The authors developed and applied two new linearized reference tissue models for parametric images of binding potential ( BP) and relative delivery ( R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate ( k′2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k′2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTMO from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.
SUMMARY Obesity-related leptin resistance manifests in loss of leptin’s ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB1 receptor (CB1R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB1R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB1R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB1R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.
Permeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer 11 C-N-desmethyl-loperamide ( 11 C-dLop). We examined the ability of 11 C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp. Methods: Seventeen healthy volunteers had a total of 23 PET scans with 11 C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with 15 O-H 2 O to measure cerebral blood flow. Brain uptake of 11 C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC 10-30 ). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K 1 ) and efflux from (k 2 ) the brain. Results: Brain uptake of radioactivity was negligible at baseline and increased only slightly (;30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2-and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K 1 ), because efflux (k 2 ) and cerebral blood flow did not differ between tariquidartreated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K 1 correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of 11 C-dLop. AUC 10-30 correlated linearly with K 1 . Conclusion: P-gp function at the blood-brain barrier in humans can be quantified using PET and 11 C-dLop. A simple measure of brain uptake (AUC 10-30 ) may be used as a surrogate of the fully quantified rate constant for brain entry (K 1 ) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).
We recently demonstrated that 11 C-MePPEP, a PET ligand for CB 1 receptors, has such high uptake in the human brain that it can be imaged for 210 min and that receptor density can be quantified as distribution volume (V T ) using the gold standard of compartmental modeling. However, 11 C-MePPEP had relatively poor retest and intersubject variabilities, which were likely caused by errors in the measurements of radioligand in plasma at low concentrations by 120 min. We sought to find an analog of 11 C-MePPEP that would provide more accurate plasma measurements. We evaluated several promising analogs in the monkey brain and chose the 18 F-di-deutero fluoromethoxy analog ( 18 F-FMPEP-d 2 ) to evaluate further in the human brain. Methods: 11 C-FMePPEP, 18 F-FEPEP, 18 F-FMPEP, and 18 F-FMPEP-d 2 were studied in 5 monkeys with 10 PET scans. We calculated V T using compartmental modeling with serial measurements of unchanged parent radioligand in arterial plasma and radioactivity in the brain. Nonspecific binding was determined by administering a receptorsaturating dose of rimonabant, an inverse agonist at the CB 1 receptor. Nine healthy human subjects participated in 17 PET scans using 18 F-FMPEP-d 2 , with 8 subjects having 2 PET scans to assess retest variability. To identify sources of error, we compared intersubject and retest variability of brain uptake, arterial plasma measurements, and V T . Results: 18 F-FMPEP-d 2 had high uptake in the monkey brain, with greater than 80% specific binding, and yielded less radioactivity uptake in bone than did 18 F-FMPEP. High brain uptake with 18 F-FMPEP-d 2 was also observed in humans, in whom V T was well identified within approximately 60 min. Retest variability of plasma measurements was good (16%); consequently, V T had a good retest variability (14%), intersubject variability (26%), and intraclass correlation coefficient (0.89). V T increased after 120 min, suggesting an accumulation of radiometabolites in the brain. Radioactivity accumulated in the skull throughout the entire scan but was thought to be an insignificant source of data contamination. Conclusion: Studies in monkeys facilitated our development and selection of 18 F-FMPEP-d 2 , compared with 18 F-FMPEP, as a radioligand demonstrating high brain uptake, high percentage of specific binding, and reduced uptake in bone. Retest analysis in human subjects showed that 18 F-FMPEP-d 2 has greater precision and accuracy than 11 C-MePPEP, allowing smaller sample sizes to detect a significant difference between groups.
Incorporation coefficients (K*) of arachidonic acid (AA) in the brain are increased in a rat model of neuroinflammation, as are other markers of AA metabolism. Data also indicate that neuroinflammation contributes to Alzheimer's disease (AD). On the basis of these observations, K* for AA was hypothesized to be elevated in patients with AD. Methods: A total of 8 patients with AD with an average (6SD) Mini-Mental State Examination score of 14.7 6 8.4 (mean age, 71.7 6 11.2 y) and 9 controls with a normal Mini-Mental State Examination score (mean age, 68.7 6 5.6 y) were studied. Each subject received a 15 O-water PET scan of regional cerebral blood flow, followed after 15 min by a 1-11 C-AA scan of regional K* for AA. Results: In the patients with AD, compared with control subjects, global gray matter K* for AA (corrected or uncorrected for the partial-volume error [PVE]) was significantly elevated, whereas only PVE-uncorrected global cerebral blood flow was reduced significantly (P , 0.05). A false-discovery-rate procedure indicated that PVE-corrected K* for AA was increased in 78 of 90 identified hemispheric gray matter regions. PVE-corrected regional cerebral blood flow, although decreased in 12 regions at P , 0.01 by an unpaired t test, did not survive the false-discovery-rate procedure. The surviving K* increments were widespread in the neocortex but were absent in caudate, pallidum, and thalamic regions. Conclusion: These preliminary results show that K* for AA is widely elevated in the AD brain, particularly in regions reported to have high densities of senile (neuritic) plaques with activated microglia. To the extent that the elevations represent upregulated AA metabolism associated with neuroinflammation, PET with 1-11 C-AA could be used to examine neuroinflammation in patients with AD and other brain diseases.
Summary Obesity is associated with physical inactivity, which exacerbates the health consequences of weight gain. However, the mechanisms that mediate this association are unknown. We hypothesized that deficits in dopamine signaling contribute to physical inactivity in obesity. To investigate this, we quantified multiple aspects of dopamine signaling in lean and obese mice. We found that D2-type receptor (D2R) binding in the striatum, but not D1-type receptor binding or dopamine levels, was reduced in obese mice. Genetically removing D2Rs from striatal medium spiny neurons was sufficient to reduce motor activity in lean mice, while restoring Gi signaling in these neurons increased activity in obese mice. Surprisingly, while mice with low D2Rs were less active, they were not more vulnerable to diet-induced weight gain than control mice. We conclude that deficits in striatal D2R signaling contribute to physical inactivity in obesity, but inactivity is more a consequence than a cause of obesity.
Abstract[ 11 C]MePPEP is a high affinity, CB 1 receptor-selective, inverse agonist that has been studied in rodents and monkeys. We examined the ability of [ 11 C]MePPEP to quantify CB 1 receptors in human brain as distribution volume calculated with the "gold standard" method of compartmental modeling and compared results with the simple measure of brain uptake. A total of 17 healthy subjects participated in 26 positron emission tomography (PET) scans, with 8 having two PET scans to assess retest variability. After injection of [ 11 C]MePPEP, brain uptake of radioactivity was high (e.g., 3.6 SUV in putamen region at ~60 minutes) and washed out very slowly. A two-tissue compartment model yielded values of distribution volume (which is proportional to receptor density) that were both well identified (SE 5%) and stable between 60 and 210 minutes. The simple measure of brain uptake (average concentration of radioactivity between 40 and 80 minutes) had good retest variability (~8%) and moderate intersubject variability (16%, coefficient of variation). In contrast, distribution volume had two-fold greater retest variability (~15%) and, thus, less precision. In addition, distribution volume had three-fold greater intersubject variability (~52%). The decreased precision of distribution volume compared to brain uptake was likely due to the slow washout of radioactivity from brain and to noise in measurements of the low concentrations of [ 11 C]MePPEP in plasma. These results suggest that brain uptake can be used for within subject studies (e.g., to measure receptor occupancy by medications) but that distribution volume remains the gold standard for accurate measurements between groups.
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