Kenneth H. Douglass

Multicompartmental Analysis of [11C]-Carfentanil Binding to Opiate Receptors in Humans Measured by Positron Emission Tomography:

[11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kd was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 ± 0.92 to 0.26 ± 0.13 in the thalamus (p < 0.01) and from 1.8 ± 0.33 to 0.16 ± 0.065 in the frontal cortex (p < 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35–70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35–70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible.

Quantification of neuroreceptors in the living human brain. II. Inhibition studies of receptor density and affinity

A method for estimating receptor density (Bmax) in the living human brain by positron emission tomography was exemplified by a ligand, 3-N-[11C]methylspiperone ([11C]NMSP), that binds to D2 dopamine receptors with high affinity. The ligand binds essentially irreversibly (i.e., with very little dissociation) to the receptors during the 2-h scanning period. Transfer constants were estimated at steady state. In a previous article, we presented a method for the determination of k3, the rate of binding of the labeled ligand. In the present work, we varied k3 by reducing the number of available receptors with a previously administered receptor blocking agent, haloperidol. We calculated a receptor density of 9.2 pmol g−1 in the caudate nucleus of four normal volunteers, and an inhibitory constant of haloperidol of 1.4 nM by comparing tracer accumulation in the absence and the presence of the blocking agent. The values agreed with measurements of NMSP receptor density and haloperidol inhibitory potency in vitro in brain homogenates from human autopsy material.

Quantification of Human Opiate Receptor Concentration and Affinity Using High and Low Specific Activity [11C]Diprenorphine and Positron Emission Tomography

[11C]Diprenorphine, a weak partial opiate agonist, and positron emission tomography were used to obtain noninvasive regional estimates of opiate receptor concentration (Bmax) and affinity (Kd) in human brain. Different compartmental models and fitting strategies were compared statistically to establish the most reliable method of parameter estimation. Paired studies were performed in six normal subjects using high (769–5,920 Ci/mmol) and low (27–80 Ci/mmol) specific activity (SA) [11C]diprenorphine. Two subjects were studied a third time using high SA [11C]diprenorphine after a pretreatment with 1–1.5 mg/kg of the opiate antagonist naloxone. After the plasma radioactivity was corrected for metabolites, the brain data were analyzed using a three-compartment model and nonlinear least-squares curve fitting. Linear differential equations were used to describe the high SA (low receptor occupancy) kinetics. The k3/k4 ratio varied from 1.0 ± 0.2 (occipital cortex) to 8.6 ± 1.6 (thalamus). Nonlinear differential equations were used to describe the low SA (high receptor occupancy) kinetics and the curve fits provided the konf2 product. The measured free fraction of [11C]diprenorphine in plasma (f1) was 0.30 ± 0.03, the average K1/k2 ratio from the two naloxone studies was 1.1 ± 0.2, and the calculated free fraction of [11C]diprenorphine in the brain (f2) was 0.3. Using the paired SA studies, the estimated kinetic parameters, and f2, separate estimates of Bmax and Kd were obtained. Bmax varied from 2.3 ± 0.5 (occipital cortex) to 20.6 ± 7.3 (cingulate cortex) nM. The average Kd (eight brain regions) was 0.85 ± 0.17 nM.

Monitoring ventricular function at rest and during exercise with a nonimaging nuclear detector

A portable nonimaging device, the nuclear stethoscope, for measuring beat to beat ventricular time-activity curves in normal people and patients with heart disease, both at rest and during exercise, is being developed and evaluated. The latest device has several operating modes that facilitate left ventricular and background localization, measurement of transit times and automatic calculation and display of left ventricular ejection fraction. The correlation coefficient of left ventricular ejection fraction obtained with the device and with a camera-computer system was 0.92 in 35 subjects. During bicycle exercise the ejection fraction in 15 normal persons increased from 44 to 64 percent (P less than 0.001), whereas among 12 patients with heart disease it was unchanged in 5 and decreased in 7.

Scatter correction in SPECT using non-uniform attenuation data

Quantitative assessment of activity levels with SPECT is difficult because of attenuation and scattering of gamma rays within the object. To study the effect of attenuation and scatter on SPECT quantitation, phantom studies were performed with non-uniform attenuation. Simulated transmission CT data provided information about the distribution of attenuation coefficients within the source. Attenuation correction was performed by an iterative reprojection technique. Scatter correction was done by convolution of the attenuation-corrected image and an appropriate filter. The filter characteristics depended on the attenuation and activity measurement at each pixel. The scatter correction could compensate completely for the 28% scatter component from a line source, and the 61% component from a thick, extended source. Accuracy of regional activity ratios and the linearity of the relationship between true radioactivity and the SPECT measurement were both significantly improved by these corrections. The present method is expected to be valuable for the quantitative assessment of regional activity.

Assessment of [11C]-L-Methionine Transport into the Human Brain

Neutral amino acid transport into human brain was measured using a dual-probe positron detection system or positron emission tomography (PET). Rate constants (ml/min/cc) for brain accumulation of [11C]L-methionine measured with the dual detector ranged from 0.012 to 0.078 (average 0.031) under baseline conditions and from 0.010 to 0.017 (average 0.014) after administration of nonradioactive L-phenylalanine (100 mg/kg). The net rate of brain accumulation of L-methionine ranged from 0.42 to 2.89 (average 1.28) nmol/min/cc, and decreased by 27.5–91.2% (average 53.9%) after L-phenylalanine. PET-estimated accumulation rates (ml/min/cc) of [11C]L-methionine ranged from 0.004 to 0.028 (average 0.016) baseline and from 0.010 to 0.021 (average 0.017) after L-phenylalanine. Initial volumes of distribution (ml/cc) of [11C]L-methionine (dual detector) were 0.044–0.070 (average 0.058) baseline and 0.032–0.074 (average 0.051) after phenylalanine and (PET) 0.026–0.098 (average 0.051) baseline and 0.021–0.061 (average 0.042) after phenylalanine. PET permits more accurate measurement of tracer accumulation by brain, excluding noncerebral regions included in dual-detector measurements. The dual-detector system permits better temporal resolution, facilitating kinetic analysis, and requires only one-fortieth the dose of tracer needed for PET. Multiple studies in the same patient are thus possible at low cost.

Fully automated data acquisition, processing, and display in equilibrium radioventriculography

A fully automated data acquisition, processing, and display procedure was developed for equilibrium radioventriculography. After a standardized acquisition, the study is automatically analzyed to yield both right and left ventricular time-activity curves. The program first creates a series of edge-enhanced images (difference between squared images and scaled original images). A marker point within each ventricle is then identified as that pixel with maximum counts to the patients right and left of the count center of gravity of a stroke volume image. Regions of interest are selected on each frame as the first contour of local maxima of the two-dimensional second derivative (pseudo-Laplacian) which encloses the appropriate marker point, using a method developed by Goris. After shifting the left ventricular end-systolic region of interest four pixels to the patients left, a background region of interest is generated as the crescent-shaped area of the shifted region of interest not intersected by the end systolic region. The average counts/pixel in this background region in the end systolic frame of the origina study are subtracted from each pixel in all frames of the gated study. Right and left ventricular time-activity curves are then obtained by applying each region of interest to its corresponding background-subtracted frame, and the ejection fraction, end diastolic, end systolic, and stroke counts determined for both ventricles. In fourteen consecutive patients, in addition to the automatic ejection fractions, manually drawn regions of interest were used to obtain ejection fractions for both ventricles. The manual regions of interest were drawn twice, and the average obtained. For the right ventricle, the correlation between auto and average manual ejection fraction was 0.52; the correlation between the two manual ejection fractions was 0.88. For the left ventricle, the correlation between auto and average manual ejection fraction was 0.96; the correlation between the two manual ejection fractions was 0.91. Automated processing is essential for the accurate and reproducible assessment of left ventricular ejection fraction.

Quantification of left ventricular volume in gated equilibrium radioventriculography

We have developed a simple method for measuring left ventricular volume based on semi-automated analysis of 40° left anterior oblique images obtained with a standard scintillation camera after equilibrium of an intravenous injection of 20 mCi of technetium-99m in vivo labeled red blood cells. The essence of the method is the use of the dimensions and radioactivity within a segment of aorta to convert observed left ventricular count rates to volume. Four assumptions were made: 1) the aortic arch is nearly parallel to the collimator face when a patient is in the proper left anterior oblique position; 2) a segment at the top of the aortic arch, approximately 1 cm wide, is a right cylinder, 3) the edges of the aorta can be delineated as the lines where the second derivative of a cross sectional profile equals zero; 4) left ventricular and aortic arch counts undergo the same attenuation because they are nearly the same distance from the chest wall in the proper left anterior oblique position. By measuring the counts and volumes of two regions of known shape, one in the middle, the other at the edge of the aortic arch, and calculating their differences a background-independent volume count ratio (Δv/ΔC) can be obtained. The left ventricular and diastolic volume (LVEDV) is calculated with the equation: LVEDV=(Δ/ΔC) LVEDC, where LVEDC represents left ventricular end diastolic counts. Twenty-six patients were evaluated by equilibrium radio- and contrast-ventriculography, the latter analyzed by planimetry. The radionuclide method yielded an end diastolic volume that correlated well with contrast ventriculography (r=0.96, Y=0.91 X+21 ml). In addition to its simplicity and objectivity, a major advantage of this method of determining ventricular volume is that it does not require a blood sample.

Performance of a fully automated program for measurement of left ventricular ejection fraction

A fully automated program developed by us for measurement of left ventricular ejection fraction from equilibrium gated blood pool studies was evaluated in 130 additional patients. Both 6-min (130 studies) and 2-min (142 studies in 31 patients) gated blood pool studies were acquired and processed. The program successfully generated ejection fractions in 86% of the studies. These automatically generated ejection fractions were compared with ejection fractions derived from manually drawn regions of interest. When studies were acquired for 6-min with the patient at rest, the correlation between automated and manual ejection fractions was 0.92. When studies were acquired for 2-min, both at rest and during bicycle exercise, the correlation was 0.81. In 25 studies from patients who also underwent contrast ventriculography, the program suceessfully generated regions of interest in 22 (88%). The correlation between the ejection fraction determined by contrast ventribulography and the automatically generated radionuclide ejection fraction was 0.79.

Use of color display for selection of left ventricular regions of interest.

Scintigraphic images of the cardiac blood pool were displayed in color, with red indicating tracer distribution during diastole and green indicating systole. This display permits easy identification of vascular structures.