a similar covalent adduct at the active site serine of acetylcholinesterase. The radiolabeled O‐(1‐[18F]fluoropropan‐2‐yl)‐O‐(4‐nitrophenyl) methylphosphonate ([18F] fluorosarin surrogate) has not been previously prepared. In this paper, we report the first radiosynthesis of this tracer from the reaction of bis‐(4‐nitrophenyl) methylphosphonate with 1‐[18F]fluoro‐2‐propanol in the presence of DBU. The 1‐[18F]fluoro‐2‐propanol was prepared by reaction of propylene sulfite with Kryptofix 2.2.2 and [18F] fluoride ion. The desired tracer O‐(1‐[18F]fluoropropan‐2‐yl)‐O‐(4‐nitrophenyl) methylphosphonate was obtained in a >98% radiochemical purity with a 2.4% ± 0.6% yield (n = 5, 65 minutes from start of synthesis) based on starting [18F] fluoride ion and a molar activity of 49.9 GBq/μmol (1.349 ± 0.329 Ci/μmol, n = 3). This new facile radiosynthesis routinely affords sufficient quantities of [18F] fluorosarin surrogate in high radiochemical purity, which will further enable the tracer development as a novel radiolabeled OP acetylcholinesterase inhibitor for assessment of OP modes of action with PET imaging in vivo. Synthesis of a fluorine‐18‐labeled PET tracer surrogate of sarin to evaluate the exposure mechanism and reactivation of acetylcholinesterase. [ABSTRACT FROM AUTHOR]

A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin–lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C]valine), significant increase of their T1 was observed at 3 T with deuterium labeling (+26%, 22%, +16%, +25% and +29%, respectively). Remarkably, in the case of [2-13C]alanine, [2-13C]serine and [2-13C]lactate, deuterium labeling led to a greater than four fold increase in T1. [1-13C,2-2H]alanine, produced using this method, was applied to in vitro enzyme assays with alanine aminotransferase, demonstrating a kinetic isotope effect. [ABSTRACT FROM AUTHOR]

[11C]Carfentanil ([11C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol. [ABSTRACT FROM AUTHOR]

O-(2-Fluoroethyl)-O-( p-nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl-serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[18F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [ 18 F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [ 18 F]1 tracer synthesis was slow even with microwave acceleration, required high-performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis-(O,O-p-nitrophenyl) methylphosphonate, 2, with 2-fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [ 18 F]1, was obtained in a non-decay-corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [ 18 F]1, which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo. [ABSTRACT FROM AUTHOR]

Purpose: Altered metabolism, including increased glycolysis and de novo lipogenesis, is one of the hallmarks of cancer. Radiolabeled nutrients, including glucose and acetate, are extensively used for the detection of various tumors, including hepatocellular carcinomas (HCCs). High signal of [(11)C]acetate positron emission tomography (PET) in tumors is often considered to be associated with increased expression of fatty acid synthase (FASN) and increased de novo lipogenesis in tumor tissues. Defining a subset of tumors with increased [(11)C]acetate PET signal and thus increased lipogenesis was suggested to help select a group of patients, who may benefit from lipogenesis-targeting therapies.Procedures: To investigate whether [(11)C]acetate PET imaging is truly associated with increased de novo lipogenesis along with hepatocarcinogenesis, we performed [(11)C]acetate PET imaging in wild-type mice as well as two mouse HCC models, induced by myrAKT/Ras(V12) (AKT/Ras) and PIK3CA(1047R)/c-Met (PI3K/Met) oncogene combinations. In addition, we analyzed FASN expression and de novo lipogenesis rate in these mouse liver tissues.Results: We found that while HCCs induced by AKT/Ras co-expression showed high levels of [(11)C]acetate PET signal compared to normal liver, HCCs induced by PI3K/Met overexpression did not. Intriguingly, elevated FASN expression and increased de novo lipogenesis rate were observed in both AKT/Ras and PI3K/Met HCCs.Conclusion: Altogether, our study suggests that [(11)C]acetate PET imaging can be a useful tool for imaging of a subset of HCCs. However, at molecular level, the increased [(11)C]acetate PET imaging is not always associated with increased FASN expression or de novo lipogenesis. [ABSTRACT FROM AUTHOR]

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized 13C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its 13C chemical shift within the physiologic range. [ABSTRACT FROM AUTHOR]

Synthesis of the acetylcholinesterase inhibitor paraoxon (POX) as a carbon-11 positron emission tomography tracer ([ 11 C]POX) and profiling in live rats is reported. Naïve rats intravenously injected with [ 11 C]POX showed a rapid decrease in parent tracer to ∼1%, with an increase in radiolabeled serum proteins to 87% and red blood cells (RBCs) to 9%. Protein and RBC leveled over 60 minutes, reflecting covalent modification of proteins by [ 11 C]POX. Ex vivo biodistribution and imaging profiles in naïve rats had the highest radioactivity levels in lung followed by heart and kidney, and brain and liver the lowest. Brain radioactivity levels were low but observed immediately after injection and persisted over the 60-minute experiment. This showed for the first time that even low POX exposures (∼200 ng tracer) can rapidly enter brain. Rats given an LD 50 dose of nonradioactive paraoxon at the LD 50 20 or 60 minutes prior to [ 11 C]POX tracer revealed that protein pools were blocked. Blood radioactivity at 20 minutes was markedly lower than naïve levels due to rapid protein modification by nonradioactive POX; however, by 60 minutes the blood radioactivity returned to near naïve levels. Live rat tissue imaging-derived radioactivity values were 10%-37% of naïve levels in nonradioactive POX pretreated rats at 20 minutes, but by 60 minutes the area under the curve (AUC) values had recovered to 25%-80% of naïve. The live rat imaging supported blockade by nonradioactive POX pretreatment at 20 minutes and recovery of proteins by 60 minutes. SIGNIFICANCE STATEMENT: Paraoxon (POX) is an organophosphorus (OP) compound and a powerful prototype and substitute for OP chemical warfare agents (CWAs) such as sarin, VX, etc. To study the distribution and penetration of POX into the central nervous system (CNS) and other tissues, a positron emission tomography (PET) tracer analog, carbon-11-labeled paraoxon ([ 11 C]POX), was prepared. Blood and tissue radioactivity levels in live rats demonstrated immediate penetration into the CNS and persistent radioactivity levels in tissues indicative of covalent target modification., (Copyright © 2024 by The Author(s).)

Noninvasive methods to study glucocorticoid receptor (GR) signaling are urgently needed to elaborate the complexity of GR signaling in normal physiology and human disorders, as well as to identify selective GR modulators to treat diseases. Here, we report evidence supporting translational studies with (±)- 11 C-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]-quinoline ((±)- 11 C-YJH08), a radioligand for PET that engages the ligand binding domain on GR. Methods: (±)- 11 C-YJH08 was synthesized by reacting the phenol precursor with 11 C-methyl iodide. The biodistribution was studied in vivo. Specific binding was tested in vivo with adrenalectomy and ligand competition. A library of analogs was synthesized and studied in vitro and in vivo to understand the (±)- 11 C-YJH08 structure-activity relationship. Rodent dosimetry studies were performed to estimate the human-equivalent doses of (±)- 11 C-YJH08. Results: (±)- 11 C-YJH08 was synthesized by reaction of the phenolic precursor with 11 C-methyl iodide, giving a radiochemical yield of 51.7% ± 4.7% (decay-corrected to starting 11 C-methyl iodide). Specific binding was observed in many tissues, including the brain. An analysis of the (±)-YJH08 structure-activity relationship showed that ( R )- and ( S )-enantiomers are equally avid for GR by occupying discrete binding modes. A focused chemical screen revealed that the aryl fluoride motif on YJH08 is essential for high-affinity GR binding in vitro, high tissue uptake in vivo, and efficient passage across the blood-brain barrier. Lastly, we performed dosimetry studies on rodents, from which we estimated the human-equivalent doses of (±)- 11 C-YJH08 to be commensurate with the widely used 11 C and 18 F tracers. Conclusion: These studies reveal the molecular determinants of a high-affinity and high-selectivity ligand-receptor interaction and support the use of (±)- 11 C-YJH08 PET to make the first measurements of GR expression in human subjects., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Oxime antidotes regenerate organophosphate-inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [ 18 F]-VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [ 18 F]-VXS was evaluated after an LD 50 dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [ 18 F]-VXS tracer alone had significantly higher radioactivity (two- to threefold) in the heart and lung than rats given LD 50 POX at 20 or 60 min prior to [ 18 F]-VXS. When rats were given LD 50 POX followed by 2-PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI-6 or MMB-4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX-treated rats. This new in vivo dynamic platform using [ 18 F]-VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats., (© 2020 New York Academy of Sciences.)

The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR's role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report 18 F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4- f ]quinoline ( 18 F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR ( K i ∼ 0.4 nM) with ∼100-fold selectivity compared to nuclear hormone receptors in the same subfamily. 18 F-YJH08 was prepared via Cu(OTf) 2 (py) 4 -mediated radiofluorination of an arylboronic acid pinacol ester with ∼12% decay corrected radiochemical yield from the starting 18 F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18 F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18 F-YJH08 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, 18 F-YJH08 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo.

Boron neutron capture therapy (BNCT) is a therapeutic modality which has been used for the treatment of cancers, including brain and head and neck tumors. For effective treatment via BNCT, efficient and selective delivery of a high boron dose to cancer cells is needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer imaging and drug delivery. In this study, we conjugated boronic acid or carborane functional groups to a well-established PSMA inhibitor scaffold to deliver boron to prostate cancer cells and prostate tumor xenograft models. Eight boron-containing PSMA inhibitors were synthesized. All of these compounds showed a strong binding affinity to PSMA in a competition radioligand binding assay (IC 50 from 555.7 to 20.3 nM). Three selected compounds 1a , 1d , and 1f were administered to mice, and their in vivo blocking of 68 Ga-PSMA-11 uptake was demonstrated through a positron emission tomography (PET) imaging and biodistribution experiment. Biodistribution analysis demonstrated boron uptake of 4-7 μg/g in 22Rv1 prostate xenograft tumors and similar tumor/muscle ratios compared to the ratio for the most commonly used BNCT compound, 4-borono-l-phenylalanine (BPA). Taken together, these data suggest a potential role for PSMA targeted BNCT agents in prostate cancer therapy following suitable optimization.

Compelling evidence points to immune cell infiltration as a critical component of successful immunotherapy. However, there are currently no clinically available, noninvasive methods capable of evaluating immune contexture prior to or during immunotherapy. In this study, we evaluate a T-cell-specific PET agent, [18F]F-AraG, as an imaging biomarker predictive of response to checkpoint inhibitor therapy. We determined the specificity of the tracer for activated T cells in vitro and in a virally induced model of rhabdomyosarcoma. Of all immune cells tested, activated human CD8 + effector cells showed the highest accumulation of [18F]F-AraG. Isolation of lymphocytes from the rhabdomyosarcoma tumors showed that more than 80% of the intratumoral signal came from accumulation of [18F]F-AraG in immune cells, primarily CD8 + and CD4 + . Longitudinal monitoring of MC38 tumor-bearing mice undergoing anti-PD-1 treatment revealed differences in signal between PD-1 and isotype antibody-treated mice early into treatment. The differences in [18F]F-AraG signal were also apparent between responders and nonresponders to anti-PD-1 therapy. Importantly, we found that the signal in the tumor-draining lymph nodes provides key information about response to anti-PD-1 therapy. Overall, [18F]F-AraG has potential to serve as a much needed immunomonitoring clinical tool for timely evaluation of immunotherapy. SIGNIFICANCE: These findings reveal differences in T-cell activation between responders and nonresponders early into anti-PD-1 treatment, which may impact many facets of immuno-oncology, including patient selection, management, and development of novel combinatorial approaches., (©2019 American Association for Cancer Research.)

2-Pyridinealdoxime methiodide (2-PAM) is a widely used antidote for the treatment of organophosphorus (OP) exposure that reactivates the target protein acetylcholinesterase. Carbon-11 2-PAM was prepared to more fully understand the in vivo mode of action, distribution, and dynamic qualities of this important countermeasure. Alkylation of 2-pyridinealdoxime with [ 11 C]CH 3 I provided the first-in-class [ 11 C]2-PAM tracer in 3.5% decay corrected radiochemical yield from [ 11 C]CH 3 I, >99% radiochemical purity, and 4831 Ci/mmol molar activity. [ 11 C]2-PAM tracer distribution was evaluated by ex vivo biodistribution and in vivo dynamic positron emission tomography (PET) imaging in naïve (OP exposure deficient) rats. Tracer alone and tracer coinjected with a body mass-scaled human therapeutic dose of 30 mg/kg nonradioactive 2-PAM demonstrated statistically similar tissue and blood distribution profiles with the greatest uptake in kidney and significantly lower levels in liver, heart, and lung with lesser amounts in blood and brain. The imaging and biodistribution data show that radioactivity uptake in brain and peripheral organs is rapid and characterized by differential tissue radioactivity washout profiles. Analysis of arterial blood samples taken 5 min after injection showed ∼82% parent [ 11 C]2-PAM tracer. The imaging and biodistribution data are now established, enabling future comparisons to outcomes acquired in OP intoxicated rodent models.

O-(1-Fluoropropan-2-yl)-O-(4-nitrophenyl) methylphosphonate is a reactive organophosphate ester (OP) developed as a surrogate of the chemical warfare agent sarin that forms a similar covalent adduct at the active site serine of acetylcholinesterase. The radiolabeled O-(1-[ 18 F]fluoropropan-2-yl)-O-(4-nitrophenyl) methylphosphonate ([ 18 F] fluorosarin surrogate) has not been previously prepared. In this paper, we report the first radiosynthesis of this tracer from the reaction of bis-(4-nitrophenyl) methylphosphonate with 1-[ 18 F]fluoro-2-propanol in the presence of DBU. The 1-[ 18 F]fluoro-2-propanol was prepared by reaction of propylene sulfite with Kryptofix 2.2.2 and [ 18 F] fluoride ion. The desired tracer O-(1-[ 18 F]fluoropropan-2-yl)-O-(4-nitrophenyl) methylphosphonate was obtained in a >98% radiochemical purity with a 2.4% ± 0.6% yield (n = 5, 65 minutes from start of synthesis) based on starting [ 18 F] fluoride ion and a molar activity of 49.9 GBq/μmol (1.349 ± 0.329 Ci/μmol, n = 3). This new facile radiosynthesis routinely affords sufficient quantities of [ 18 F] fluorosarin surrogate in high radiochemical purity, which will further enable the tracer development as a novel radiolabeled OP acetylcholinesterase inhibitor for assessment of OP modes of action with PET imaging in vivo., (© 2018 John Wiley & Sons, Ltd.)

A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin-lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C]valine), significant increase of their T1 was observed at 3 T with deuterium labeling (+26%, 22%, +16%, +25% and +29%, respectively). Remarkably, in the case of [2-13C]alanine, [2-13C]serine and [2-13C]lactate, deuterium labeling led to a greater than four fold increase in T1. [1-13C,2-2H]alanine, produced using this method, was applied to in vitro enzyme assays with alanine aminotransferase, demonstrating a kinetic isotope effect.

Occult bacterial infections represent a worldwide health problem. Differentiating active bacterial infection from sterile inflammation can be difficult using current imaging tools. Present clinically viable methodologies either detect morphologic changes (CT/ MR), recruitment of immune cells ( 111 In-WBC SPECT), or enhanced glycolytic flux seen in inflammatory cells ( 18 F-FDG PET). However, these strategies are often inadequate to detect bacterial infection and are not specific for living bacteria. Recent approaches have taken advantage of key metabolic differences between prokaryotic and eukaryotic organisms, allowing easier distinction between bacteria and their host. In this report, we exploited one key difference, bacterial cell wall biosynthesis, to detect living bacteria using a positron-labeled D-amino acid. After screening several 14 C D-amino acids for their incorporation into E. coli in culture, we identified D-methionine as a probe with outstanding radiopharmaceutical potential. Based on an analogous procedure to that used for L-[methyl- 11 C]methionine ([ 11 C] L-Met), we developed an enhanced asymmetric synthesis of D-[methyl- 11 C]methionine ([ 11 C] D-Met), and showed that it can rapidly and selectively differentiate both E. coli and S. aureus infections from sterile inflammation in vivo. We believe that the ease of [ 11 C] D-Met radiosynthesis, coupled with its rapid and specific in vivo bacterial accumulation, make it an attractive radiotracer for infection imaging in clinical practice.

[ 11 C]Carfentanil ([ 11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [ 11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [ 11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [ 11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol., (Copyright © 2017 John Wiley & Sons, Ltd.)

O-(2-Fluoroethyl)-O-(p-nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl-serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[ 18 F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [ 18 F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [ 18 F]1 tracer synthesis was slow even with microwave acceleration, required high-performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis-(O,O-p-nitrophenyl) methylphosphonate, 2, with 2-fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [ 18 F]1, was obtained in a non-decay-corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [ 18 F]1, which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo., (Copyright © 2017 John Wiley & Sons, Ltd.)

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Solid tumors are hypoxic with altered metabolism, resulting in secretion of acids into the extracellular matrix and lower relative pH, a feature associated with local invasion and metastasis. Therapeutic and diagnostic agents responsive to this microenvironment may improve tumor-specific delivery. Therefore, we pursued a general strategy whereby caged small-molecule drugs or imaging agents liberate their parent compounds in regions of low interstitial pH. In this manuscript, we present a new acid-labile prodrug method based on the glycosylamine linkage, and its application to a class of positron emission tomography (PET) imaging tracers, termed [(18)F]FDG amines. [(18)F]FDG amines operate via a proposed two-step mechanism, in which an acid-labile precursor decomposes to form the common radiotracer 2-deoxy-2-[(18)F]fluoro-d-glucose, which is subsequently accumulated by glucose avid cells. The rate of decomposition of [(18)F]FDG amines is tunable in a systematic fashion, tracking the pKa of the parent amine. In vivo, a 4-phenylbenzylamine [(18)F]FDG amine congener showed greater relative accumulation in tumors over benign tissue, which could be attenuated upon tumor alkalinization using previously validated models, including sodium bicarbonate treatment, or overexpression of carbonic anhydrase. This new class of PET tracer represents a viable approach for imaging acidic interstitial pH with potential for clinical translation.

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized (13)C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its (13)C chemical shift within the physiologic range.