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Peripheral Benzodiazepine Receptors
- 2. Benzodiazepine • A benzodiazepine (sometimes colloquially "benzo"; often abbreviated "BZD") is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring. • Benzodiazepines enhance the effect of the neurotransmitter gamma- aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties.
- 3. CBR and PBR Central benzodiazepine receptor GABAA receptor CNS α-subunit binding Inhibitory effect Peripheral benzodiazepine receptor TSPO Peripheral tissues and glial cells Heteromeric complex Cholesterol transport • BZDs also bind to other receptors, located mainly in peripheral tissues and glial cells in the brain.
- 4. TSPO The translocator protein (18 kDa) (TSPO) is a five transmembrane domain protein that is localized primarily in the outer mitochondrial membrane.
- 5. PBR distribution • The PBR is widely expressed throughout the body, with high densities found in steroid-producing tissues. Christopher J. Endres et. al.
- 6. Functions • Cholesterol transport: TSPO binds with high affinity to cholesterol and transports it across the mitochondrial membrane where it is used in steroid synthesis. • Immunomodulation: Expression of TSPO has been linked to inflammatory responses that occur after ischemia-reperfusion injury, following brain injury, and in some neurodegenerative diseases. • Apoptosis: Ligands of TSPO have been shown to induce apoptosis in human colorectal cancer cells. • Cell proliferation • An indicator of the importance of TSPO is that disruption of the gene in mice results in embryonic death.
- 7. Structure of TSPO, docking with cholesterol and mitochondrial localization Rupprecht R et.al. Nat Rev Drug Discov. 2010 Dec;9(12):971-88. doi: 10.1038/nrd3295.
- 9. Therapeutic Applications • TSPO has been shown to be involved in a number of processes such as inflammation,and TSPO ligands may be useful anti-cancer drugs. Activation of TSPO is also required for steroidogenesis to take place, and this is particularly important for the production of neuroactive steroids such as allopregnanolone in the brain. This makes some TSPO ligands such as emapunil (XBD-173) useful as potential anxiolytics which may have less side effects than traditional benzodiazepine-type drugs.
- 10. Emapunil (XBD-173) - potential anxiolytic XBD173 (AC-5216, emapunil) is a phenylpurine with high and rather selective affinity to TSPO, which has recently been investigated for the treatment of anxiety disorders. XBD173 enhances neurosteroidogenesis in the brain, thereby exerting anxiolytic properties in animal models and in humans. Eur Arch Psychiatry Clin Neurosci (2012) 262 (Suppl 2):S107–S112 score
- 11. Ligands • The benzodiazepine Ro5-4864 and the isoquinoline carboxamide PK11195 exhibit nanomolar affinity for the PBR, and are the archetypic pharmacological tools for characterizing the receptor and its function. • PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylprolyl)-3-isoquinoline carboxamide,] is currently the most widely used PBR ligand.
- 12. Effect of PBR ligands on cellular activity in different cell types Gavish et. al. 1999
- 13. A translocator protein ligand PK11195 shows antigrowth activity in human choriocarcinoma cells • BeWo choriocarcinoma cells showed significant sensitivity to PK11195 with a concentration of 8.0×10−5M which caused a 50 % inhibition (ED50) in their growth. On the other hand, choriocarcinoma cells showed little sensitivity to diazepam from a concentration of 1×10−7 to 1×10−4 M. • PK11195 led to a dramatic increase in the sub-G0/G1 apoptotic cell population and G0/G1 phases of the cell cycle compared to treatment with vehicle alone, with a concomitant decrease in the proportion of cells in the S phase. Tumor Biol. (2012) 33:1505–1510
- 14. Alterations in PBR binding characteristics in various hyperplastic and cancer tissues Noninvasive molecular imaging of TSPO expression could form the basis of a predictive cancer imaging biomarker. Gavish et. al. 1999
- 15. PK or not PK Historically, the TSPO ligand used most commonly with PET is 11C-R-PK11195. Although it has been used successfully for numerous clinical studies, 11C-R-PK11195 has pharmacokinetic properties, such as high nonspecific binding, that are suboptimal for imaging. Alex Sik Chung Ching et.al. Insights Imaging(2012)3:111–119
- 16. Quantitative Preclinical Imaging of TSPO Expression in Glioma Using 18F-DPA-714 Tang et. al. JNuclMed2012;53:287–294
- 17. Take home message Pro-apoptotic effect Neuro- protective effect Outcome depends on: *Ligand type *Ligand concentration *Disease type
Editor's Notes
- Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely Based on its pharmacological profile, the PBR was initially considered a subtYpe of CBR The translocator protein (TSPO) was originally discovered and named the peripheral-type benzodiazepine receptor (PBR) in 1977 when investigators found a second binding site for the benzodi-azepine diazepam in renal tissue distinct from GABAAreceptorwithin the central nervous system
- Cytosolic loops 1and 2 are responsible for the binding of small molecule ligands, such as benzodiazepines or pyrazolopyrimidines. The cytosolic C-terminal region binds cholesterol molecules.
- Summed coronal 2-dimensional projections of tracer activity after bolus injection of 11C-DPA-713. Seven whole-body passes were performed as described. Images from left to right are from passes 1, 3, and 5 and show tracer biodistribution from 1 to 3, from 10 to 16, and from 28 to 42 min after injection, respectively. Images are displayed to same maximum. Lung uptake is prominent immediately after injection. Substantial tracer uptake is also observed in kidneys, spleen, liver, and brain. The highest residence times were obtained in the lungs, liver, red marrow, brain, kidney, and small intestine. The highest absorbed doses were obtained in the lungs, spleen, kidney, pancreas, heart, and liver.
- TSPO expression may constitute a biomarker for brain inflammation that could be monitored by using TSPO tracers as neuroimaging agents.
- cholesterol recognition amino acid consensus (CRAC)
- The PBR appears to be a heteromeric complex of at least three different subunits, including an isoquinoline binding subunit (18 kDa), a VDAC (32 kDa), and an adenine nucleotide carrier PAP7 is a functional element of the hormone-induced signal transduction cascade leading to steroidogenesis
- Fig. 3 Modified according to [46]. Effect of XBD173 on CCK-4 induced panic. a Area under the time curve (AUC) of the acute panic inventory (API) score of healthy male volunteers during a first (before treatment) and a second (after 7 days of treatment) CCK-4 challenge. Box plots represent the median equivalent to the 50 % percentile (line within the boxes), the range containing all individual values above the 25 % and below the 75 % percentile (boxes) and the range of individual values within 150 % above or below the difference between the 75 % and the 25 % percentile (error bars). Open circles represent outliers located more than 150 %, and asterisks represent extreme values located more than 300 % of the box height above the 75 % percentile. b Decrease in CCK-4 induced panic (delta APIAUC) after treatment with different dosages of XBD173, the BZD alprazolam or placebo in relation to baseline AUC (mean ± SEM). Asterisks indicate a significant difference from placebo (ANCOVA: 90 mg XBD173 P\0.036, alprazolam P\0.019) In contrast to BZDs, XBD173 did not directly enhance GABAA receptor-mediated chloride currents [46]. XBD173 counteracted pharmacologically induced panic attacks in rodents without exerting sedative effects [46]. In healthy male volunteers, the antipanic efficacy of XBD173 was comparable to the BZD alprazolam during pharmacologically induced panic by cholecystokinin tetrapeptide (CCK-4) [46] (Fig. 3). This placebo–controlled, parallel group-proof of concept study included subjects with a sufficient panic response after CCK-4 application. Seventyone subjects were randomized to a 7-day treatment with placebo, 10, 30 or 90 mg/day XBD173 or 2 mg/day alprazolam. At the end of the study, subjects underwent a second CCK-4 challenge. The difference in the acute panic inventory (API) (area under the time curve; AUC) between the first and the second CCK-4 challenge relative to the effects of placebo was defined as readout for anxiolytic efficacy. For both alprazolam and the highest dose of XBD173, a significant difference from placebo could be demonstrated. Interestingly, the XBD173 groups did not suffer from sedation or withdrawal symptoms after the 7-day treatment in contrast to alprazolam treated subjects.
- positron emission tomography (PET) PET principle: imaging agents used for PET are radioactive probes emitting positively charged anti-electrons (positrons). The positron travels a short distance (∼1–3 mm) before it annihilates with any electron to give two photons of 511 keV travelling under a mutual angle of 180°. It is this pair of coincident high energy photons that underly the PET principle allowing in vivo quantitative 3D imaging through coincident detection using a gantry of multiple detectors around the patient
- (A)T2-weightedMRimageofC6glioma–bearingratinrightbrainhemisphere.(B)CoronalPETimageobtainedfromdynamic scanof 18F-DPA-714PET(summeddynamicscan,0–90min).(C) 18F-DPA-714time–activitycurvesfortumor(blue),contralateralbrain (green),andplasma(red).(D)TransversePETimageobtainedfromdynamicscanof 18F-DPA-714PET(summeddynamicscan,0–90min). (E)Standard hematoxylin and eosin staining of serial tissue section.(F)ImmunohistochemistryanalysisofTSPOexpressionintypicalC6 glioma.Tumorlocationisindicatedwitharrowsinimages.%ID/cc 5 percentageinjecteddosepercubiccentimeter.