Combined PET and X-ray Computed Tomography Imaging in Pulmonary Infections and Inflammation

Jamshed Bomanji; Ahmad Almuhaideb; Alimuddin Zumla

Disclosures

Curr Opin Pulm Med. 2011;17(3):197-205. 

In This Article

Mechanism of Uptake

This is a brief summary of the mechanism of uptake for the few PET tracers that are used or could be used in the management of pulmonary infection or inflammation.

18F-fluorodeoxyglucose

The most common tracer used for PET/CT imaging is 18F-FDG. The enhanced uptake of this tracer in activated inflammatory cells such as neutrophils, lymphocytes, and macrophages is related to significantly increased levels of glycolysis as a result of increased numbers of cell surface glucose transporter proteins and increased intracellular hexokinase and phosphofructokinase levels, particularly after cellular stimulation by multiple cytokines.[3–5] Once 18F-FDG has been phosphorylated, structural changes made by a hexose–phosphate bond prevent 18F-FDG from being catabolized or transported back into the extracellular space in substantial amounts. This process is called 'metabolic trapping', and it leads to increased uptake and accumulation of 18F-FDG within abnormally metabolizing tumor cells.[6] The hexose monophosphate shunt is stimulated by phagocytosis, with increases of 20–30 times the baseline value, which is the cause of high 18F-FDG uptake.[7]

Increased 18F-FDG activity has been reported in the course of several experimental and clinical inflammatory or infectious processes in the lungs and elsewhere in the body. The uptake of 18F-FDG in acute inflammation or infection occurs primarily by activated neutrophils, whose metabolism (especially during the respiratory burst triggered by the rolling and adhesion phase) is heavily dependent on anaerobic glycolysis, requiring elevated uptake of glucose. Micro-autoradiography has shown that the only type of cell to emit 18F-FDG signal is the neutrophils.[4]

In variable inflammatory or infective conditions, including abscesses, the glycolytic metabolism is elevated in the region of leukocytic infiltration associated with inflammatory processes, and consequently FDG uptake is elevated.[6] Inflammatory cells increase the expression of glucose transporters when they are activated, and multiple cytokines and growth factors can facilitate glucose transport without actually increasing the number of glucose transporters.[8]

68Ga-citrate

68Ga is a positron emitter produced by a 68Ge/68Ga generator (t ½ 68 min, β+ 88%) and is not dependent on a cyclotron. Gallium-67 citrate (67Ga-citrate) is a well-established gamma-emitting radiopharmaceutical and its mechanism has been studied extensively. 68Ga-citrate is similar to 67Ga-citrate but is a positron-emitting radiopharmaceutical and shares the same uptake pathway. Multiple factors contribute to the accumulation and retention of 67Ga/68Ga-citrate in inflammatory lesions. Adequate blood supply is essential. 67Ga/68Ga-citrate, mainly in the form of transferrin–67Ga/68Ga complex, is delivered to the inflammatory lesions through capillaries with increased permeability. At the site of inflammation, some 67Ga/68Ga-citrate is taken up by leukocytes and bacteria when they are present. In addition, 67Ga/68Ga-citrate may bind to lactoferrin and bacterial siderophores. Multiple contributing factors often co-exist at any given inflammatory lesion. The nature and intensity of the inflammation affects the relative contribution of these factors. More recently, it has been shown that 68Ga-labeled siderophore desferri-triacetylfusarinine C displays highly selective accumulation by Aspergillus fumigatus in vivo, thus providing the ability to image invasive pulmonary aspergillosis.[9•]

68Ga-DOTATATE

Somatostatin receptors (SSRs) have been identified on human immune cells including mononuclear leucocytes[10] and peripheral blood lymphocytes, whereas granulocytes and red blood cells do not express SSRs.[11] Thus, SSR expression can be detected in vivo by SSRs scintigraphy using 111In-octreotide.[12]

DOTATATE, a somatostatin type 2 receptor (SSR-2) analog, is labeled with 68Ga, a positron emitter. 68Ga-DOTATATE has higher affinity for SSR-2 than do other ligands in current use, is rapidly excreted from nontarget sites, offers good target to nontarget imaging properties, and hence is an ideal potential candidate tracer for imaging granulomatous diseases expressing SSR-2 receptors.

In view of these considerations, it appears evident that the three above-mentioned PET tracers have potential for imaging of pulmonary infection or inflammation that remains to be exploited.

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