Positron emission tomography imaging peripheral benzodiazepine receptors in the living brain

Advances in positron emission tomography (PET) have made possible non-invasive visualization and measurement of specific biochemical processes in the living brain with exquisite resolution. A detailed technical description of this technique is beyond the scope of this chapter.6667 Briefly, PET is based on the use of short-lived (minutes), positron-emitting radioisotopes (carbon-11, fluorine-18) for labeling organic molecules or drugs which are part of specific biochemical reactions or interact with specific recognition sites in the brain such as receptors or enzymes. Following the intravenous injection of a radioactively labeled ligand, the distribution of the radioactivity in the brain can be measured by coincidence detection of geometrically opposite gamma rays (0.511 KeV) that are emitted when the positron radiation emitted decays. The gamma rays are detected in coincidence by a ring of detectors in the PET scanner and the distribution of the radioactivity is computer reconstructed to form an image. The image is a direct reflection of the amount and spatial distribution of the interaction of the radiolabeled ligand with its biological target. Figure 28.4 is a PET image representing the normal distri-

Figure 28.3 (See color insert following page 392.) Total binding of [3H]-R-PK11195 to peripheral benzodiazepine receptors in horizontal rat brain sections of cuprizone treated (top) animals (0.2% in diet for 4 weeks) and controls (bottom). Note the high levels of binding in cuprizone-treated brain in the corpus collosum (CC) and deep cerebellar nuclei (CN). Increased binding was also present in other brain structures such as the hippocampus (Hipp), cerebral cortex (Ctx), caudate/putamen (C/P), entorhinal cortex (Ec) and thalamus (Thal). High level of [3H]-R-PK11195 to peripheral benzodiazepine receptors is normally found in the choroid plexus (cp) and ventricles (3v, third ventricle). The cerebellum (Cb) is noted as an anatomical landmark. Red represents high levels of binding; yellow-green, intermediate levels; and blue, low levels.

Figure 28.3 (See color insert following page 392.) Total binding of [3H]-R-PK11195 to peripheral benzodiazepine receptors in horizontal rat brain sections of cuprizone treated (top) animals (0.2% in diet for 4 weeks) and controls (bottom). Note the high levels of binding in cuprizone-treated brain in the corpus collosum (CC) and deep cerebellar nuclei (CN). Increased binding was also present in other brain structures such as the hippocampus (Hipp), cerebral cortex (Ctx), caudate/putamen (C/P), entorhinal cortex (Ec) and thalamus (Thal). High level of [3H]-R-PK11195 to peripheral benzodiazepine receptors is normally found in the choroid plexus (cp) and ventricles (3v, third ventricle). The cerebellum (Cb) is noted as an anatomical landmark. Red represents high levels of binding; yellow-green, intermediate levels; and blue, low levels.

bution of the PBR selective ligand [nC]-R-PK11195 and the dopamine transporter selected ligand [11C]-WIN 35,428 in a normal nonhuman primate brain. PBR expression is found at low concentrations and homogeneously distributed throughout the brain neuropil indicative of resident glial cells. On the other hand, the distribution of [11C]-WIN 35,428 is concentrated in the caudate/putamen, a brain area highly enriched in high affinity dopam-inergic transporters. We are currently using these imaging techniques to assess brain damage resulting from specific chemical exposures in nonhuman primates.

A. Positron emission tomography of peripheral benzodiazepine receptor expression in human neurological disease

The use of PBR-PET has received increased attention in recent years. Although PBR-PET studies were performed in the late 1980s when PET

Figure 28.4 (See color insert following page 392.) PET studies of [UC]-R-PK11195 to peripheral benzodiazepine receptors (right) and [11C]-WIN 35,428 to dopamine transporters (left) in a normal nonhuman primate (baboon) brain (transaxial view). Note the highly concentrated levels of dopamine transporters in the caudate/putamen (C/P). A much more homogeneous distribution of peripheral benzodiazepine receptors in the brain neuropil is observed in the same animal. The brain is delineated by the white boundaries. Red represents high levels of binding; yellow-green, intermediate levels; and blue, low levels.

Figure 28.4 (See color insert following page 392.) PET studies of [UC]-R-PK11195 to peripheral benzodiazepine receptors (right) and [11C]-WIN 35,428 to dopamine transporters (left) in a normal nonhuman primate (baboon) brain (transaxial view). Note the highly concentrated levels of dopamine transporters in the caudate/putamen (C/P). A much more homogeneous distribution of peripheral benzodiazepine receptors in the brain neuropil is observed in the same animal. The brain is delineated by the white boundaries. Red represents high levels of binding; yellow-green, intermediate levels; and blue, low levels.

scanners were becoming available at research institutions, few studies were performed. The lack of studies was the result of poor image quality due to the use of racemic PK11195, poor spatial resolution of PET scanners, inherently low levels of PBR in the brain and the lack of appropriate mathematical models to accurately quantify PBR expression. The limited number of studies performed was related to the detection of gliomas, brain tumors that express high levels of PBR,6869 and the damage produced by stroke.70 More recently, PBR-PET has been used in a number of human neurological diseases because advances in all of the areas that previously contributed to poor image quality have been made. For example, current PET scanners have better spatial resolution and greater axial sampling, the pharmacologically active (R)-PK11195 enantiomer is available and advanced mathematical models are currently used to accurately quantify brain radioactivity.

The use of PBR-PET has now been described in human studies of multiple sclerosis,7172 Rasmussen's encephalitis,73 cerebral vasculitis associated with refractory epilepsy74 and improved imaging of ischemic stroke.75 From the above mentioned studies, it appears that the PBR is a useful marker of inflammation and ongoing gliosis and, in an indirect way, a marker of brain injury. For example, in multiple sclerosis PBR-PET was able to identify active lesions from nonactive lesions as defined by magnetic resonance imaging.71,72 Further, PBR-PET was able to identify additional areas of brain damage beyond the lesion sites. In summary, it appears that PBR-PET provides a molecular marker of disease activity that can be monitored in the living human brain. Thus, it can be potentially useful to follow disease progression as well as to assess the effectiveness of therapeutic interventions.

B. Future application of in vivo imaging of peripheral benzodiazepine receptors in rodent and nonhuman primate models of disease

1. The use of quantitative receptor autoradiography has been a valuable tool to monitor the temporal and anatomical changes in [3H]-R-PK11195 binding to PBR in rodent models of neurotoxicity. One of the limitations of this technique is that it requires postmortem brain tissue. The possibility of imaging biochemical reactions or recognition sites in the brain of living animals such as rodents and small nonhuman primates has now become a reality. This is due to the fact that unprecedented advances have taken place in the development of dedicated small animal PET scanners.7677 There are currently an emerging number of small animal scanners to perform PET studies in rodents and small nonhuman primates that offer spatial resolution in the order of 2-3 mm. Further, the resolution of the next generation of small animal scanners is in the order of 1 mm or less. These advances make it feasible to perform PET studies in the brain of living mice and rats as well as small monkeys. There are a number of advantages to this approach:

2. Small animal imaging allows investigators to monitor molecular changes in the living brain as a result of experimental treatments in real time, and can be measured in the same animal from development to aging.

3. The ability to monitor the animal in a longitudinal fashion reduces the number of animals needed to perform a particular study, since the animals do not have to be euthanized at specific time points during treatment to harvest brain tissue. Further, the animal serves as its own control, thus reducing biological variability.

4. Animal imaging allows the investigator to follow molecular changes in the brain in parallel with other cellular or behavioral outcomes that can be measured in the live animal.

5. Animal imaging saves having to terminate valuable rodent models such as transgenics, knockouts, or expensive and valuable nonhuman primates.

Animal imaging makes it possible to perform multiple studies per day in the same animal. The advances that can be by made by small animal PET imaging in combination with advances in genomics and proteomics, is only limited by the imagination of the scientists using it.

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