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Background Positron emission tomography (PET) is a highly sensitive imaging modality that can provide in vivo quantitative information of biological processes at a biochemical level. PET relies upon the administration of a chemical probe, often called a radiopharmaceutical, that is labeled with a short-lived positron-emitting radionuclide, examples of which are $\ce{^{11}C} \ (t_{1/2} = \pu{20.4 min})$ and $\ce{^{18}F} \ (t_{1/2} = \pu{109.7 min})$. Carbon-11 is one of the most useful radionuclides for PET chemistry, since its introduction into a biologically active molecule has minimal effects on the (bio)chemical properties of the compound (Ref.: Dahl, et al., Clin. Transl. Imaging 2017, 5, 275–289)

Biologicals of interest Beta-2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of b2-ARs, which are densely located on ASM. The presumed cellular mechanism of action involves the canonical signaling pathway via activation of Adenylyl cyclase (AC) and generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase A (PKA) and Epac, a Rap1 guanine nucleotide exchange factor. However, there is still little known regarding these pathways in airway cells (Ref.: Am J Respir. Crit. Care Med. 2013, 187(7), 690–696).

Question Currently radiolabeled lung studies use labeled drugs that are produced for inhalation are "association” products, that is, the label is associated with the drug but not firmly bound to the drug. Without a firm bond between the active pharmaceutical ingredient (API) and the radiotracer, images must be acquired immediately post-inhalation before the dissociation of the label from the drug leads to a circulating level of absorbed radioactivity that could introduce an unacceptable error in the measurement of radioactivity in the lung. Carbon-11 radiolabeled ICS or Beta-2 agonists would enhance our understanding of the cellular mechanism of action. Anyone aware of work in this area?


References:

  1. Kenneth Dahl, Christer Halldin, Magnus Schou, "New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals," Clinical and Translational Imaging 2017, 5, 275–289 (DOI: https://doi.org/10.1007/s40336-017-0223-1).
  2. Mario Cazzola, Clive P. Page, Paola Rogliani, M. Gabriella Matera, "$\beta_2$-Agonist Therapy in Lung Disease," Am. J. Respir. Crit. Care Med. 2013, 187(7), 690–696 (DOI: https://doi.org/10.1164/rccm.201209-1739PP).
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    $\begingroup$ What does ICS stand for? $\endgroup$
    – orthocresol
    Apr 27 at 11:13
  • $\begingroup$ @orthocresol: ICS stands for " inhaled corticosteroid"! (from Ref.2 sighted) $\endgroup$ Apr 27 at 11:46
  • $\begingroup$ It might be possible. But very hard as it would require a very rapid process (ie one taking significantly less time than the half life) to synthesise and isolate a complex molecule. That's not easy, even less so for steroids than beta-agonists. $\endgroup$
    – matt_black
    Apr 27 at 16:50
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Positron emission tomography (PET) has been taken using $\ce{^{11}C}$- and $\ce{^{18}F}$-labelled reagents, although they are not $\beta_2$-agonists (Ref.1). The abstract states that:

Positron emission tomography (PET) provides three-dimensional images of the distributions of radionuclides that have been inhaled or injected into the lungs. By using radionuclides with short half-lives, the radiation exposure of the subject can be kept small. By following the evolution of the distributions of radionuclides in gases or compounds that participate in lung function, information about such diverse lung functions as regional ventilation, perfusion, shunt, gas fraction, capillary permeability, inflammation, and gene expression can be inferred. Thus PET has the potential to provide information about the links between cellular function and whole lung function in vivo. In this paper, recent advancements in PET methodology and techniques and information about lung function that have been obtained with these techniques are reviewed.

It is clear that unto 2007, there are no evidence for the use of radiolabeled $\beta_2$-agonist or corticosteroids for PET in literature. However, there are other radiolabeled reagents have been use for the imaging. For instance, the mixed-venous content is obtained by imaging the right heart during the infusion, and the alveolar concentration is obtained by imaging the lung, after the blood volume is subtracted from the image using a separate $\ce{^{11}C}$-labeled carbon monoxide ($\ce{^{11}CO}$) inhalation.

References:

  1. R. Scott Harris, Daniel P. Schuster, "Visualizing lung function with positron emission tomography," J. Appl. Physiol. 2007, 102(1), 448-458 (DOI: https://doi.org/10.1152/japplphysiol.00763.2006)(PDF).
  2. C. G. Rhodes, S. O. Valind, L. H. Brudin, P. E. Wollmer, T. Jones, P. D. Buckingham, J. M. Hughes, "Quantification of regional V/Q ratios in humans by use of PET. II. Procedure and normal values," J. Appl. Physiol. 1989, 66(4), 1905–1913 (DOI: https://doi.org/10.1152/jappl.1989.66.4.1905).
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