A number of studies have shown a relationship between “sexual orientation” and size of various brain nuclei. We hypothesized that neurotransmitter differences might parallel neuroanatomical differences in the hypothalamus. We administered 40 mg of fluoxetine as a challenge to the serotonergic systems of exclusively homosexual and exclusively heterosexual men and measured cerebral metabolic changes with fluorodeoxyglucose positron emission tomography (FDG-PET). The metabolic differences we observed might reflect underlying neurochemical differences between homosexual and heterosexual men.

Genetics, neuroscience, and imaging science have advanced greatly in the last few years. These advances can be brought together and applied in creative new ways to make available better drugs for treating neuropsychiatric disorders and for getting candidate drugs through the development process faster. One particular approach, built around [18F]fluordeoxyglucose positron emission tomography, is described.

The process of discovering and developing new drugs is complicated. Neuroimaging methods can facilitate this process. An analysis of the conceptual bases and practical limitations of different neuroimaging modalities reveals that each technique can best address different kinds of questions. Radioligand studies are well suited to preclinical and Phase II questions when a compound is known or suspected to affect well-understood mechanisms; they are also useful in Phase IV to characterize effective agents. Cerebral blood flow studies can be extremely useful in evaluating the effects of a drug on psychological tasks (mostly in Phase IV). Glucose metabolism studies can answer the simplest questions about whether a compound affects the brain, where, and how much. Such studies are most useful in confirming central effects (preclinical and early clinical phases), in determining effective dose ranges (Phase II), and in comparing different drugs (Phase IV).

In victims of electrical trauma, electroporation of cell membrane, in which lipid bilayer is permeabilized by thermal and electrical forces, is thought to be a substantial cause of tissue damage. It has been suggested that certain mild surfactant in low concentration could induce sealing of permeabilized lipid bilayers, thus repairing cell membranes that had not been extensively damaged. With an animal model of electrically injured hind limb of rats, we have demonstrated and validated the use of radiotracer imaging technique to assess the physiology of the damaged tissues after electrical shock and of their repairs after applying surfactant as a therapeutic strategy. For example, using Tc-99m labeled pyrophosphate (PYP), which follows calcium in cellular function and is known to accumulate in damaged tissues, we have established a physiological imaging approach for assessment of the extent of tissue injury for diagnosis and surgical planning, as well as for evaluation of responses to therapy. With the use of a small, hand-held, miniature gamma camera, this physiological imaging method can be employed at patient's bedside and even in the field, for example, at accident site or during transfer for emergency care, rapid diagnosis, and prompt treatment in order to maximize the chance for tissue survival.

We have identified the value of 18F-fallypride [(S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide], as a dopamine D-2 receptor radiotracer for the study of striatal and extrastriatal receptors. Fallypride exhibits high affinities for D-2 and D-3 subtypes and low affinity for D-4 (3H-spiperone IC50s: D-2 = 0.05 nM [rat striata], D-3 = 0.30 nM [SF9 cell lines, rat recombinant], and D-4 = 240 nM [CHO cell lines, human recombinant]). Biodistribution in the rat brain showed localization of 18F-fallypride in striata and extrastriatal regions such as the frontal cortex, parietal cortex, amygdala, hippocampus, thalamus, and hypothalamus. In vitro autoradiographic studies in sagittal slices of the rat brain showed localization of 18F-fallypride in striatal and several extrastriatal regions, including the medulla. Positron emission tomography (PET) experiments with 18F-fallypride in male rhesus monkeys were carried out in a PET VI scanner. In several PET experiments, apart from the specific binding seen in the striatum, specific binding of 18F-fallypride was also identified in extracellular regions (in a lower brain slice, possibly the thalamus). Specific binding in the extrastriata was, however, significantly lower compared with that observed in the striata of the monkeys (extrastriata/cerebellum = 2, striata/cerebellum = 10). Postmortem analysis of the monkey brain revealed significant 18F-fallypride binding in the striata, whereas binding was also observed in extrastriatal regions such as the thalamus, cortical areas, and brain stem.

Annals of the New York Academy of SciencesVolume 888, Issue 1 p. 285-299 Radiotracers for Imaging Electroporation† K. L. MATTHEWS II, K. L. MATTHEWS II Department of Medical Physics, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612Search for more papers by this authorJ. N. AARSVOLD, J. N. AARSVOLD Department of Radiology, Emory University, and Nuclear Medicine Service, Veterans Affairs Medical Center, Atlanta, Georgia 30033Search for more papers by this authorR. A. MINTZER, R. A. MINTZER Department of Radiology, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorC-T. CHEN, C-T. CHEN Department of Radiology, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorM. CAPELLI-SCHELLPFEFFER, M. CAPELLI-SCHELLPFEFFER Department of Surgery, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorM. COOPER, M. COOPER Department of Radiology, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorR. C. LEE, R. C. LEE Department of Surgery, University of Chicago, Chicago, Illinois 60637Search for more papers by this author K. L. MATTHEWS II, K. L. MATTHEWS II Department of Medical Physics, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612Search for more papers by this authorJ. N. AARSVOLD, J. N. AARSVOLD Department of Radiology, Emory University, and Nuclear Medicine Service, Veterans Affairs Medical Center, Atlanta, Georgia 30033Search for more papers by this authorR. A. MINTZER, R. A. MINTZER Department of Radiology, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorC-T. CHEN, C-T. CHEN Department of Radiology, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorM. CAPELLI-SCHELLPFEFFER, M. CAPELLI-SCHELLPFEFFER Department of Surgery, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorM. COOPER, M. COOPER Department of Radiology, University of Chicago, Chicago, Illinois 60637Search for more papers by this authorR. C. LEE, R. C. LEE Department of Surgery, University of Chicago, Chicago, Illinois 60637Search for more papers by this author First published: 06 February 2006 https://doi.org/10.1111/j.1749-6632.1999.tb07963.xCitations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume888, Issue1OCCUPATIONAL ELECTRICAL INJURY: AN INTERNATIONAL SYMPOSIUMNovember 1999Pages 285-299 RelatedInformation

We have developed an innovative use of positron emission tomography that has broad applications in drug development. Based on the FDG method (Phelps et al. 1979) for assessing glucose metabolism, the method requires rigorous experimental control of subjects and standardized data acquisition and analyses. In localizing net metabolic drug effects, measured in quantifiable terms, we have derived a new conceptual basis for examining pharmacologically induced changes in brain function and a new model for predicting drug effectiveness. We applied this method to studies of drugs in three different classes and noted marked differences in distribution and magnitude of metabolic effects. This approach presents an opportunity to selectively examine measurements of the glucose metabolic changes induced by specific pharmacological probes on intermediary metabolic pathways, including regulation of gene expression and the metabolic consequences of neurotransmitter alteration in pharmacologically targeted neuronal systems. Development of these methods provides new approaches for studying neurobiological mechanisms, and can contribute significantly to the process of new drug development.

High-voltage electrical shock can produce minimal external signs of damage with widespread damage to the skeletal muscle. The injury can be thermally mediated or the result of electroporation of cell membranes. Radiotracer imaging is one method for assessing the extent of damage in skeletal muscle. The authors are using radiotracer imaging in an in vivo animal model to investigate the effects of novel therapies, such as surfactants, for repairing electroporation damage. In this work, the authors report the results of region-of-interest (ROI) analysis and principal component analysis (PCA) of the data collected from the animal model. These analytical methods may provide a tool to assist in clinical monitoring of electrical injury victims.

We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D-2 receptor positron emission tomography (PET) radioligand, F-18-fallypride. In vitro dissociation of F-18-fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, k(off), of 1.76 x 10(-2) min(-1) while the association rate constant, k(on) was found to be 5.30 x 10(8) M-1 min(-1). This resulted in a dissociation constant, K-D of 33 pM for F-18-fallypride. For in vivo studies, we investigated the effects of reserpine and d-amphetamine treatment on F-18-fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with F-18-fallypride in two male rhesus monkeys were carried out in a PETT VI scanner In control experiments, rapid specific uptake of F-18-fallypride in the striata was observed (0.05-0.06% injected dose (ID)/g) while nonspecifically bound tracer cleared from other parts of the brain. Striata/cerebellum ratios for F-18-fallypride were approximately 8 at 80 min postinjection; respectively. The monkeys received various doses (0.25 to 1.50 mg/kg) of d-amphetamine (AMPH) pre- and postinjection of the radioligand. There was a decrease of specifically bound F-18-fallypride as well as evidence of an enhanced clearance of specifically bound F-18-fallypride after administering AMPH in the two monkeys. The dissociation rates, k(off), of F-18-fallypride without AMPH was <10(-4) min(-1) but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 x 10(-3) min(-1) and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 x 10(-3) to 4.0 x 10(-3) min(-1). Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of F-18-fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that F-18-fallypride has a maximum response at doses of 0.75-1.50 mg/kg, with an approximately 16%/hour reduction in binding. These results indicate that AMPH stimulated release of endogenous dopamine reduces the specific binding of F-18-fallypride. (C) 1997 Wiley-Liss, Inc.

We have developed (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-18F-fluoropropyl)-2-methoxybenzamide (18F-desmethoxyfallypride) as a fluorine-18 radiotracer with properties analogous to that of 11C-raclopride. In vitro experiments in rat brain homogenates showed an association rate constant of 2.16 × 108 M−1min−1 and a dissociation rate constant of 0.073 min−1. High striatal uptake (up to 0.08% injected dosecc,) of 18F-desmethoxyfallypride in rhesus monkeys was observed in PET experiments. The radiotracer cleared from the striata with a dissociation rate of 1.80 × 10−2 min−1. Striatum to cerebellum ratios peaked at 3.0 in 30 min after which they decreased steadily. Intravenously administered haloperidol displaced specifically bound 18F-desmethoxyfallypride with a koff of 0.058 min−1. Synaptic dopamine released by the treatment of the monkeys with d-amphetamine increased the dissociation rate of 18F-desmethoxyfallypride to 0.83 min−1 thus reducing specifically bound 18F-desmethoxyfallypride by 56% over a period of 42 mins compared to a reduction of only 20% in controls during this time period. The sensitivity of 18F-desmethoxyfallypride towards competition with dopamine should make this radiotracer useful in PET studies to evaluate in vivo pharmacological effects of various agents that alter levels of endogenous dopamine.

In PET, SPECT, and other tomographic imaging modalities, dynamic image sequences are typically obtained by reconstructing the individual time frames independently. This frame-by-frame reconstruction approach can be highly suboptimal because it fails to take into account the temporal correlations in the signal. The authors propose an alternative approach, based on a Karhunen-Loeve transformation of the dynamic-image reconstruction problem, that can offer both significant improvement of the reconstructed images and a substantial reduction in the computation required to reconstruct an image sequence