**3.3 Measurement of the Vesicular Monoamine Transporter (VMAT) 2**

In neurodegenerative diseases there are typically characteristic losses of particular types of neurons in the human brain. As outlined above, progressive losses of dopaminergic neurons is the hallmark of Parkinson's disease. Reflecting this, a number of strategies have been developed for *in vivo* imaging of such neuronal losses. One such approach involves targeting the vesicular monoamine transporter type 2 (VMAT2) using radioligands such as (+)-α-[11C]dihydrotetrabenazine ([11C]DTBZ: (2*R*,3*R*,11b*R*)-(1,3,4,6,7,11b-hexahydro-9- [11C]methoxy-10-methoxy)-3-(2-methylpropyl)-2-hydroxy-2H-benzo[a]quinolizine) (K. A. Frey, et al., 2001). The VMAT2 is not specific for any monoamine, but is a common protein capable of transporting dopamine, norepinephrine, serotonin and histamine (Eiden and Weihe, 2011). Despite this non-specificity, the utility of VMAT2 imaging in neurodegenerative disease is still possible due to the compartmentalization of neuronal types in the human brain (K. A. Frey, et al., 2001). For example, dopaminergic nerve terminals predominate in the basal ganglia, and so enable specificity for examining losses of such terminals in PD patients (Figure 3). The VMAT2 is found in presynaptic vesicles, and transports monoamines from the cell cytosol into the storage vesicle, from where they can be released into the synapse (Wimalasena, 2011).

Lee and colleagues conducted a comparison between [11C]DTBZ, [18F]DOPA and [11C]methylphenidate (a radiopharmaceutical targeting the dopamine transporter (DAT)) (C. S. Lee, et al., 2000). Reflecting the upregulation of aromatic amino acid decarboxylase, and concomitant down regulation of the DAT, that occurs to increase dopamine turnover and reduce its reuptake in Parkinson's disease patients, this study found that [18F]DOPA Ki was reduced less than the [11C]DTBZ binding potential in the PD striatum, and [11C]DTBZ binding was reduced when compared to [11C]methylphenidate binding. The authors suggest that [11C]DTBZ PET is the most reliable method for quantifying dopaminergic terminal density although, per Pavese and Brooks (Pavese and Brooks, 2009), this needs to be validated and the effect of dopaminergic drugs upon [11C]DTBZ uptake determined.

Reflecting the drive to convert short lived carbon-11 labeled radiopharmaceuticals (t1/2 = 20 min) into longer lived fluorine-18 labeled analogs (t1/2 = 110 min) to facilitate distribution to satellite PET centers that do not own a cyclotron, [18F]FP-TBZ ([18F]AV-133) has also been developed to image the VMAT2, and is licensed to Avid Radiopharmaceuticals (H. F. Kung, et al., 2008). In studies by Frey and colleagues, AV-133 PET of normal and PD patients were compared (K. A. Frey, et al., 2008). Findings were similar to [11C]DTBZ, and AV-133 PET provided excellent images of the VMAT2. All PD patients had severe reduction of AV-133 accumulation in the striatum, most severe in the PP contralateral to worst PD symptoms. Similar findings were confirmed in further studies by Okamura and co-workers in 2010 (N. Okamura, et al., 2010), and very clear images showing the differences in AV-133 PET between PD patients and healthy controls were obtained (Figure 4).
