J. James Frost

Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects.

Accuracy in in vivo quantitation of brain function with positron emission tomography (PET) has often been limited by partial volume effects. This limitation becomes prominent in studies of aging and degenerative brain diseases where partial volume effects vary with different degrees of atrophy. The present study describes how the actual gray matter (GM) tracer concentration can be estimated using an algorithm that relates the regional fraction of GM to partial volume effects. The regional fraction of GM was determined by magnetic resonance imaging (MRI). The procedure is designated as GM PET. In computer simulations and phantom studies, the GM PET algorithm permitted a 100% recovery of the actual tracer concentration in neocortical GM and hippocampus, irrespective of the GM volume. GM PET was applied in a test case of temporal lobe epilepsy revealing an increase in radiotracer activity in GM that was undetected in the PET image before correction for partial volume effects. In computer simulations, errors in the segmentation of GM and errors in registration of PET and MRI images resulted in less than 15% inaccuracy in the GM PET image. In conclusion, GM PET permits accurate determination of the actual radiotracer concentration in human brain GM in vivo. The method differentiates whether a change in the apparent radiotracer concentration reflects solely an alteration in GM volume or rather a change in radiotracer concentration per unit volume of GM.

Imaging brain mu-opioid receptors in abstinent cocaine users: Time course and relation to cocaine craving

BACKGROUNDnCocaine treatment upregulates brain mu-opioid receptors (mOR) in animals. Human data regarding this phenomenon are limited. We previously used positron emission tomography (PET) with [11C]-carfentanil to show increased mOR binding in brain regions of 10 cocaine-dependent men after 1 and 28 days of abstinence.nnnMETHODSnRegional brain mOR binding potential (BP) was measured with [11C]carfentanil PET scanning in 17 cocaine users over 12 weeks of abstinence on a research ward and in 16 healthy control subjects.nnnRESULTSnMu-opioid receptor BP was increased in the frontal, anterior cingulate, and lateral temporal cortex after 1 day of abstinence. Mu-opioid receptor BP remained elevated in the first two regions after 1 week and in the anterior cingulate and anterior frontal cortex after 12 weeks. Increased binding in some regions at 1 day and 1 week was positively correlated with self-reported cocaine craving. Mu-opioid receptor BP was significantly correlated with percentage of days with cocaine use and amount of cocaine used per day of use during the 2 weeks before admission and with urine benzoylecgonine concentration at the first PET scan.nnnCONCLUSIONSnThese results suggest that chronic cocaine use influences endogenous opioid systems in the human brain and might explain mechanisms of cocaine craving and reinforcement.

Pain activation of human supraspinal opioid pathways as demonstrated by [11C]-carfentanil and positron emission tomography (PET)

&NA; The role of the supraspinal endogenous opioid system in pain processing has been investigated in this study using positron emission tomography imaging of [11C]‐carfentanil, a synthetic, highly specific &mgr; opioid receptor (&mgr;‐OR) agonist. Eight healthy volunteers were studied during a baseline imaging session and during a session in which subjects experienced pain induced by applying capsaicin topically to the dorsal aspect of the left hand. A pain‐related decrease in brain &mgr;‐OR binding was observed in the contralateral thalamus consistent with competitive binding between [11C]‐carfentanil and acutely released endogenous opioid peptides. This decrease varied directly with ratings of pain intensity. These results suggest that the supraspinal &mgr;‐opioid system is activated by acute pain and thus may play a substantial role in pain processing and modulation in pain syndromes.

Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain.

Abstract Though it is clear that genomic variability plays an integral role in accounting for pain sensitivity, controversy exists over which genes are involved. While recent data suggest a “protective” (i.e., less pain) haplotype in the GTP cyclohydrolase (GCH1) gene, other research has failed to confirm this association. Possibly, the effects of single nucleotide polymorphisms (SNPs) vary depending on the pain task. The current investigation analyzed the association of five previously identified GCH1 SNPs with ratings of pain induced by topical high concentration (10%) capsaicin applied to the skin of 39 healthy human volunteers. Each of the GCH1 polymorphisms was associated with lower pain ratings. When combined, three of the five accounted for a surprisingly high 35% of the inter‐individual variance in pain ratings. We conclude that SNPs of the GCH1 gene may profoundly affect the ratings of pain induced by capsaicin.

Mu-opioid receptor binding measured by [11C]carfentanil positron emission tomography is related to craving and mood in alcohol dependence

BACKGROUNDnThe endogenous opioid system has been linked to alcohol dependence through animal and human studies. We investigated the relationship between alcohol craving and brain mu opioid receptors (mu-OR) in alcohol-dependent subjects.nnnMETHODSnRegional brain mu-OR binding potential (BP) was measured using [(11)C]carfentanil positron emission tomography in eight male alcohol-dependent subjects undergoing alcohol withdrawal and eight matched control subjects. Self-reported alcohol craving, withdrawal, and mood were measured.nnnRESULTSnLower mu-OR BP was associated with higher craving in the right dorsal lateral prefrontal cortex, the right anterior frontal cortex, and right parietal cortex. In these regions, alcoholics showed lower mean mu-OR BP compared with control subjects. Mu-OR BP in four other brain regions also correlated with craving, but there were no group differences in receptor binding potential. Mu-OR BP also correlated with depressive symptoms in five brain regions, three of which were identified in the craving analyses.nnnCONCLUSIONSnResults show a strong functional relationship between alcohol craving, mood, and mu-OR binding in specific brain regions of recently abstinent, alcohol-dependent men.

Differences in δ - and μ -Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Blockade of brain μ-opioid receptor (μ-OR) and δ-opioid receptor (δ-OR) was investigated in recently abstinent alcohol-dependent subjects (N=21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50u2009mg) on days 15–19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-β-naltrexol. Regional brain μ-OR binding potential (BP) and δ-OR Ki was measured using [11C]carfentanil (CAR) positron emission tomography (PET) and [11C]methyl naltrindole ([11C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [11C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean+SD% inhibition=94.9+4.9%). Naltrexone only partially inhibited the [11C]MeNTI Ki and there was more variability across subjects (mean+SD% inhibition=21.1+14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of δ-OR Ki in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of μ-OR BP. Peak levels of 6-β-naltrexol were not significantly correlated with % inhibition of μ-OR BP or δ-OR Ki. Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the μ-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of δ-OR and greater variability in δ-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in δ-OR blockade by naltrexone and clinical outcomes should be explored.

Brain mu-opioid receptor binding predicts treatment outcome in cocaine-abusing outpatients

BACKGROUNDnCocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown.nnnMETHODSnWe determined whether regional brain mOR binding before treatment correlates with outcome and compared it with standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine abstinence reinforcement, whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography with [¹¹C]]-carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment; and 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology.nnnRESULTSnElevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sublobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use.nnnCONCLUSIONSnElevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction.

Imaging Muscarinic Cholinergic Receptors in Human Brain in vivo with SPECT, [123I]4-Iododexetimide, and [123I]4-Iodolevetimide

A method to image muscarinic acetylcholine receptors (muscarinic receptors) noninvasively in human brain in vivo was developed using [123I]4-iododexetimide ([123I]IDex), [123I]4-iodolevetimide ([123I]ILev), and single photon emission computed tomography (SPECT). [123I]IDex is a high-affinity muscarinic receptor antagonist. [123I]ILev is its pharmacologically inactive enantiomer and measures nonspecific binding of [123I]IDex in vitro. Regional brain activity after tracer injection was measured in four young normal volunteers for 24 h. Regional [123I]IDex and [123I]ILev activities were correlated early after injection, but not after 1.5 h. [123I]IDex activity increased over 7–12 h in neocortex, neostriatum, and thalamus, but decreased immediately after the injection peak in cerebellum. [123I]IDex activity was highest in neostriatum, followed in rank order by neocortex, thalamus, and cerebellum. [123I]IDex activity correlated with muscarinic receptor concentrations in matching brain regions. In contrast, [123I]ILev activity decreased immediately after the injection peak in all brain regions and did not correspond to muscarinic receptor concentrations. [123I]IDex activity in neocortex and neostriatum during equilibrium was six to seven times higher than [123I]ILev activity. The data demonstrate that [123I]IDex binds specifically to muscarinic receptors in vivo, whereas [123I]ILev represents the nonspecific part of [123I]IDex binding. Subtraction of [123I]ILev from [123I]IDex images on a pixel-by-pixel basis therefore reflects specific [123I]IDex binding to muscarinic receptors. Owing to its high specific binding, [123I]IDex has the potential to measure small changes in muscarinic receptor characteristics in vivo with SPECT. The use of stereoisomerism directly to measure nonspecific binding of [123I]IDex in vivo may reduce complexity in modeling approaches to muscarinic acetylcholine receptors in human brain.

Influence of OPRM1 Asn40Asp variant (A118G) on [11C]carfentanil binding potential: preliminary findings in human subjects

The Asn40Asp variant (A118G) of the μ opioid receptor (OPRM1) gene is thought to contribute to the development and treatment of alcohol dependence. Employing positron emission tomography (PET), we first examined whether the single nucleotide polymorphism (SNP) modifies binding potential (BP(ND)) of the μ-selective ligand [(11)C]carfentanil in healthy control (Con) and 5-d abstinent alcohol-dependent (AD) subjects (unblocked basal scan). Second, we examined whether the allelic variants were associated with differences in OPRM1 occupancy by naltrexone (50 mg) in AD subjects. Con and AD carriers of the G allele (AG) had lower global BP(ND) at the basal scan than subjects homozygous for the A allele (AA). In AD subjects, naltrexone occupancy was slightly higher in AG subjects (98.9%) compared to AA subjects (93.1%), but this was not significant. We are the first to demonstrate using PET in healthy normal and AD subjects that the A118G SNP alters OPRM1 availability.

PET imaging of human cardiac opioid receptors

Abstract. The presence of opioid peptides and receptors and their role in the regulation of cardiovascular function has been previously demonstrated in the mammalian heart. The aim of this study was to image µ and δ opioid receptors in the human heart using positron emission tomography (PET). Five subjects (three females, two males, 65±8 years old) underwent PET scanning of the chest with [11C]carfentanil ([11C]CFN) and [11C]-N-methyl-naltrindole ([11C]MeNTI) and the images were analyzed for evidence of opioid receptor binding in the heart. Either [11C]CFN or [11C]MeNTI (20xa0mCi) was injected i.v. with subsequent dynamic acquisitions over 90xa0min. For the blocking studies, either 0.2xa0mg/kg or 1xa0mg/kg of naloxone was injected i.v. 5xa0min prior to the injection of [11C]CFN and [11C]MeNTI, respectively. Regions of interest were placed over the left ventricle, left ventricular chamber, lung and skeletal muscle. Graphical analysis demonstrated average baseline myocardial binding potentials (BP) of 4.37±0.91 with [11C]CFN and 3.86±0.60 with [11C]MeNTI. Administration of 0.2xa0mg/kg naloxone prior to [11C]CFN produced a 25% reduction in BP in one subject in comparison with baseline values, and a 19% decrease in myocardial distribution volume (DV). Administration of 1xa0mg/kg of naloxone before [11C]MeNTI in another subject produced a 14% decrease in BP and a 21% decrease in the myocardial DV. These results demonstrate the ability to image these receptors in vivo by PET. PET imaging of cardiac opioid receptors may help to better understand their role in cardiovascular pathophysiology and the effect of abuse of opioids and drugs on heart function.