P. Vaska

Evidence That Brain MAO A Activity Does Not Correspond to MAO A Genotype in Healthy Male Subjects

BACKGROUND A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects. METHODS Brain MAO A activity was measured with positron emission tomography and [(11)C]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism. RESULTS There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes. CONCLUSIONS The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects.

Small animal simultaneous PET/MRI: initial experiences in a 9.4 T microMRI

We developed a non-magnetic positron-emission tomography (PET) device based on the rat conscious animal PET that operates in a small-animal magnetic resonance imaging (MRI) scanner, thereby enabling us to carry out simultaneous PET/MRI studies. The PET detector comprises 12 detector blocks, each being a 4 × 8 array of lutetium oxyorthosilicate crystals (2.22 × 2.22 × 5 mm(3)) coupled to a matching non-magnetic avalanche photodiode array. The detector blocks, housed in a plastic case, form a 38 mm inner diameter ring with an 18 mm axial extent. Custom-built MRI coils fit inside the positron-emission tomography (PET) device, operating in transceiver mode. The PET insert is integrated with a Bruker 9.4 T 210 mm clear-bore diameter MRI scanner. We acquired simultaneous PET/MR images of phantoms, of in vivo rat brain, and of cardiac-gated mouse heart using [(11)C]raclopride and 2-deoxy-2-[(18)F]fluoro-D-glucose PET radiotracers. There was minor interference between the PET electronics and the MRI during simultaneous operation, and small effects on the signal-to-noise ratio in the MR images in the presence of the PET, but no noticeable visual artifacts. Gradient echo and high-duty-cycle spin echo radio frequency (RF) pulses resulted in a 7% and a 28% loss in PET counts, respectively, due to high PET counts during the RF pulses that had to be gated out. The calibration of the activity concentration of PET data during MR pulsing is reproducible within less than 6%. Our initial results demonstrate the feasibility of performing simultaneous PET and MRI studies in adult rats and mice using the same PET insert in a small-bore 9.4 T MRI.

Low monoamine oxidase B in peripheral organs in smokers

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,l-[11C]deprenyl and deuterium-substituted l-[11C]deprenyl (l-[11C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.

PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( --)-cocaine.

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (−)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods: d- and l-methamphetamine and (−)-cocaine were labeled with 11C via alkylation of the norprecursors with 11C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2–3 h apart to determine the distribution and kinetics of 11C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11C-d-Methamphetamine pharmacokinetics were compared with 11C-l-methamphetamine and 11C-(−)-cocaine in both brain and peripheral organs in the same animal. Results: 11C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11C-d-methamphetamine and 11C-(−)-cocaine showed that 11C-d-methamphetamine peaked later in the brain than did 11C-(−)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for 11C-d-methamphetamine. Conclusion: Brain pharmacokinetics did not differ between d-and l-methamphetamine and thus cannot account for the more intense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade by methamphetamine indicates that the PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of 11C-d-methamphetamine and 11C-(−)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (−)-cocaine. High kidney uptake of d-methamphetamine or its labeled metabolites may account for the reported renal toxicity of d-methamphetamine in humans.

Digital Coincidence Processing for the RatCAP Conscious Rat Brain PET Scanner

The RatCAP has been designed and constructed to image the awake rat brain. In order to maximize system performance, offline digital coincidence data processing algorithms including offset delay correction and prompt and delayed coincidence detection have been developed and validated. With offset delay correction using a singular value decomposition (SVD) technique, overall time resolution was improved from 32.6 to 17.6 ns FWHM. The experimental results confirm that the ratio of prompts to randoms was improved because a narrower timing window could be used. 18F-fluoride rat bone scan data were reconstructed using our fully 3-D ML-EM algorithm with a highly accurate detector response model created from Monte Carlo simulation.

A Simultaneous PET/MRI scanner based on RatCAP in small animals

The ability to acquire high resolution anatomical data as well as quantitative functional information in vivo is becoming an increasingly important factor in the diagnosis of disease. Simultaneous acquisition of PET and MRI data would provide essentially perfect co-registration between the two images which is particularly important for tissues whose position and shape can change between sequential scans. RatCAP is a complete 3D tomograph that is designed to image the brain of an awake rat. A special MRI coil composed of 2 saddle elements working in quadrature mode was mounted on a Delrin cylinder specifically designed to fit inside the RatCAP but allowing the rats head to be placed inside as well. Simultaneous PET/MRI images of the rat brain have been acquired in a 4 T MRI scanner using the RatCAP detector, with minimal effect on MRI images.

A prototype CZT-based PET scanner for high resolution mouse brain imaging

One of the most challenging and potentially rewarding research applications of PET is imaging of the mouse brain. Although very high spatial resolution is required (< ~1 mm), there is a much wider variety of transgenic models in mouse compared to the rat. The solid state material CdZnTe (CZT) has long held promise for high resolution PET. Compared to scintillators, its limitations in time resolution and sensitivity can in some ways be compensated by its extremely high spatial and energy resolution, its compact geometry, and by sophisticated data processing techniques. Using such techniques, a time resolution of ~10 ns has been demonstrated for ~1 cm thick CZT pixel detectors, and this may be sufficient for mouse studies. The depth-of-interaction capability and high energy resolution can improve sensitivity by allowing detectors to be placed very close to the subject and by enabling both reconstruction of detector-scattered events and rejection of object-scattered events. A full-ring prototype scanner has been designed to demonstrate feasibility of the concept, consisting of 6 CZT pixel detectors in a novel geometry. The design of the detector, front-end electronics components, and data acquisition are presented, along with performance characterization of the custom-manufactured CZT detectors.

The State of Instrumentation for Combined Positron Emission Tomography and Magnetic Resonance Imaging

Efforts at developing instrumentation for combined positron emission tomography and magnetic resonance imaging have gained considerable momentum in recent years, propelled in particular by new photosensor technologies. Small preclinical prototype systems developed in academia have been scaled up to full-scale small-animal imagers, and commercial whole-body clinical positron emission tomography-magnetic resonance imaging systems are now available. A wide variety of architectures are reviewed, from sequential to simultaneous and preclinical to clinical. Whereas scintillators retain their role for gamma-ray conversion, light guides, photosensors, and electronic readout methods vary widely. Common themes relating to the technical challenges are presented, including electromagnetic interference and shielding. Technological directions that will likely gain in importance in the future are discussed, such as the ability to measure time of flight and depth of interaction.

Results from prototype II of the BNL simultaneous PET-MRI dedicated breast scanner

At Brookhaven National Laboratory, we are developing a simultaneous PET-MRI breast imaging system. A prototype II version of the PET system has been constructed. This device consists of 24 detector blocks where each block consists of a 4 × 8 array of 2.2 × 2.2 × 15 mm3 LYSO crystal directly coupled to a 4 × 8 non-magnetic APD array. The scanner has an inner diameter of 100mm and an axial extent of 18mm. Resolution measurements were carried out for the prototype system to evaluate the depth of interaction effects. Average resolution less than 2mm FWHM was maintained throughout the field of view. The prototype PET system was operated unshielded inside the RF coil of the Aurora 1.5 T dedicated breast MRI machine. Artifact free MRI images with good SNR were obtained.

Development of a simultaneous PET/MRI scanner

A combined magnetic resonance imaging (MRI) and positron emission tomography (PET) scanner would be a great benefit to nuclear medicine. The anatomical detail given by MRI and spectroscopy available with magnetic resonance spectroscopy (MRS) complement the quantitative physiological imaging obtained with PET. Such a device has not become a reality because of the incompatibilities of photomultiplier tubes (PMTs) and their associated electronics with MRIs high magnetic fields, as well as significant constraints on PET camera size due to the limited patient port of MR scanners. Recent advances in solid-state electronics have opened the possibility of replacing photomultiplier tubes with avalanche photodiodes (APDs) that are compact and do not share the vulnerabilities of PMTs to magnetic fields. Currently, we are planning to build a miniature PET tomograph using only solid-state electronics to give a combination MRI/PET scanner for small animals. This technology, once developed, can be extended to human scanner designs.