Dendritic cell responsiveness to type I interferon is required for the generation of antitumor T cell responses and tumor rejection.

Glutaminolysis is a metabolic pathway adapted by many aggressive cancers, including triple-negative breast cancers (TNBC), to utilize glutamine for survival and growth. In this study, we examined the utility of [18F](2S,4R)4-fluoroglutamine ([18F]4F-Gln) PET to measure tumor cellular glutamine pool size, whose change might reveal the pharmacodynamic (PD) effect of drugs targeting this cancer-specific metabolic pathway. High glutaminase (GLS) activity in TNBC tumors resulted in low cellular glutamine pool size assayed via high-resolution 1H magnetic resonance spectroscopy (MRS). GLS inhibition significantly increased glutamine pool size in TNBC tumors. MCF-7 tumors, with inherently low GLS activity compared to TNBC, displayed a larger baseline glutamine pool size that did not change as much in response to GLS inhibition. The tumor-to-blood-activity-ratios (T/B) obtained from [18F]4F-Gln PET images matched the distinct glutamine pool sizes of both tumor models at baseline. After a short course of GLS inhibitor treatment, the T/B values increased significantly in TNBC, but did not change in MCF-7 tumors. Across both tumor types and after GLS inhibitor or vehicle treatment, we observed a strong positive correlation between T/B values and tumor glutamine pool size measured using MRS (R2=0.71). In conclusion, [18F]4F-Gln PET tracked cellular glutamine pool size in breast cancers with differential GLS activity and detected increases in cellular glutamine pool size induced by GLS inhibitors. This study accomplished the first necessary step towards validating [18F]4F-Gln PET as a PD marker for glutaminase-targeting drugs.

Reactive oxygen species (ROS) are believed to play a major role in the proinflammatory, M1-polarized form of neuroinflammation. However, it has been difficult to assess the role of ROS and their role in neuroinflammation in animal models of disease because of the absence of probes capable of measuring their presence with the functional imaging technique positron emission tomography (PET). This study describes the synthesis and in vivo evaluation of [18F]ROStrace, a radiotracer for imaging superoxide in vivo with PET, in an LPS model of neuroinflammation. [18F]ROStrace was found to rapidly cross the blood–brain barrier (BBB) and was trapped in the brain of LPS-treated animals but not the control group. [18F]ox-ROStrace, the oxidized form of [18F]ROStrace, did not cross the BBB. These data suggest that [18F]ROStrace is a suitable radiotracer for imaging superoxide levels in the central nervous system with PET.

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Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A 2A ) receptors facilitates dopamine D 2 receptor function. In phase 2 clinical trials, A 2A antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A 2A PET radiotracer, 18 F-MNI-444, and used it to investigate the relationship between plasma levels and A 2A occupancy by preladenant and tozadenant in nonhuman primates (NHP). Methods: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical analysis) and reference-region-based (simplified reference tissue model and noninvasive Logan graphical analysis) methods. Whole-body PET images were acquired for radiation dosimetry estimates. Human pharmacokinetic parameters for tozadenant and preladenant were used to predict A 2A occupancy in humans, based on median effective concentration (EC 50 ) values estimated from the NHP PET measurements. Results: 18 F-MNI-444 regional uptake was consistent with A 2A receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A 2A PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A 2A receptor occupancy in humans. Conclusion: 18 F-MNI-444 appears to be a better PET radiotracer for A 2A imaging than currently available radiotracers. Assuming that EC 50 in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A 2A receptor occupancy than preladenant in humans at clinically tested doses. Par kinson disease (PD) has a prevalence of 1.6% in individuals over the age of 65 y (1) and a lifetime risk of 6.7% from age 45 to 100 y (2). Motor symptoms, which include tremor, bradykinesia, and rigidity, emerge when there is a loss of more than 50% of dopamine neurons in the substantia nigra (SN) (3,4). Loss of these neurons reduces dopamine input to the striatum, where dopamine binds to both D 1 and D 2 receptors. Most striatal D 1 receptors are localized in the so-called direct pathway, whereas most striatal D 2 receptors are localized in medium spiny neurons that project to the globus pallidus pars externa (indirect pathway). Adenosine signals via 4 different G-protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 (5). A 2A receptors are predominantly expressed in striatum, with lower levels present in cortex and thalamus and even lower in cerebellum (5-9). A 2A receptors may play a role in inflammation (10) and could therefore be important in a variety of neurologic diseases, including multiple sclerosis, in which A 2A receptor density is increased (11). In PD, A 2A receptors may be important because they form heterodimers with D 2 receptors in the striatum (5,12), and agonists of A 2A (e.g., adenosine) reduce the affinity of D 2 for dopamin...

A series of position-6 substituted 2-amino-4-methylpyridine analogues was synthesized and compounds 9, 18, and 20 were identified as the inhibitors with the greatest potential to serve as PET tracers for imaging inducible nitric oxide synthase (iNOS). [ 18 F]9 was synthesized and evaluated in a mouse model of lipopolysaccharide (LPS)-induced iNOS activation. In vivo biodistribution studies of [ 18 F]9 indicate higher tracer uptake in the lungs of the LPS-treated mice when compared to control mice. Tracer uptake at 60 min post-injection was reduced in a blocking study using a known inhibitor of iNOS. The expression of iNOS was confirmed by Western blot analysis of lung samples from the LPS-treated mice. MicroPET studies also demonstrated accumulation of radiotracer in the lungs of the LPS-treated mice. Taken collectively, these data suggest that [ 18 F]9 shows favorable properties as a PET tracer to image iNOS activation with PET.

The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro-positron emission tomography (microPET). The (R)- and (S)-enantiomers of [18F]4 were radiolabeled separately using the click reaction in 57% and 51% decay-corrected yields, respectively. (S)-[18F]4 was a substrate for cationic amino acid transport and, to a lesser extent, system L transport in vitro. In vivo biodistribution studies demonstrated that (S)-[18F]4 provided higher tumor uptake and higher tumor to brain ratios (15:1 at the 30- and 60-minute time points) compared to the (R)-enantiomer (7:1 at the 30- and 60-minute time points). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors. Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging.

BackgroundFast implementation of positron emission tomography (PET) into clinical and preclinical studies highly demands automated synthesis for the preparation of PET radiopharmaceuticals in a safe and reproducible manner. The aim of this study was to develop automated synthesis methods for these six 18F-labeled radiopharmaceuticals produced on a routine basis at the University of Pennsylvania using the AllinOne synthesis module.ResultsThe development of automated syntheses with varying complexity was accomplished including HPLC purification, SPE procedures and final formulation with sterile filtration. The six radiopharmaceuticals were obtained in high yield and high specific activity with full automation on the AllinOne synthesis module under current good manufacturing practice (cGMP) guidelines.ConclusionThe study demonstrates the versatility of this synthesis module for the preparation of a wide variety of 18F-labeled radiopharmaceuticals for PET imaging studies.