Sensing Living Bacteria <i>in Vivo</i> Using <scp>d</scp>-Alanine-Derived <sup>11</sup>C Radiotracers

Parker, Matthew F.L.; Luu, Justin; Schulte, Brailee; Huynh, Tony L.; Stewart, Megan N.; Sriram, Renuka; Yu, Michelle; Jivan, Salma; Flavell, Robert R.; Rosenberg, Oren S.; Ohliger, Michael A.; Wilson, David M.

doi:10.1021/acscentsci.9b00743

Cited by 60 publications

(114 citation statements)

References 48 publications

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“…With metabolic products being consistently observed, hyperpolarized d ‐[1‐ 13 C]alanine can be employed to rapidly assess DAO activity in vitro and in vivo . When compared to other molecular imaging techniques that exploit d ‐amino acids, the main ones being PET with d ‐[methyl‐ 11 C]methionine and d ‐[3‐ 11 C]alanine as a contrast agent for bacterial infection, hyperpolarized d ‐alanine shows greater specificity for detecting DAO activity.…”

Section: Discussionmentioning

confidence: 99%

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

2020

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D-amino acid oxidase (DAO) is a peroxisomal enzyme that catalyzes the oxidative deamination of several neutral and basic D-amino acids to their corresponding -keto acids. In most mammalian species studied, high DAO activity is found in the kidney, liver, brain and polymorphonuclear leukocytes, and its main function is to maintain low circulating D-amino acid levels. DAO expression and activity have been associated with acute and chronic kidney diseases and with several pathologies related to N-methyl-D-aspartate (NMDA) receptor hypo/hyper-function;however, its precise role is not completely understood. In the present study we show that DAO activity can be detected in vivo in the rat kidney using hyperpolarized D-[1-13 C]alanine.Following a bolus of hyperpolarized D-alanine, accumulation of pyruvate, lactate and bicarbonate was observed only when DAO activity was not inhibited. The measured lactate-to-D-alanine ratio was comparable to the values measured when the L-enantiomer was injected. Metabolites downstream of DAO were not observed when scanning the liver and brain. The conversion of hyperpolarized D-[1-13 C]alanine to lactate and pyruvate was detected in blood ex vivo, and lactate and bicarbonate were detected on scanning the blood pool in the heart in vivo; however, the bicarbonate-to-D-alanine ratio was significantly lower compared with the kidney. These results demonstrate that the specific metabolism of the two enantiomers of hyperpolarized [1-13 C]alanine in the kidney and in the blood can be distinguished, underscoring the potential of D-[1-13 C]alanine as a probe of D-amino acid metabolism. INTRODUCTIONWhile being less abundant than L-amino acids, D-amino acids are widespread in nature and take part in normal mammalian metabolism. Aside from D-serine and D-aspartate, which humans can synthesize endogenously, most D-amino acids are taken up through the diet, and their levels are regulated by D-amino acid oxidase (DAO) and D-aspartate oxidase. 1 DAO, a peroxisomal flavoenzyme, catalyzes the conversion of basic and neutral D-amino acids into the corresponding -keto acids in two steps. First, the D-amino acid is oxidized to an imino acid, and the flavin adenine dinucleotide coenzyme is concomitantly reduced. The imino acid then undergoes non-enzymatic hydrolysis to yield the -keto acid and ammonia. In mammals, DAO is abundantly present in the kidneys, where it is expressed in the epithelial cells of the S2 and S3 segments of the proximal tubules. Although it is also expressed in hepatocytes, in the central nervous system (CNS) and in polymorphonuclear (PMN) leukocytes, the physiological and pathological role of D-amino acids and DAO in these tissues is not completely understood. DAO has been shown to play a detoxifying role in the kidneys, as it helps maintain low D-amino acid levels. 2 Since it controls D-serine levels, DAO activity in the CNS has been associated with conditions affecting N-methyl-D-aspartate (NMDA) receptor signaling/dysfunction, including schizophrenia, 3 amyotrophic lateral sclerosis ...

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Section: Discussionmentioning

confidence: 99%

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

2020

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“…Moreover, a recently published paper by Parker et al showed a 3.5-fold higher accumulation of 11 C-D-ala in a mouse model of acute bacterial myositis compared with the sterile inflammation control, whereas 68 Ga-citrate showed only 2-fold higher accumulation in the same model. Furthermore, in a vertebral diskitis-osteomyelitis modal, 11 C-D-ala showed a 3.3-fold higher uptake than in adjacent disk spaces and a 1.8-fold uptake in P. aeruginosa pneumonia relative to normal lung ( Figure 5C) (73).…”

Section: D-amino Acidsmentioning

confidence: 96%

Nuclear Imaging of Bacterial Infection: The State of the Art and Future Directions

et al. 2020

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Learning Objectives: On successful completion of this activity, participants should be able to describe (1) the clinical justifications for using nuclear medicine techniques in imaging bacterial infections; (2) the mechanisms of nuclear imaging methods used to detect bacterial infections; and (3) the bacterial-metabolism specific imaging techniques currently under development. Financial Disclosure: Dr. Ohliger travels and speaks for General Electric. The authors of this article have indicated no other relevant relationships that could be perceived as a real or apparent conflict of interest. CME Credit: SNMMI is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing education for physicians. SNMMI designates each JNM continuing education article for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity. For CE credit, SAM, and other credit types, participants can access this activity through the SNMMI website (http://www.snmmilearningcenter.org) through December 2023. Increased mortality rates from infectious diseases is a growing public health concern. Successful management of acute bacterial infections requires early diagnosis and treatment, which are not always easy to achieve. Structural imaging techniques such as CT and MRI are often applied to this problem. However, these methods generally rely on secondary inflammatory changes and are frequently not specific to infection. The use of nuclear medicine techniques can add crucial complementary information, allowing visualization of infectious pathophysiology beyond morphologic imaging. This review will discuss the current structural and functional imaging techniques used for the diagnosis of bacterial infection and their roles in different clinical scenarios. We will also present several new radiotracers in development, with an emphasis on probes targeting bacteria-specific metabolism. As highlighted by the current coronavirus disease 2019 epidemic, caused by the novel severe acute respiratory syndrome coronavirus 2, similar thinking may apply in imaging viral pathogens; for this case, prominent effects on host proteins, most notably angiotensin-converting enzyme 2, might also provide worthwhile imaging targets.

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“…The polymyxin B is an antibiotic, usually used for multidrug-resistant Gram-negative bacteria, that acts like an amphipathic antimicrobial peptide. Similarly, D-amino acids, molecules targeting the folate pathway in bacteria and siderophores have also been studied as bacterial specific imaging agents [34][35][36][37][38][39].…”

Section: Imaging Bacteria In Animal Modelsmentioning

confidence: 99%

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

Artiko

Conserva

Ferro-Flores

et al. 2020

JCM

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Bacterial infections are the main cause of patient morbidity and mortality worldwide. Diagnosis can be difficult and delayed as well as the identification of the etiological pathogen, necessary for a tailored antibiotic therapy. Several non-invasive diagnostic procedures are available, all with pros and cons. Molecular nuclear medicine has highly contributed in this field by proposing several different radiopharmaceuticals (antimicrobial peptides, leukocytes, cytokines, antibiotics, sugars, etc.) but none proved to be highly specific for bacteria, although many agents in development look promising. Indeed, factors including the number and strain of bacteria, the infection site, and the host condition, may affect the specificity of the tested radiopharmaceuticals. At the Third European Congress on Infection/Inflammation Imaging, a round table discussion was dedicated to debate the pros and cons of different radiopharmaceuticals for imaging bacteria with the final goal to find a consensus on the most relevant research steps that should be fulfilled when testing a new probe, based on experience and cumulative published evidence.

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Sensing Living Bacteria in Vivo Using d-Alanine-Derived ¹¹C Radiotracers

Cited by 60 publications

References 48 publications

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

Nuclear Imaging of Bacterial Infection: The State of the Art and Future Directions

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

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Sensing Living Bacteria in Vivo Using d-Alanine-Derived 11C Radiotracers

Cited by 60 publications

References 48 publications

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐13C]alanine

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐13C]alanine

Nuclear Imaging of Bacterial Infection: The State of the Art and Future Directions

Imaging Bacteria with Radiolabelled Probes: Is It Feasible?

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Product

Resources

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Sensing Living Bacteria in Vivo Using d-Alanine-Derived ¹¹C Radiotracers

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine