Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters
Introduction
There are two vesicular monoamine transporters (VMATs): VMAT1, found in the adrenal tissue, and VMAT2, a neuronal vesicular membrane monoamine transporter found in the brain. VMAT2 is an integral part of the mechanism for the vesicular storage of monoamine neurotransmitters in brain neurons. In contrast to the situation at the synaptic membrane where there are specific transporters for active reuptake of dopamine, serotonin or norepinephrine from the synapse, movement of monoamines (dopamine, serotonin and norepinephrine) from the cytosol to the vesicular lumen is via a common adenosine triphosphate-dependent transporter. Therefore, imaging VMAT2 in the brain provides a measurement reflecting the integrity (total number) of all three monoaminergic neurons [1].
Parkinson's disease (PD) is a movement disorder characterized by tremor and dyskinesia. Degeneration of nigrostriatal dopamine neurons plays a central role in PD. Currently, the development of neuroprotective agents to slow down or prevent the progression of this disease is actively being pursued. There is a compelling need for positron emission tomography (PET) and single photon emission computer tomography (SPECT) imaging agents for early diagnosis and monitoring of the progression of PD [2]. Based on mechanisms of localization, current PET and SPECT imaging agents for PD can be generally divided into three categories: (1) enzymatic activity (aromatic amino acid decarboxylase, AADC); (2) dopamine transporters (DATs); and (3) VMATs (VMAT2). The 18F-labeled 6-fluoro-dopa (FDOPA) was the first PET imaging agent for PD and remains to be a commonly used PET agent. It is a false substrate for AADC, the first step of synthesis of dopamine. PET imaging with [18F]6-FDOPA provides a glimpse of neuronal function — in situ synthesis of dopamine (or the lack thereof) [3], [4]. The AADC is localized not only in dopamine neurons but also in other brain cells. In the brains of patients with PD, the AADC enzyme is often up-regulated and the peripheral metabolites, O-methylated derivatives, will also be taken up in the brain, contributing to background noise. [18F]6-FDOPA imaging reflects the loss of neuronal function related to AADC and may underestimate the degree of neuronal loss due to compensatory changes [2], [5], [6]. In the past 10 years, there has been a plethora of DAT imaging agents, most of which are tropane (or cocaine) derivatives that have varying degrees of affinity to serotonin and norepinephrine transporters [7], [8]. A recent report [9] pointed out deficiencies in imaging PD based on DAT tracers, which highlighted the urgent need for imaging agents that can reliably diagnose and predict the progress of this neurodegenerative disease. As an alternative, 11C-labeled tetrabenazine (TBZ) derivatives have been successfully developed targeting VMAT2 and tested in humans [10]. Animal data strongly suggested that [11C](±)-dihydrotetrabenazine (DTBZ) is less sensitive to drugs affecting dopamine levels in the brain; therefore, it reflects more accurately the concentration of viable monoamine neurons [11], [12], [13], [14]. Using VMAT2 as a marker of identified neuronal populations has also suggested selective degeneration of projection neurons in Huntington's disease striatum (ST) [12], [13]. It is clear that the optically resolved isomer [11C](±)-DTBZ (2) (labeled at the 9-MeO position) is an excellent PET tracer for measuring VMAT2 sites in the brain [15], [16].
To further improve the availability of PET imaging for studying VMAT2 binding sites of dopamine, serotonin and norepinephrine neurons in the brain, we have been searching for 18F-labeled DTBZ analogs (T1/2=110 min), which will greatly increase the application of these tracers in clinics equipped with PET scanners but not with sufficient resources to make [11C]2 (T1/2=20 min). It is likely that an 18F-labeled VMAT2 tracer could be readily manufactured and distributed by a national network of radiopharmacies currently supplying [18F]FDG for PET imaging studies in the clinics. When an 18F-labeled VMAT2 tracer is approved by the FDA, the same supply network may also provide the 18F tracers to achieve a widespread application. Reported in the present study are the syntheses of two fluorinated compound 2 derivatives. To our knowledge, these are the first examples of 18F-labeled PET imaging agents targeting VMAT2 binding sites of dopamine, serotonin and norepinephrine neurons in the brain.
Section snippets
Methods
All reagents used in synthesis were commercial products and were used without further purification unless otherwise indicated. 1H-NMR spectra were obtained on a Bruker DPX spectrometer (200 MHz) in CDCl3. Chemical shifts are reported as δ values (parts per million) relative to internal TMS. Coupling constants are reported in hertz. Multiplicity is defined as s (singlet), d (doublet), t (triplet), br (broad), or m (multiplet). Mass spectrometry was performed by the staff of the Mass Spectrometry
Results and discussion
In the past two decades, various TBZ derivatives have been used as potential ligands for mapping or imaging VMAT2 [10], [12] (Fig. 1). Our earlier work on developing SPECT ligands (i.e., [123I]2-iodovinyl-DTBZ, labeled at the C-2 position) for visualizing VMAT2 did not result in successful imaging probes [17]. In the past few years, our laboratory has renewed the effort and focused on developing 18F-labeled DTBZ derivatives as specific VMAT2 ligands for PET. The successful development of 18
Acknowledgments
This work was supported by grants awarded by the National Institutes of Health (EB-002171 for H.F.K. and NS-015655 for M.R.K.).
We thank the NIMH's Chemical Synthesis and Drug Supply Program for providing compounds 1 and 2.
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