On several areas, nuclear medicine may help to solve the problem of the unknown aetiology of CFS/ME. For the serotonergic system, the two published studies use tracers that are labelled with ¹¹C, which has a short half-life. Maybe future studies have to be performed with ¹⁸F-labelled tracers, such as [¹⁸F]methoxyphenyl-pyridinyl-fluoro-benzamide-methylpiperazine (MPPF), which is already successfully used for binding to the 5-HT receptor.

Several investigations reveal causes at the molecular level, and maybe in future nuclear medicine and molecular imaging may help to clarify the underlying pathogenesis.

For example, a study in Swedish patients with CSF mentioned reduced expression levels of the oestrogen receptor beta (Gräns et al. 2007). Others mention modifications in serotonin transporter genes (Narita et al. 2003; Falkenberg et al. 2011), glucocorticoid receptor genes (Rajeevan et al. 2007) and involvement of the human leukocyte antigen (HLA) class II (Carlo-Stella et al. 2009). Specific targeting of these molecules with radionuclides may reveal differences between patients with CFS/ME and healthy subjects.

A well-known PET tracer for neuroinflammation is [¹¹C]PK11195, which binds to the peripheral benzodiazepine receptors (PBRs). Expression of PBRs is linked to microglial activation and considered a hallmark of neuroinflammation (Doorduin et al. 2008). This tracer may be suitable for studies in CFS/ME patients.

A last area in which nuclear medicine may have added value is the role that cytokines play in the development of CFS/ME. It has been reported that patients with CFS/ME have experienced infections. In response to a peripheral infection, innate immune cells produce proinflammatory cytokines that act on the brain. When activation of the peripheral immune system continues unabated, the resultant immune signaling to the brain can lead to an exacerbation of feeling unwell. Cytokines produced in the brain exert various central actions, including activation of the sympathetic nervous system and impairment of learning memory. This opens the possibility that brain cytokines may play a role in the pathogenesis of CFS/ME (Chen et al. 2008). Levels of granulocyte-macrophage colony stimulating factor were lower in CFS/ME patients than in healthy controls; levels of interleukin (IL)-8 were higher in CFS/ME patients who experienced sudden, influenza-like onset compared with controls and patients who experienced gradual onset; IL-10 levels were higher in CFS/ME patients with abnormal spinal fluids than in those with normal spinal fluids or healthy controls (Natelson et al. 2005). Proinflammatory cytokines such as IL-1β, IL-6 and tumour necrosis factor (TNF)-α can elicit or aggravate fatigue and symptoms of anxiety and depression; IL-2 and interferon (INF)-α can promote depressive symptoms that are attenuated by antidepressant treatment (Anisman et al. 2005). Excessive sleepiness and night-time insomnia can be exacerbated by IL-6 and TNF-α (Vgontas and Chrousos 2002). Nuclear medicine is able to label most of these cytokines, in most cases with SPECT tracers, but developments are also ongoing in labelling cytokines with ¹⁸F.