Monoamines

Dopaminergic function (Fig. 33D.1) can be assessed using 6-[¹⁸F]fluoro-l-dopa (FD), an analog of levodopa that is decarboxylated to [¹⁸F]fluorodopamine and trapped in synaptic vesicles, or by its false neurotransmitter analog 6-[¹⁸F]fluoro-meta-tyrosine (FMT). The membrane dopamine transporter (DAT) can be assessed using either PET or SPECT using a variety of tropane (cocaine-like) analogs labeled with C-11, F-18, iodine-123 (¹²³I), or technetium-99m (^99mTc), or with the non-tropane [¹¹C]d-threo-methylphenidate. FD uptake/decarboxylation and expression are subject to changes that may arise as a compensatory mechanism or in response to pharmacological manipulations. In contrast, [¹¹C]dihydrotetrabenazine (DTBZ), which labels the vesicular monoamine transporter type 2 (VMAT2) responsible for packaging monoamines into synaptic vesicles, is theoretically less subject to such influences. VMAT2 is, however, expressed by all monoaminergic neurons and is therefore not specific for dopamine (although dopaminergic nerve terminals represent the majority of VMAT2 binding in the striatum).

Fig. 33D.1 Schematic of a dopaminergic nerve terminal with examples of positron emitting labels. ¹¹C-DTBZ, [¹¹C]dihydrotetrabenazine; ¹¹C-MP, [¹¹C]d-threo-methylphenidate; ¹¹C-RAC, [¹¹C]raclopride; DAT, plasmalemmal dopamine transporter; D₂R, dopamine D₂ receptor; ¹⁸F-dopa, 6-[¹⁸F]fluoro-l-dopa; ¹⁸F-DA, 6-[¹⁸F]fluorodopamine; VMAT2, type 2 vesicular monoamine transporter.

Dopamine receptors can be studied using a variety of C-11- or F-18-labeled ligands for the D₂ receptor (some ¹²³I-labeled ligands are available for SPECT as well), with fewer options available for the D₁ receptor. Some D₂ receptor ligands are susceptible to competition from endogenous dopamine or by pharmacological agents that bind to dopamine receptors. On the one hand, this can lead to problems of interpretation because differences in binding could potentially reflect alterations in receptor occupancy by endogenous neurotransmitter rather than changes in receptor expression. However, this property may also be extremely useful for estimating changes in dopamine release in response to a variety of behavioral (Monchi et al., 2006), pharmacological (Piccini et al., 2003; Tedroff et al., 1996), or physical (Strafella et al., 2003) interventions.

Serotonin (5-hydroxytryptamine [5HT]) nerve terminal function can be studied by the radiolabeled precursor α-[¹¹C]methyl-l-tryptophan (analogous to FD uptake as a measure of dopaminergic integrity) or by agents that bind to the membrane 5HT transporter, of which the most widely accepted example is [¹¹C]DASB. The 5HT₂ receptor can be labeled with [¹¹C]MDL 100,907 or [¹⁸F]setoperone, but these tracers have suboptimal kinetics (MDL) or selectivity (setoperone). Another option is [¹⁸F]altanserin, whose binding characteristics are very similar to those of [³H]MDL 100,907 in vitro (Kristiansen et al., 2005). Binding is relatively insensitive to endogenous 5HT, and interpretation could theoretically be affected by the presence of radiolabeled metabolites that cross the blood-brain barrier (BBB) (Price et al., 2001), but standard graphical analysis appears to be adequate, and changes are seen in Alzheimer disease (AD; decreased) (Marner et al., 2010) and Tourette syndrome (TS) (increased) (Haugbol et al., 2007). Binding of [¹⁸F]altanserin correlates with response to tonic heat pain (Kupers et al., 2009), and 5HT_1A receptors can be labeled with [¹¹C]WAY 100,635. In the raphe, the latter agent binds to presynaptic somatodendritic autoreceptors, and its binding accordingly gives an indirect measure of serotonergic integrity, whereas binding in other regions is predominantly postsynaptic. Unlike the situation with dopamine receptor binding, changes in the binding of serotonergic ligands cannot routinely be used to assess alterations in the availability of endogenous 5HT.

Cholinergic Systems

Presynaptic cholinergic function can be assessed using agents that bind to the vesicular cholinergic transporter, such as [¹²³I]iodo-benzovesamicol or substrates for acetylcholinesterase such as [¹¹C]PMP or [¹¹C]MP4A. The latter are hydrolyzed and cleared, and it is the clearance that is measured as an indicator of neuronal activity.

A number of ligands have been developed for both muscarinic (Asahina et al., 1998; Eckelman, 2006) and nicotinic (Ding et al., 2006; Horti et al., 2010) cholinergic receptors.

Neuropeptides

Opioid peptide receptors have been most widely studied using PET with [¹¹C]diprenorphine (nonselective) or [¹¹C]carfentanil (selective for µ-opioid receptors). Both agents are thought to be susceptible to competition from endogenous opioids. In the case of [¹¹C]carfentanil, this property has been used to demonstrate opioid release in response to pain (Zubieta et al., 2001) and to placebo analgesia (Zubieta et al., 2005). In vivo imaging of opioid receptors has been extensively reviewed in a recent paper (Henriksen and Willoch, 2008).

Amino Acids

The agent [¹¹C]flumazenil is a benzodiazepine receptor inverse agonist and can be used to assess γ-aminobutyric acid (GABA)_A receptors. It is not clear, however, whether its binding is susceptible to competition from endogenous GABA. The peripheral benzodiazepine receptor is used as a marker of microglial activation and will be discussed later under pathology-seeking agents.

There has been relatively limited use of agents to study excitatory amino acid receptors, but recently agents for the mGluR5 (Honer et al., 2007; Kimura et al., 2010; Lucatelli et al., 2009; Mu et al., 2010; Patel et al., 2007; Sanchez-Pernaute et al., 2008; Treyer et al., 2007; Yu, 2007), as well as the N-methyl-d-aspartate (NMDA) (Robins et al., 2010; Waterhouse, 2003) and glycine-binding site of the NMDA receptor (Fuchigami et al., 2009) have been developed.

Inflammation

The peripheral benzodiazepine receptor (PBR) ligand, [¹¹C]PK 11195, has been used as a marker of microglial activation; [¹¹C]PK 11195 binding is increased in disorders with known inflammatory response such as multiple sclerosis (MS) (Banati et al., 2000), encephalitis (Banati et al., 1999; Cagnin et al., 2001b