Helen S. Mayberg

Correction of PET data for partial volume effects in human cerebral cortex by MR imaging.

Due to the limited spatial resolution of positron emission tomography (PET), the accuracy of quantitative measurements of regional metabolism or neuroreceptor concentration is influenced by partial volume averaging of brain with CSF, bone, and scalp. This effect is increased in the presence of cortical atrophy, as in patients with Alzheimer disease (AD). Correction for this underestimation in PET measurements is necessary for the comparison of AD patients and normal controls. We have developed a method for three-dimensional correction of human PET data using magnetic resonance (MR) imaging. A composite brain tissue image is created by summing the binary representation of nine MR images, weighted to the PET z-axis line-spread function. This composite tissue image is convolved to the resolution of the PET image. The original PET image is divided by the convolved tissue image on a pixel-by-pixel basis, resulting in an atrophy-corrected PET image in which count density represents activity per volume of brain tissue rather than spatial volume. This has been performed in [11C]carfentanil mu-opiate receptor PET studies of the temporal cortex in two AD patients and one normal volunteer. After correction, average regional increases in count density were 11% (range = 4–21%) in the normal and 46% (range = 28–99%) and 48% (range = 14–109%) in the patient studies. The accuracy of this method of partial volume correction was estimated using a spherical phantom.

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 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.

Measurement of Benzodiazepine Receptor Number and Affinity in Humans Using Tracer Kinetic Modeling, Positron Emission Tomography, and [11C]Flumazenil

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration (Bmax) and equilibrium dissociation constant (Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/k2 estimate of 0.68 ± 0.08 ml/ml (linear three-compartment model, nine brain regions). The free fraction of flumazenil in plasma (f1) was determined for each study (high SA f1: 0.50 ± 0.03; low SA f1: 0.48 ± 0.05). The free fraction in brain (f2) was calculated using the inhibition K1/k2 ratio and each volunteers mean f1 value (f2 across volunteers = 0.72 ± 0.03 ml/ml). Three methods (Methods I–III) were examined. Method I determined five kinetic parameters simultaneously [K1, k2, k3 (= konf2Bmax), k4, and konf2/SA] with no a priori constraints. An average kon value of 0.030 ± 0.003 nM−1 min−1 was estimated for receptor-rich regions using Method I. In Methods II and III, the konf2/SA parameter was specifically constrained using the Method I value of kon and the volunteers values of f2 and low SA (Ci/μmol). Four parameters were determined simultaneously using Method II. In Method III, K1/k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 0.61 in the thalamus. Fixing the K1/k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f2 and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 ± 25 nM in the occipital cortex, 64 ±18 nM in the cerebellum, and 38 ± 5.5 nM in the thalamus; the average Kd was 8.9 ± 1.0 nM (five brain regions).

Comparison of [11C]Diprenorphine and [11C]Carfentanil Binding to Opiate Receptors in Humans by Positron Emission Tomography:

The kinetics and regional distribution of [11C]carfentanil, a μ-selective opiate receptor agonist, and [11C]diprenorphine, a nonselective opiate receptor antagonist, were compared using paired positron emission tomography studies in two normal volunteers. Kinetics of total radioactivity (counts/mCi/pixel) was greater for [11C]diprenorphine than [11C]carfentanil in all regions. [11C]Carfentanil binding (expressed as the total/nonspecific ratio) reached near equilibrium at ∼40 min, whereas [11C]diprenorphine showed a linear increase until ∼60 min. Kinetics of specific binding demonstrated significant dissociation of [11C]carfentanil from opiate receptors, whereas little dissociation of [11C]diprenorphine was observed during the 90-min scan session. Regional distributions of [11C]carfentanil and [11C]diprenorphine were qualitatively and quantitatively different: Relative to the thalamus (a region with known predominance of μ-receptors), [11C]diprenorphine displayed greater binding in the striatum and cingulate and frontal cortex compared to [11C]carfentanil, consistent with labeling of additional, non-μ sites by [11C]diprenorphine. We conclude from these studies that [11C]diprenorphine labels other opiate receptor subtypes in addition to the μ sites selectively labeled by [11C]carfentanil. The nonselective nature of diprenorphine potentially limits its usefulness in defining abnormalities of specific opiate receptor subtypes in various diseases. Development of selective tracers for the δ- and κ-opiate receptor sites, or alternatively use of unlabeled inhibitors to differentially displace μ, δ, and κ subtypes, will help offset these limitations.

Detection and quantification of opiate receptors in Man by positron emission tomography. Potential applications to the study of pain

Opiate receptors in the brain are the target of endogenous opioids and of exogenous synthetic opiates. It is well established that these receptors play a major role in the modulation of pain perception. With positron emission tomography (PET) and the appropriate radioligands, it is now possible to image and quantify neuroreceptors in vivo. We used 11C-diprenorphine and the extremely potent mu opiate receptor agonist 11C-carfentanil to image the distribution of opiate receptors in the human brain and to quantify their density, affinity, and occupancy. Several important methodological aspects of the in vivo opiate receptor labeling with PET in relation to the study of pain are considered in this paper. Monitoring receptor occupancy by opiate drugs as a function of pain relief has the potential to reveal better ways to treat pain.