Malcolm Cooper

Preliminary assessment of extrastriatal dopamine d-2 receptor binding in the rodent and nonhuman primate brains using the high affinity radioligand, 18F-fallypride

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.

Sustained human chemosignal unconsciously alters brain function.

The human chemosignal, Δ4,16-androstadien-3-one modulates psychological state without being consciously discernible as an odor. This study demonstrates that Δ4,16-androstadien-3-one (androstadienone) alters cerebral glucose utilization both in subcortical regions and in areas of the neocortex not exclusively associated with olfaction. These widely distributed changes are consistent with modulation of an integrated neural network for regulation of emotional and attentional states. This is the first study to demonstrate the effects of a sustained chemosignal on brain metabolism and to show that they are similar to those of long acting chemical substances that affect psychological states. Moreover, this provides the first evidence that a human chemosignal has distributed effects on cortical processes and brain metabolism even when it is not detected consciously.

Evaluation of d-amphetamine effects on the binding of dopamine D-2 receptor radioligand, 18F-fallypride in nonhuman primates using positron emission tomography

We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D2 receptor positron emission tomography (PET) radioligand, 18F‐fallypride. In vitro dissociation of 18F‐fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, koff, of 1.76 × 10−2 min−1 while the association rate constant, kon, was found to be 5.30 × 108 M−1 min−1. This resulted in a dissociation constant, KD of 33 pM for 18F‐fallypride. For in vivo studies, we investigated the effects of reserpine and d‐amphetamine treatment on 18F‐fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with 18F‐fallypride in two male rhesus monkeys were carried out in a PETT VI scanner. In control experiments, rapid specific uptake of 18F‐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 18F‐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 18F‐fallypride as well as evidence of an enhanced clearance of specifically bound 18F‐fallypride after administering AMPH in the two monkeys. The dissociation rates, koff, of 18F‐fallypride without AMPH was <10−4 min−1 but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 × 10−3 min−1 and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 × 10−3 to 4.0 × 10−3 min−1. Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of 18F‐fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that 18F‐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 18F‐fallypride. Synapse 27:1–13, 1997.

Design considerations for a single tube gamma camera

It is pointed out that many potentially practical applications for nuclear medicine diagnostic procedures are difficult or impossible to perform because of the physical size of existing mobile gamma cameras. With the commercial availability of position sensitive photomultiplier tubes (PSPMTs) the development of an instrument ideally suited to these applications now appears to be practical. The major components necessary to construct such a camera have been tested, and a circuit configuration designed to provide a high level of clinical performance in such a device is proposed. Spatial resolution and linearity data from a developmental prototype are provided. Measurements have shown that by using conventional sum and difference analog circuits only, a 76-mm/sup 2/ PSPMT has good linearity and therefore uniformity of sensitivity over only the central 60% of its absolute field of view. It is believed that this high-quality imaging area can be increased to virtually the full field of view by implementing a digital geometric correction scheme using a position vector lookup table. >

Comparison of Various Icing Times in Decreasing Bone Metabolism and Blood Flow in the Knee

In a previous study we used technetium-99m bone scans to show that cooling a knee for 20 minutes with a standard ice wrap will decrease soft tissue blood flow by a mean of 26%, and skeletal blood flow and me tabolism by 19%. The present study examined the ef fects of shorter and longer icing periods to determine minimum cooling time for a measurable and consistent decrease, and time to produce maximal decrease within a safe period of icing (<30 minutes). Thirty-eight sub jects were studied. An ice wrap was applied to one knee for an assigned time (5, 10, 15, 20, or 25 minutes). Triple-phase bone scans of knees were obtained; mean percentages of decrease in the iced knee for each of the five time groups at each of the three phases of the bone scan were calculated and compared. Mean decreases of 11.1 % in soft tissue blood flow, and 5.1% in skeletal metabolism and blood flow were measured at 5 min utes ; maximums of 29.5% and 20.9%, respectively, were obtained at 25 minutes. A small but consistent decrease in soft tissue blood flow and skeletal blood flow and metabolism in a knee appear to be obtained with as little as 5 minutes of ice application. This effect is time-dependent and can be enhanced three- to four fold by increasing the ice application time to 25 minutes.

The Role of Gallium-67 Scanning in the Clinical Staging and Preoperative Evaluation of Patients with Carcinoma of the Lung

Gallium-67 scanning was evaluated in 100 patients with proved carcinoma of the lung. It was valuable in separating primary from secondary lung tumors, determining the extent of contralateral hilar or mediastinal lymph node involvement, and detecting distant organ metastases. In addition to multiplane whole-body Ga-67 tomographic scanning, colloid liver scans, bone scans, and computerized axial tomography scans of the brain were obtained to determine the presence of distant metastasis. The gallium scan detected 11 of 12 occult metastases and identified 7 of 7 liver, 9 of 14 brain, 4 of 4 soft tissues, 1 of 4 contralateral lung, and 9 of 11 bone metastases. The whole-body gallium scan accurately detected or excluded extrathoracic metastatic disease in 11 of 12 patients examined postmortem within three months of a gallium scan. An approach is recommended using gallium scanning along with chest roentgenograms for clinical staging and preoperative evaluation of patients with carcinoma of the lung. Specific organ scans should be reserved for the occasional symptomatic patient with a negative gallium scan or for clarification of an indeterminate gallium scan.

18F-desmethoxyfallypride: A fluorine-18 labeled radiotracer with properties similar to carbon-11 raclopride for pet imaging studies of dopamine D2 receptors

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 x 10(8) M(-1)min(-1) and a dissociation rate constant of 0.073 min(-1). High striatal uptake (up to 0.08% injected dose/cc) of 18F-desmethoxyfallypride in rhesus monkeys was observed in PET experiments. The radiotracer cleared from the striata with a dissociation rate of 1.80 x 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.

Fluoxetine effects on cerebral glucose metabolism

In a counterbalanced, double-blind, placebo-controlled trial, 40 mg of fluoxetine was administered to four healthy adult volunteers (three men, one woman; age range 20-39 years), 90 min before injection of 6-7.5 mCi of [18F]-2-deoxyglucose to measure cerebral metabolic rate of glucose (CMRglu). Subjects were engaged in a visual monitoring task shortly before and during scanning with a PETT-VI tomograph. Global CMRglu did not differ when placebo (8.93 +/- 0.96 mg 100 g-1 min-1) was compared to fluoxetine (8.22 +/- 0.86 mg 100 g-1 min-1; paired t-test = 0.82, df = 3, p < 0.48). However, statistical parametric mapping of differences in CMRglu between placebo and fluoxetine conditions revealed regional effects of fluoxetine shown by decreased metabolism in the amygdaloid complex, hippocampal formation and ventral striatum, and by increased metabolism centered in the right superior parietal lobe (Brodmann area 7). Parametric mapping for use in PET studies of glucose metabolism represents a significant new tool for studying drug effects in humans.

Retrospective fusion of radiographic and MR data for localization of subdural electrodes

Prior to epilepsy surgery, subdural electrodes are often implanted and monitored for a few days to identify the focus of abnormal electrical activity. During the implantation and subsequent brain resection, there may be uncertainty about the exact location of the electrodes with respect to features of brain anatomy such as specific gyral convolutions or lesions. In experiments with a phantom and patients, implanted electrodes were imaged with multiplanar skull radiographs (or CT scans). After retrospective registration with pre-implantation MR data, the electrodes were mapped from these studies onto an MR-derived three-dimensional brain model. The resulting multimodality displays showed the relationship of the electrodes to brain anatomy. In one patient the position of each electrode with respect to a metabolic lesion was also displayed by mapping preimplantation PET data onto the same brain model. This new display of electrode positions may strengthen the interpretation of subdural electrical recordings and thereby reduce uncertainty in planning the resection of epileptic tissue.

Basal ganglia regional glucose metabolism asymmetry during a catatonic episode

The pathophysiology of catatonic symptoms remains unknown, although several anatomical sites, including the basal ganglia (Kleist et al. 1960) and brainstem (Blasco et al. 1986), have been implicated. We have attempted to study the physiological substrate of these symptoms by employing positron emission tomography (PET) in the first PET study of a patient with catatonia. The patient was a 22-year-old black woman admitted to our research unit with a DSMIIf diagnosis of schizoaffect~ve disorder. She had a 4-year history of episodes of psychoses associated with auditory hallucinations and loose associations. She had been treated with antipsychotic medications during most of this period. On admission, she showed labile effect with racing thoughts, hypersexuality. and paranoid delusions. During a s-week drug-free period. she became increasingly psychotic and catatonic. Despite a subsequent week of lithium treatment (1200 mg daily, lithium level 0.8 mEqiliter), she continued to show mutism, posturing, waxy flexibility, and decreased psychomotor activity. In this state, she underwent a first PET scan. Seventeen days later, while on the same dose and blood level of lithium, she was retested in the PET procedure. At this time, there was no evidence of catatonia.