High-resolution imaging of brain 5-HT 1B receptors in the rhesus monkey using [11C]P943.

The serotonin 5-HT(1B) receptors regulate the release of serotonin and are involved in various disease states, including depression and schizophrenia. The goal of the study was to evaluate a high affinity and high selectivity antagonist, [(11)C]P943, as a positron emission tomography (PET) tracer for imaging the 5-HT(1B) receptor. [(11)C]P943 was synthesized via N-methylation of the precursor with [(11)C]methyl iodide or [(11)C]methyl triflate using automated modules. The average radiochemical yield was approx. 10% with radiochemical purity of >99% and specific activity of 8.8+/-3.6 mCi/nmol at the end-of-synthesis (n=37). PET imaging was performed in non-human primates with a high-resolution research tomograph scanner with a bolus/infusion paradigm. Binding potential (BP(ND)) was calculated using the equilibrium ratios of regions to cerebellum. The tracer uptake was highest in the globus pallidus and occipital cortex, moderate in basal ganglia and thalamus, and lowest in the cerebellum, which is consistent with the known brain distribution of 5-HT(1B) receptors. Infusion of tracer at different specific activities (by adding various amount of unlabeled P943) reduced BP(ND) values in a dose-dependent manner, demonstrating the saturability of the tracer binding. Blocking studies with GR127935 (2 mg/kg iv), a selective 5-HT(1B)/5-HT(1D) antagonist, resulted in reduction of BP(ND) values by 42-95% across regions; for an example, in occipital region from 0.71 to 0.03, indicating a complete blockade. These results demonstrate the saturability and specificity of [(11)C]P943 for 5-HT(1B) receptors, suggesting its suitability as a PET radiotracer for in vivo evaluations of the 5-HT(1B) receptor system in humans.

Characterization of membrane potential-dependent uptake of the novel PET tracer 18F-fluorobenzyl triphenylphosphonium cation.

PURPOSE: Mitochondrial dysfunction has been attributed a critical role in the etiology and pathogenesis of numerous diseases, and is manifested by alterations of the organelle's membrane potential (Deltapsi(m)). This suggests that Deltapsi(m) measurement can be highly useful for diagnostic purposes. In the current study, we characterized the capability of the novel PET agent (18)F-fluorobenzyl triphenylphosphonium ((18)F-FBnTP) to assess Deltapsi(m), compared with the well-established voltage sensor (3)H-tetraphenylphosphonium ((3)H-TPP). METHODS: (18)F-FBnTP and (3)H-TPP uptake under conditions known to alter Deltapsi(m) and plasma membrane potential (Deltapsi(p)) was assayed in the H345 lung carcinoma cell line. (18)F-FBnTP biodistribution was assessed in CD1 mice using dynamic PET and ex vivo gamma well counting. RESULTS: (18)F-FBnTP and (3)H-TPP demonstrated similar uptake kinetics and plateau concentrations in H345 cells. Stepwise membrane depolarization resulted in a linear decrease in (18)F-FBnTP cellular uptake, with a slope (-0.58+/-0.06) and correlation coefficient (0.94+/-0.07) similar (p>0.17) to those measured for (3)H-TPP (-0.63+/-0.06 and 0.96+/-0.05, respectively). Selective collapse of Deltapsi(m) caused a substantial decrease in cellular uptake for (18)F-FBnTP (81.6+/-8.1%) and (3)H-TPP (85.4+/-6.7%), compared with control. Exposure to the proapoptotic staurosporine, known to collapse Deltapsi(m), resulted in a decrease of 68.7+/-10.1% and 71.5+/-8.4% in (18)F-FBnTP and (3)H-TPP cellular uptake, respectively. (18)F-FBnTP accumulated mainly in kidney, heart and liver. CONCLUSION: (18)F-FBnTP is a mitochondria-targeting PET radiopharmaceutical responsive to alterations in membrane potential with voltage-dependent performance similar to that of (3)H-TPP. (18)F-FBnTP is a promising new voltage sensor for detection of physiological and pathological processes associated with mitochondrial dysfunction, such as apoptosis, using PET.

Imaging delta- and mu-opioid receptors by PET in lung carcinoma patients.

UNLABELLED: In the present study, we measured the kinetics and distribution in vivo of the selective delta-opioid antagonist 11C-methylnaltrindole (11C-MeNTI) and the mu-opioid agonist 11C-carfentanil (11C-CFN) in patients with lung carcinoma using PET. METHODS: Paired measurements of 11C-MeNTI and 11C-CFN binding were performed in biopsy-proven small-cell (n = 2), squamous (n = 2), and adenocarcinoma (n = 3) lung cancer patients. Dynamic PET scans of increasing duration (0.5-8 min) were acquired over 90 min after an intravenous bolus injection of 370 MBq of tracer. Time-activity curves for tumor and normal lung parenchyma binding were generated using the region-of-interest (ROI) method. The mean activity at equilibrium was measured, and the specific-to-nonspecific binding ratio (tumor - lung)/lung was calculated. Four of 7 patients underwent an additional static 18F-FDG PET scan for clinical indications. Three of 7 patients underwent surgery, and stained sections of tumor were inspected for inflammation, necrosis, and scar tissue. RESULTS: Increased binding of 11C-MeNTI and 11C-CFN was detected in all tumor types studied. 11C-MeNTI binding in tumor and healthy lung tissue was significantly more intense than that of 11C-CFN. The average specific-to-nonspecific binding ratio across cell types for 11C-MeNTI (4.32 +/- 1.31; mean +/- SEM) was greater than that of 11C-CFN (2.42 +/- 1.17) but lower than that of 18F-FDG (7.74 +/- 0.53). Intravenous naloxone produced 50% and 44% decreases in the specific-to-nonspecific binding ratios of 11C-MeNTI and 11C-CFN, respectively. CONCLUSION: These data provide in vivo evidence for the presence of delta- and mu-opioid receptor types in the 3 major human lung carcinomas and suggest the suitability of 11C-MeNTI and 11C-CFN as investigational probes of lung carcinoma biology.

Characterization of uptake of the new PET imaging compound 18F-fluorobenzyl triphenyl phosphonium in dog myocardium.

UNLABELLED: 18F-Labeled p-fluorobenzyl triphenyl phosphonium cation (18F-FBnTP) is a member of a new class of positron-emitting lipophilic cations that may act as myocardial perfusion PET tracers. Here, we characterize the 18F-FBnTP uptake and retention kinetics, in vitro and in vivo, as well as the myocardial and whole-body biodistribution in healthy dogs, using PET. METHODS: Time-dependent accumulation and retention of 18F-FBnTP in myocytes in vitro was studied. Seven anesthetized, mongrel dogs underwent dynamic PET scans of the heart after intravenous administration of 126-240 MBq 18F-FBnTP. In 4 of the 7 dogs, at the completion of a 60-min dynamic scan, whole-body scans (4 bed positions, 5-min emission and 3-min transmission per bed) were acquired. Arterial blood samples were collected at 0, 5, 10, 20, 30, and 60 min after administration, plasma activity was counted, and high-performance liquid chromatographic analyses for metabolites were performed. The extent of defluorination was assessed by measuring 18F-FBnTP bone uptake in mice, compared with 18F-fluoride. RESULTS: The metabolite fraction comprised <5% of total activity in blood at 5 min and gradually increased to 25% at 30 min after injection. In vivo, 18F-FBnTP myocardial concentration reached a plateau level within a few minutes, which was retained throughout the scanning time. In contrast, activity in the blood pool and lungs cleared rapidly (half-life = 19.5 +/- 4.4 and 30.7 +/- 11.6 s, respectively). Liver uptake did not exceed the activity measured in the myocardium. At 60 min, the uptake ratios of left ventricular wall to blood, lung, and liver (mean of 7 dogs) were 16.6, 12.2, and 1.2, respectively. Summation of activity from 5 to 15 min and from 30 to 60 min after injection produced high-quality cardiac images of similar contrast. Circumferential sampling and a polar plot revealed a uniform distribution, near unitary value, throughout the entire myocardium. The mean coefficient of variance, on 30- to 60-min images along the septum-to-anterior wall and the apex-to-base axes was 7.58% +/- 1.04% and 6.11% +/- 0.89% (mean +/- SD; n = 7), respectively, and on 5- to 15-min images was 7.25% +/- 1.43% and 6.12% +/- 1.88%, respectively. 18F-FBnTP whole-body distribution was highly organ specific with the kidney cortex being the major target organ, followed by the heart and the liver. CONCLUSION: 18F-FBnTP is a promising new radionuclide for cardiac imaging using PET with rapid kinetics, uniform myocardial distribution, and favorable organ biodistribution.

Application of MRI-based partial-volume correction to the analysis of PET images of mu-opioid receptors using statistical parametric mapping.

UNLABELLED: The accurate quantification of brain radioactivity concentration is limited by the spatial resolution of the PET scanner for structures smaller than 2-3 times the resolution. In the presence of enlarged cerebrospinal fluid spaces or regions of cortical neuronal loss, a significant underestimation of gray-matter radioactivity concentration due to the resulting partial-volume averaging can potentially occur. To recover the true radioactivity concentration from PET data, algorithms that use the high-resolution anatomic information provided by MRI have been developed. Their effect on PET quantification has been assessed using regions of interest and non-operator-dependent voxel-based analyses such as statistical parametric mapping (SPM), although the mechanisms that lead to an improvement in PET quantification after partial-volume correction (PVC), compared with no PVC, have not been addressed. METHODS: We studied the influence of our previously described MRI-based PVC algorithm on SPM analysis of age effects on mu-opioid receptor (mu -OR) binding using (11)C-carfentanil PET in 14 healthy subjects (age range, 29-74 y). RESULTS: Mu-OR binding increased with age at a rate of about 0.9% per year in the left temporal cortex after PVC, consistent with the results obtained from human autoradiographic studies. Without PVC, no significant relationship with age was observed. PVC decreased mainly the residual variability of voxel mu-OR binding values around the age regression line. CONCLUSION: MRI-based PVC improves the sensitivity and accuracy of voxel-based statistical analysis of PET data.

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

BACKGROUND: The 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. METHODS: Regional 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. RESULTS: Lower 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. CONCLUSIONS: Results show a strong functional relationship between alcohol craving, mood, and mu-OR binding in specific brain regions of recently abstinent, alcohol-dependent men.

Naloxone increases pain induced by topical capsaicin in healthy human volunteers.

Opioid receptors occur in locations of strategic importance within the central nervous system for modulation of pain. Is pain reduced by ongoing inhibition mediated by activation of these receptors? Experiments to date in which the opioid-receptor antagonist, naloxone, is administered during a painful event have yielded unclear results. Topically applied capsaicin can be used to induce tonic pain of moderate to severe intensity without tissue injury and is an ideal stimulus for studying acute pain modulation. We therefore conducted a placebo-controlled double-blind crossover study to investigate the effects of naloxone on capsaicin-induced pain (five men, four women, aged 29 +/- 5 years). Capsaicin (10%) was applied topically and subjects rated pain every 2 min. The subjects were told that any drug given to them could increase, decrease, or not change their pain sensation. Pain plateaued after 20 min. At 26 min subjects received either naloxone or placebo in double-blind fashion. At 56 min subjects received the alternative (placebo or naloxone). In a second session the order of presentation was reversed. The naloxone induced a significant increase in pain compared both to baseline (P < 0.01) and placebo (P < 0.01). The peak effect, reached at 12-20 min after naloxone delivery, was 59% greater than placebo. This experiment suggests that acute pain is actively suppressed by endogenous opioid-receptor activation.