The most general applied tracer in PET and for neurology in particular is 2-[¹⁸F]fluoro-2-desoxyglucose (FDG). Using FDG regional cerebral glucose consumption rate can be measured quantitatively. In several neurological diseases (dementia, PD, AD, stroke), glucose consumption is reduced in specific brain regions indicating impaired functionality of these areas. Numerous articles including review papers on the use of FDG have appeared in the literature in many cases applied in combination with targeted tracers as described in this chapter (Demetriades 2002; Mielke and Heis 1998). In addition, several chapters in this volume will address the use of FDG-PET imaging.

Microglia are cells in the brain governing the activity of other immune cells. Activated microglia cells are correlated with neuroinflammation, which plays an important role in the onset of neurodegenerative disease. TSPO, formerly known as the peripheral benzodiazepine receptor (PBR), is overexpressed at activated microglia (Politis et al. 2012). Several PET tracers binding to TSPO have been developed. (R)-[¹¹C]PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] is the first non-benzodiazepine and selective TSPO PET ligand (Hashimoto et al. 1989). The compound has nanomolar affinity for TSPO (Chauveau et al. 2008). The PET tracer is widely applied in TSPO PET imaging. (R)-[¹¹C]PK11195 has been used in many human CNS studies, including multiple sclerosis, Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, HIV, herpes encephalitis, and schizophrenia. Although (R)-[¹¹C]PK11195 shows increased brain uptake in several neurodegenerative disorders, there are several disadvantages. The sensitivity is low and it is difficult to quantify small changes in TSPO expression in vivo. (R)-[¹¹C]PK11195 displays high plasma protein binding and high nonspecific binding because of its high lipophilicity. The lack of sensitivity and specificity of (R)-[¹¹C]PK11195 has hampered development of a standard quantitative method of analysis. For this reason, several new TSPO tracers have been developed. Most of these new TSPO tracers are still in the early stage of investigation. Many research efforts in preclinical studies are aimed at the following issues: (1) metabolic stability of the tracer, (2) binding potential (BP), (3) ligand receptor kinetics, and (4) quantitation methods. R-[¹¹C]PK11195 PET has been used mainly for assessing microglia/macrophage activation as an indication of neuronal and tissue damage in various neurodegenerative disorders. Most of these human studies used a reference tissue to measure the uptake of radioactivity. A kinetic plasma (metabolite-corrected) input with a reversible two-tissue compartment model was shown to be the best for analyzing R-[¹¹C]PK11195 kinetics in brain.

Radioligands such as [¹¹C]PBR28, [¹¹C]DAA1106, [¹⁸F]FEDAA1106, and [¹⁸F]PBR111 have been developed to image TSPO in vivo (Dollé et al. 2009; de Vries et al. 2006). Published data using these second-generation PET tracers [¹¹C]DAA1106 and [¹⁸F]FEDAA1106 in humans are promising, as they showed significantly higher brain uptake than [¹¹C]PK11195. Furthermore, increased [¹¹C]DAA1106 binding was reported in AD patients. A study using [¹¹C]PBR28 found areas of focal increases in radiotracer binding in the brain of multiple sclerosis patients.

The development of epilepsy has been associated with the impairment of gamma-aminobutyric acid (GABA) neurotransmission in the brain. The high-affinity ligand [¹¹C]flumazenil has been used widely for the investigation of GABA receptors (Hammers 2004) and was labeled in various positions (Halldin et al. 1988). [¹¹C]Flumazenil is available commercially in the United States and has been approved by Federal Drug Agency (FDA) for use in various clinical trials. Using [¹¹C]flumazenil with PET in patients with acute hemispheric ischemic stroke, it was shown that this tracer is a suitable tracer to distinguish between irreversibly damaged and viable neuronal tissue during early onset of the disease. With [¹¹C]flumazenil, it was possible to measure a reduction in the number of GABA/central benzodiazepine receptors in the hippocampus of patients with mesial temporal lobe epilepsy caused by unilateral hippocampal sclerosis. [¹¹C]Flumazenil has also been used to estimate the synaptic density of benzodiazepine in persons who became blind. Compared with sighted controls, a significantly lower benzodiazepine density was reported in the cerebellum of the blind subjects.

The dopaminergic system plays a major role in neurological and psychiatric disorders such as PD, Huntington’s disease, tardive dyskinesia, and schizophrenia. The neurotransmitter dopamine plays an important role in the mediation of movement, cognition, and emotion. Changed levels of dopamine also play a role in various neuropsychiatric disorders, such as autism, attention deficit hyperactivity disorder, and drug abuse. Knowledge on changed dopamine synthesis, receptor densities, and status is important for understanding the mechanisms underlying the pathogenesis and therapy of these diseases (Elsinga et al. 2006).

To investigate presynaptic function, PET and SPECT tracers have been developed to measure dopamine synthesis and transport. For measuring dopamine synthesis, the most commonly used tracer is 6-[¹⁸F]FDOPA, whereas for dopamine transport, several radiolabeled tropane analogs are used in the clinic. Postsynaptically, dopamine exerts actions through several subtypes of the dopamine receptor. The dopamine receptor family consists of five subtypes D₁–D₅. In order to investigate the role of each receptor subtype, selective and high-affinity PET radioligands are required. To a lesser extent, work has been published related to radioiodinated tracers for SPECT. For the dopamine D₁ subtype, the most commonly used ligand is [¹¹C]SCH23390 or [¹¹C]NNC112 (Kosaka et al. 2010), whereas for the D₂/D₃ subtype, [¹¹C]raclopride is a common tracer. [¹⁸F]Fallypride is a suitable PET tracer for the investigation of extrapyramidal D₂ receptors. For SPECT, [¹²³I]IBZM is commercially available. For the other subtypes, no suitable radioligands have been developed yet (Tissingh et al. 1997).

6-[¹⁸F]Fluoro-L-DOPA (FDOPA) is used to evaluate the central dopaminergic function of presynaptic neurons (Eidelberg et al. 1990; Sioka et al. 2010). Uptake of FDOPA is an indicator of DOPA transport into the neurons, its decarboxylation by amino acid decarboxylase (AADC) to 6-[¹⁸F]fluorodopamine, and capacity of dopamine storage mainly in striatum. 6-[¹⁸F]Fluorodopamine can be converted by catechol-O-methyltransferase (COMT) to 3-O-methyl-6-[¹⁸F]fluoro-L-DOPA, which is uniformly distributed throughout the brain. 6-[¹⁸F]Fluorodopamine is also metabolized via monoamine oxidase to yield 6-[¹⁸F]fluoro-3,4-dihydroxyphenylacetic acid and subsequently by COMT to yield 6-[¹⁸F]fluorochomovanillic acid. In clinical studies, AADC is commonly inhibited with carbidopa. As a result of this inhibition of peripheral AADC, there is increased availability of FDOPA in the brain.

The first FDOPA PET study of human brain was reported in 1983 showing increased accumulation of radioactivity in the striatum. In patients with established bilateral PD, FDOPA PET showed influx constant reductions in the caudate, putamen, striatal nigra, and midbrain. The decline in FDOPA uptake was more rapid in PD than normal subjects. FDOPA PET is a good tool to monitor progression of PD and therapies.

In AD, many advances have been made to understand the involved neuropathological processes. The accumulation of beta-amyloid is a primary pathological event leading to formation of neurofibrillary tangles and loss of synapses and neurons (Huang and Mucke 2012). The first clinically specific tracer for beta-amyloid imaging was ¹¹C-labeled Pittsburgh compound B (PIB) (Klunk et al. 2004). PIB is an analog of thioflavin T that binds to fibrillar beta-amyloid deposits with high sensitivity and specificity. PIB binds to both extracellular amyloid plaques and vascular amyloid deposits. At tracer dosages, PIB does not bind to neurofibrillary tangles or Lewy bodies (Zhang et al. 2012).

To improve the accessibility of beta-amyloid imaging with PET, a second generation of ¹⁸F-amyloid tracers was developed. Four ¹⁸F-amyloid imaging agents are in advanced stages of development: flutemetamol, a 3′-fluoro analog of PIB (Thurfjell et al. 2012); florbetapir, a styrylpyridine derivative (Doraiswamy et al. 2012); FDDNP, a naphthol analog (Ossenkoppele et al. 2012); and florbetaben, a derivative of stilbene (Barthel and Sabri 2011). With the exception of FDDNP, these tracers show comparable results to PIB in clinical populations, although nonspecific white matter binding appears to be higher.

Besides these three [¹⁸F tracers, a few more ligands have been evaluated in man. A human study with [¹¹C]BF-227 showed that retention of radioactivity is higher in brain regions that are known to contain beta-amyloid plaques in AD patients than in control subjects (Furukawa et al. 2010). No significant difference was observed in any brain regions between young and aged normal subjects. 2-(1-(6-[(2-[¹⁸F]Fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([¹⁸F]FDDNP) showed higher binding in AD brain than those of healthy controls. Despite of its slow clearance kinetics for PET imaging, [¹⁸F]FDDNP is used for detection of both neurofibrillary tangles and beta-amyloid plaques in patients with AD. In a comparative study between [¹¹C]PIB and [¹⁸F]FDDNP, cortical binding potential of [¹¹C]PIB showed higher binding in patients with AD than in controls and patients with mild cognitive impairment (MCI). [¹⁸F]FDDNP uptake was higher in brains of AD patients than in healthy controls, but MCI could not be distinguished from AD or from controls. Differences in binding potentials between patients with AD, or MCI, and healthy controls were more pronounced for PIB.

Glycine acts as a neurotransmitter and is a modulator of the neuroexcitatory activity of the N-methyl-d-aspartate (NMDA) receptor. Impaired function of the NMDA receptor is responsible for cognitive dysfunction in patients suffering from neuropsychiatric diseases, like schizophrenia and related disorders (Zorumski and Izumi 2012). Specific transporters are responsible for the uptake of glycine into the brain. The high-affinity transporters, GlyT-1 and GlyT-2, block the activity of glycine on the NMDA receptor in the synapse. GlyT-1 has been shown to maintain low levels of glycine at the synapse. Inhibition of GlyT-1 would increase glycine concentrations around the synapse, resulting in enhanced activity of the NMDA receptor. Several imaging agents for GlyT-1, such as [¹⁸F]-2,4-dichloro-N-((1-(propylsulphonyl)-4-(6-fluoropyridine-2-yl)piperidine-4-yl)methyl)benzamide ([¹⁸F]MK-6577 and [¹¹C]GSK931145 were developed. Although the tracer is slowly metabolized, [¹¹C]GSK931145 has been successfully evaluated for the in vivo visualization of GlyT-1a humans (Gunn et al. 2011).

Permeability of the blood–brain barrier (BBB) is one of the factors of protection of the brain against harmful compounds (Bartels 2011). The BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. In addition, there are transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and organic anion-transporting polypeptides (OATPs). The action of these carrier systems results in rapid efflux of harmful compounds from the central nervous system (CNS). P-gp is the most studied transporter with PET and SPECT. PET studies related to P-gp were directed to (i) direct evaluation of the effect of P-gp modulators on the cerebral uptake of therapeutic drugs, (ii) assessment of mechanisms underlying drug resistance in epilepsy, (iii) examination of the role of the BBB in the pathophysiology of neurodegenerative and affective disorders, and (iv) exploration of the relationship between polymorphisms of transporter genes and the pharmacokinetics of test compounds within the CNS (Colabufo et al. 2010; Elsinga et al. 2005).

Several radiotracers have been prepared to study P-glycoprotein function in vivo with PET or these tracers unintendedly proved to be P-gp substrates. These include alkaloids ([¹¹C]colchicine), anticancer drugs ([¹¹C]daunorubicin, [¹⁸F]paclitaxel, [¹¹C]tariquidar, [¹¹C]elacridar), calcium antagonists ([¹¹C]-R-(+)-verapamil), ß-adrenoceptor antagonists ([¹¹C]-(S)-carazolol, [¹⁸F]-(S)-1′-fluorocarazolol, [¹¹C]carvedilol), serotonin 5-HT_1A receptor antagonists ([¹⁸F]MPPF), opioid receptor antagonists ([¹¹C]loperamide, [¹¹C]carfentanyl), and various ⁶⁴Cu-labeled copper complexes. By far, [¹¹C]verapamil is the most investigated PET tracer for P-gp. The tracer has been administered to healthy volunteers and blocking studies with the immunosuppressant agent cyclosporin A were carried out. The results indicated that P-gp activity at the human BBB can be measured despite its high lipophilicity. Using the distribution volume as parameter, [¹¹C]verapamil uptake in the midbrain was significantly increased (18 %) in Parkinson’s disease patients compared with healthy controls. This suggests a decrease in P-gp activity at the BBB of PD patients (Bartels et al. 2010).

Loperamide is an opiate agonist and a substrate for P-gp at the BBB. [¹¹C]Loperamide ([¹¹C]Lop) has been applied for studying P-gp function and multidrug resistance in tumors and normal tissues noninvasively. However, demethylation of [¹¹C]Lop to [N–methyl–¹¹C]-N-desmethyl-loperamide ([¹¹C]dLop) hampers its use as PET tracer for P-gp function since [¹¹C]dLop is also a good substrate for P-gp. Therefore, [¹¹C]dLop has been studied as a PET tracer for studying P-gp function (Seneca et al. 2009). In a study with healthy volunteers, there was minimal brain uptake of [¹¹C]dLop. There were five hydrophilic radiometabolites. Because of much lower nonspecific binding, [¹¹C]dLop is preferred over [¹¹C]verapamil.