In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma.

Several lines of evidence suggest aberrant immune response in schizophrenia, including elevated levels of cytokines. These cytokines are thought to be produced by activated microglia, the innate immune cells of the central nervous system. However, increase in translocator protein 18 kDa (TSPO), a marker of activated glia, has not been found in patients with chronic schizophrenia using second-generation radiotracers and positron emission tomography (PET)-based neuroimaging. In this study we focused on patients with recent onset of schizophrenia (within 5 years of diagnosis). Quantified levels of TSPO in the cortical and subcortical brain regions using the PET-based radiotracer [(11)C]DPA-713 were compared between the patients and healthy controls. Markers of inflammation, including interleukin 6 (IL-6), were assessed in the plasma and cerebrospinal fluid (CSF) in these participants. We observed no significant change in the binding of [(11)C]DPA-713 to TSPO in 12 patients with recent onset of schizophrenia compared with 14 controls. Nevertheless, the patients with recent onset of schizophrenia showed a significant increase in IL-6 in both plasma (P<0.001) and CSF (P=0.02). The CSF levels of IL-6 were significantly correlated with the levels of IL-6 in plasma within the total study population (P<0.001) and in patients with recent onset of schizophrenia alone (P=0.03). Our results suggest that increased levels of IL-6 may occur in the absence of changed TSPO PET signal in the brains of medicated patients with recent onset of schizophrenia. Future development of PET-based radiotracers targeting alternative markers of glial activation and immune response may be needed to capture the inflammatory signature present in the brains of patients with early-stage disease.

Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography.

OBJECTIVE: To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 ([(18)F]-AV-45) and cognitive performance in a pilot study. DESIGN: Cross-sectional comparison of [(18)F]-AV-45 in AD patients versus controls. SETTING: Three specialty memory clinics. PARTICIPANTS: Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants. MEASUREMENTS: Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of [(18)F]-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency. RESULTS: Greater [(18)F]-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had [(18)F]-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment. CONCLUSION: [(18)F]-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD.

Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB.

OBJECTIVE: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia. METHOD: [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. RESULTS: [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. CONCLUSIONS: Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.

Preparation of a bromine-76 labelled analogue of epibatidine: a potent ligand for nicotinic acetylcholine receptor studies.

Epibatidine analogues have been labelled with I-123 for single photon emission computed tomography and with short half-life positron emitters (C-11 and F-18) for PET. For easier radiopharmacological studies the bromo analogue of epibatidine (norchlorobromoepibatidine or exo-7-azabicyclo-2-(2-bromo-5-pyridyl)-[2.2.1]heptane) was labelled with Br-76, a longer half-life positron emitter, (T1/2 = 16.2h). [76Br]-norchlorobromoepibatidine was prepared by using a Cu+ assisted bromodeiodination exchange from the iodo analogue in reducing conditions at 190 degrees C. The tracer purified by RP-HPLC was obtained in 70% radiochemical yield with a specific radioactivity of 20 GBq/micromol. Radiochemical and chemical purities measured by radio-TLC and HPLC were >98%.

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

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 mu opioid receptor (mu-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 mu-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 mu-opioid system is activated by acute pain and thus may play a substantial role in pain processing and modulation in pain syndromes.

PET imaging of brain acetylcholinesterase using [11C]CP-126,998, a brain selective enzyme inhibitor.

PET and [(11)C]CP-126,998, an N-benzylpiperidinebenzisoxazole, were used to image brain acetylcholinesterase (AChE) distribution in healthy controls before and after administration of 5 mg donepezil p.o., a reversible AChE inhibitor. Logan plots were used to compute distribution volumes (V(T)). The V(T) of [(11)C]CP-126,998 was highest in the basal ganglia and cerebellum and lowest in the cerebral cortex, thalamus, amygdala, and hippocampus. The regional V(T) values correlated well with AChE concentration measured in vitro. Donepezil, given 4 h before PET scanning, induced a substantial inhibition of [(11)C]CP-126,998 binding (43-62%) in all brain regions when compared to the baseline PET study. The results of this study indicate that PET imaging of [(11)C]CP-126,998 may be useful in quantifying the distribution of regional brain AChE. This new PET radiotracer may potentially be employed in the diagnosis and treatment of patients with disorders of cholinergic neurotransmission, such as Alzheimer's disease.

In vivo labeling of endothelin receptors with [(11)C]L-753,037: studies in mice and a dog.

UNLABELLED: Endothelin (ET) is a potent mammalian vasoconstrictive peptide and a pressor agent. Its 3 isoforms, ET-1, ET-2, and ET-3, mediate several physiologic actions in several organ systems, binding to 2 major receptor subtypes: ET(A) and ET(B). This study was undertaken to evaluate [(11)C]L-753,037 [(+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxy-propyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno [1,2-beta]pyridine-6-carboxylate), a new mixed ET receptor A and B antagonist, as a tracer for in vivo labeling of ET receptors in mice and a dog. METHODS: [(11)C]L-753,037 was synthesized, purified, and formulated from a normethyl precursor, L-843,974, and [(11)C]H(3)I. The tracer was studied for its in vivo kinetics, biodistribution, and ET receptor binding characteristics in mice. In the dog, PET imaging was performed to evaluate binding of [(11)C]L-753,037 to ET receptors in the heart. Specificity of binding was studied in the heart with the selective ET(A) antagonist L-753,164. RESULTS: Kinetic studies in mice showed highest tracer uptake at 5 min after injection in liver (25.0 percentage injected dose per gram [%ID/g]), kidneys (18.7 %ID/g), lungs (15.2 %ID/g), and heart (5.6 %ID/g). Initial high uptake in liver, lungs, and kidneys was followed by rapid washout during the next 10 min and a very slow clearance during the time of observation (2 h after injection). By contrast, the radioactivity in the heart remained constant over 2 h. Administration of both ET(A) (L-753,164) and mixed ET(A)/ET(B) (L-753,137) receptor antagonists resulted in dose-dependent inhibition of [(11)C]L-753,037 binding in mouse heart, lungs, and kidneys but not in the liver. Radioactivity in the brain was very low, indicating that the tracer does not cross the blood-brain barrier. In the dog, a dynamic PET study of the heart showed high tracer accumulation at 55-95 min after injection. Injection of L-753,164 at 30 min before [(11)C]L-753,037 administration led to a significant reduction in tracer binding. [(11)C]methyl triphenyl phosphonium was used as a tracer for reference images of the dog heart muscle. CONCLUSION: The results suggest that [(11)C]L-753,037 binds to ET receptors in vivo and is, therefore, a promising candidate for investigation of these receptors and their occupancy by ET receptor antagonists using PET.

Comparison of myocardial oxygen consumption using 11C acetate positron emission tomography scanning in a working and non-working heart transplant model.

OBJECTIVE: In acute cardiac rejection, changes in myocardial oxygen consumption occur; non-invasive detection of these metabolic changes would have obvious clinical utility. In the classic cervical, heterotopic, canine, transplant model, the heart is non-working. It has a low myocardial oxygen consumption. Creation of a working model with normal myocardial oxygen consumption would enhance validity of non-human studies. METHODS: Clearance of 11C acetate was determined by positron emission tomography (PET) scanning and compared with myocardial oxygen consumption in normal and transplanted canine hearts. Donor hearts from mongrel dogs (2.5-3 kg; n=4) were transplanted into the neck of adult beagles (12-15 kg; n=4), no immunosuppression was given. Two non-working hearts were modified to eject only coronary flow via the right ventricle. In two hearts, a novel working model was created with aortic regurgitation to load the left ventricle. Working and non-working hearts underwent PET scanning on post-operative days 2 and 4. Normal dog hearts (n=2) and native hearts of transplanted dogs (n=3) were used to validate the scanning technique. Coronary sinus and aortic oxygen saturation data along with myocardial blood flow (radiolabeled microspheres) confirmed that clearance of 11C acetate in normal and transplanted hearts followed a bi-exponential model. RESULTS: Myocardial oxygen consumption was correlated with the rate constant of 11C acetate rapid phase clearance (r=0.91) in normal and transplanted hearts. The working hearts had increased myocardial oxygen consumption compared to non-working hearts. CONCLUSIONS: This study (1) introduces a model of a working heterotopic cardiac transplantation with near-normal oxygen consumption; and (2) demonstrates that regional myocardial oxygen consumption in transplanted hearts can be detected by 11C acetate PET.

Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity.

The negative effects of sleep deprivation on alertness and cognitive performance suggest decreases in brain activity and function, primarily in the thalamus, a subcortical structure involved in alertness and attention, and in the prefrontal cortex, a region subserving alertness, attention, and higher-order cognitive processes. To test this hypothesis, 17 normal subjects were scanned for quantifiable brain activity changes during 85 h of sleep deprivation using positron emission tomography (PET) and (18)Fluorine-2-deoxyglucose ((18)FDG), a marker for regional cerebral metabolic rate for glucose (CMRglu) and neuronal synaptic activity. Subjects were scanned prior to and at 24-h intervals during the sleep deprivation period, for a total of four scans per subject. During each 30 min (18)FDG uptake, subjects performed a sleep deprivation-sensitive Serial Addition/Subtraction task. Polysomnographic monitoring confirmed that subjects were awake. Twenty-four hours of sleep deprivation, reported here, resulted in a significant decrease in global CMRglu, and significant decreases in absolute regional CMRglu in several cortical and subcortical structures. No areas of the brain evidenced a significant increase in absolute regional CMRglu. Significant decreases in relative regional CMRglu, reflecting regional brain reductions greater than the global decrease, occurred predominantly in the thalamus and prefrontal and posterior parietal cortices. Alertness and cognitive performance declined in association with these brain deactivations. This study provides evidence that short-term sleep deprivation produces global decreases in brain activity, with larger reductions in activity in the distributed cortico-thalamic network mediating attention and higher-order cognitive processes, and is complementary to studies demonstrating deactivation of these cortical regions during NREM and REM sleep.

Column-switching HPLC for the analysis of plasma in PET imaging studies.

A column-switch high performance liquid chromatography method for the analysis of 4 mL of plasma is described with six examples of chromatography of [(11)C]-labeled positron-emission tomography imaging agents. Complete extraction of all but the most polar metabolites by the reverse phase capture column is achieved by disruption of plasma protein binding by 8 M urea.

6-[18F]fluoro-A-85380, a novel radioligand for in vivo imaging of central nicotinic acetylcholine receptors.

A novel positron emission tomography (PET) radiotracer, 6-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[18F]fluoro-A-85380, 6-[18F]FA) was synthesized by a no-carrier-added fluorination. In vitro 6-[18F]FA bound to nicotinic acetylcholine receptors (nAChRs), with very high affinity (Kd 28 pM). In PET studies, 6-[18F]FA specifically labeled central nAChRs in the brain of the Rhesus monkey and demonstrated highest levels of accumulation of radioactivity in brain regions enriched with the alpha4beta2 subtype of nAChR. 6-[18F]FA exhibited a target-to-non-target ratio (estimated as radioactivity in the thalamus to that in the cerebellum) of binding in primate brain similar to that previously determined for a labeled analog of epibatidine, [18F]FPH. In contrast to [18F]FPH, the novel tracer is expected to exhibit substantially less toxicity. Thus, the novel radioligand, 6-[18F]FA, appears to be a suitable candidate for imaging nAChRs in human brain.

Brain activation patterns in schizophrenic and comparison volunteers during a matched-performance auditory recognition task.

OBJECTIVE: The biological characteristics of schizophrenia are often studied by using functional imaging techniques. However, since volunteers with schizophrenia routinely fail to perform as accurately or as quickly as healthy volunteers, it is difficult to ascertain whether a particular deficit in blood flow to a brain region is due to behavior or to the underlying illness. In this report, investigators used an auditory recognition task to assess brain blood flow patterns and behavioral correlates of schizophrenic patient volunteers trained on the task. METHOD: Twelve healthy volunteers and 18 volunteers with schizophrenia were trained to make tone frequency recognitions. Accuracy and stimuli were matched between groups. Participants were required to press a button to indicate whether a briefly presented tone was the high-frequency (1500 Hz) reference tone or one of a lower frequency level (level chosen to elicit an 80% accuracy score). Subjects underwent bolus [(15)O]H(2)O blood flow positron emission tomography during inactive rest, a sensory motor control condition, and the decision task. Blood flow patterns were assessed between conditions and between groups. RESULTS: As a group, the patients with schizophrenia (who performed as quickly and accurately as the comparison subjects) exhibited significantly less change in regional cerebral blood flow (rCBF) to the anterior cingulate and supplementary motor cortices when switching from the sensory motor control to the decision condition. There were also marked between-group differences in correlations between rCBF and response time. Whereas the comparison subjects exhibited progressively greater blood flow to the frontal cortex in association with longer response times, the schizophrenic patients exhibited progressively lower blood flow in conjunction with extended response times. CONCLUSIONS: The failure to appropriately enhance cingulate activity when engaged in a demanding task and the progressive, time-dependent decline in frontal blood flow suggest that patients with schizophrenia are unable to make optimal use of frontocingulate systems when maximally engaged in high-error tasks.

Radiolabeled neuronal nitric oxide synthase inhibitors: synthesis, in vivo evaluation, and primate PET studies.

UNLABELLED: The objectives of this study were to synthesize neuronal nitric oxide synthase (NOS-I)-selective imaging agents based on the 2 potent, selective inhibitors AR-R 17443 [N-(4-((2-((phenylmethyl) (methyl)-amino)ethyl)phenyl)-2-thiophenecarboximidamide)] and AR-R 18512 [(N(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-thiophenecarboxim idamide)] in positron-emitting form and to evaluate regional brain uptake in rodents and primates. METHODS: [11C]AR-R 17443 and [11C]AR-R 18512 were produced by N-alkylation of the corresponding desmethyl precursors using [11C]iodomethane. Regional brain uptake of [11C]AR-R 17443 and [11C]AR-R 18512 was assayed in rats and NOS-I knockout mice, and PET was performed in baboons. Tracer kinetic modeling used a 2-compartment plasma and brain tissue model. RESULTS: Yields of [11C]AR-R 17443 and [11C]AR-R 18512 ranged from 8% to 16% at the end of synthesis, with specific activities of 50-178 GBq/micromol (1,350-4,800 Ci/mmol) at the end of synthesis. In rat cerebellum and cortex at 30 min after injection, [11C]AR-R 17443 showed 1.01 +/- 0.01 and 1.63 +/- 0.12 percentage injected dose per gram (%ID/g) uptake, respectively, whereas [11C]AR-R 18512 showed 0.88 +/- 0.01 and 1.30 +/- 0.07 %ID/g uptake, respectively. Attempts to block tracer uptake by pretreatment with the NOS-I-selective inhibitor 7-nitroindazole or the corresponding unlabeled inhibitor (or desmethyl precursor to AR-R 17443 of similar potency) were unsuccessful. A small but significant (20%) decrease in cerebellar uptake of [11C]AR-R 18512 was present in NOS-I knockout mice compared with control mice. PET of [11C]AR-R 18512 in baboons with concurrent regional cerebral blood flow (rCBF) determination before and after administration of blocker showed dose-related decreases in cerebellar uptake that were greater than or equal to decreases in rCBF. Plasma metabolites accounted for 27% of total activity at 30 min after injection. Kinetic modeling of binding potentials revealed a distribution volume of 334 in cerebral blood that dropped 51% after blocker administration. CONCLUSION: Rodent studies for [11C]AR-R 17443 and [11C]AR-R 18512 showed little evidence of specific NOS-I binding. In baboons, we detected a higher uptake of [11C]AR-R 18512 in the cerebellum than in the cortex (approximately 5%, accounting for decreased rCBF because of blockade), indicating minimal specific binding. Analogs of higher affinity are likely required if this class of agents is to prove viable for PET.

6-[18F]Fluoro-A-85380: an in vivo tracer for the nicotinic acetylcholine receptor.

6-[18F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[18F]fluoro-A-85380 or 6-[18F]FA), a new tracer for positron emission tomography, was synthesized by no-carrier-added [18F] fluorination of 6-iodo-3-((1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy)pyridine followed by acidic deprotection. 6-[18F]FA followed the regional densities of brain nicotinic acetylcholine receptors (nAChRs) reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands as well as with unlabeled 6-FA. A preliminary toxicology study of the 6-FA showed a relatively low biological effect.

Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors.

ABSTRACT. [(18)F] SR144385 and [(18)F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [(18)F] SR147963 and 2.5 for [(18)F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A.

2-[18F]F-A-85380: a PET radioligand for alpha4beta2 nicotinic acetylcholine receptors.

2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]F-A-85380), a ligand for nicotinic acetylcholine receptors (nAChRs) was evaluated in an in vitro binding assay with membranes of rat brain and in vivo by PET in Rhesus monkey brain. The ligand has high affinity for alpha4beta2 nAChRs (K(D)=50 pM), crosses the blood-brain barrier, and distributes in the monkey brain in a pattern consistent with that of alpha4beta2 nAChRs. The specific/non-specific binding ratio increased steadily, reaching a value of 3.3 in the thalamus at 4 h. The specific binding of 2-[18F]F-A-85380 was reversed by cytisine. These results, in combination with the data demonstrating low toxicity of 2-[18F]F-A-85380, indicate that this ligand shows promise for use with PET in human subjects.

Quantification of delta-opioid receptors in human brain with N1'-([11C]methyl) naltrindole and positron emission tomography.

The regional binding of N1'-([11C]methyl)naltrindole (MeNTI), a selective delta-opioid antagonist, was studied in healthy human subjects with positron emission tomography (PET). After the bolus intravenous administration of high specific activity [11C]MeNTI, PET was performed over 90 minutes. Arterial plasma samples were obtained during the scanning period and assayed for the presence of radiolabeled metabolites. The data were analyzed with various kinetic (two- and three-compartment models, Patlak graphical analysis) and nonkinetic (apparent volume of distribution and activity at a late scanning time) approaches. This tracer showed irreversible binding characteristics during the scanning period used. The results of the analyses also were compared with the density and distribution of delta-opioid receptors in the human brain in vitro. Additionally, computer simulations were performed to assess the effects of changes in receptor binding and tracer transport changes on the perceived binding parameters obtained with the models. A constrained three-compartment kinetic model was demonstrated to be superior to other quantification models for the description of MeNTI kinetics and quantification of delta receptor binding in the human brain with 11C-labeled MeNTI.

Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand.

The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (fT), and its normalized retention (f(rel) = fT/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (fT,f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [11C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k1 and k2 and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3.09). The variance of the distribution volumes was acceptable when the logarithmic transform lnDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less (r = 0.652 for the three-parameter model) than the correlation of the noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [11C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k1, k2, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.

Synthesis and characterization of binding of 5-[76Br]bromo-3-[[2(S)-azetidinyl]methoxy]pyridine, a novel nicotinic acetylcholine receptor ligand, in rat brain.

5-[76Br]Bromo-3-[[2(S)-azetidinyl]methoxy]pyridine ([76Br]BAP), a novel nicotinic acetylcholine receptor ligand, was synthesized using [76Br]bromide in an oxidative bromodestannylation of the corresponding trimethylstannyl compound. The radiochemical yield was 25%, and the specific radioactivity was on the order of 1 Ci/micromol. The binding properties of [76Br]BAP were characterized in vitro and in vivo in rat brain, and positron emission tomography (PET) experiments were performed in two rhesus monkeys. In association experiments on membranes of the cortex and thalamus, >90% of maximal specific [76Br]BAP binding was obtained after 60 min. The dissociation half-life of [76Br]BAP was 51 +/- 6 min in cortical membranes and 56 +/- 3 min in thalamic membranes. Saturation experiments with [76Br]BAP revealed one population of binding sites with dissociation constant (K(D)) values of 36 +/- 9 and 30 +/- 9 pM in membranes of cortex and thalamus, respectively. The maximal binding site density (Bmax) values were 90 +/- 17 and 207 +/- 33 fmol/mg in membranes of cortex and thalamus, respectively. Scatchard plots were nonlinear, and the Hill coefficients were <1, suggesting the presence of a lower-affinity binding site. In vitro autoradiography studies showed that binding of [76Br]BAP was high in the thalamus and presubiculum, moderate in the cortex and striatum, and low in the cerebellum and hippocampus. A similar pattern of [76Br]BAP accumulation was observed by ex vivo autoradiography. In vivo, binding of [76Br]BAP in whole rat brain was blocked by preinjection of (S)(-)-nicotine (0.3 mg/kg) by 27, 52, 68, and 91% at survival times of 10, 25, 40, 120, and 300 min, respectively. In a preliminary PET study in rhesus monkeys, the highest [76Br]BAP uptake was found in the thalamus, and radioactivity was displaceable by approximately 60% with cytisine and by 50% with (S)(-)-nicotine. The data of this study indicate that [76Br]BAP is a promising radioligand for the characterization of nicotinic acetylcholine receptors in vivo.

Enhanced uptake of [11C]TPMP in canine brain tumor: a PET study.

UNLABELLED: In vitro studies have demonstrated the membrane potential-dependent enhanced uptake of phosphonium salts, including [3H]triphenylmethylphosphonium (TPMP), into mitochondria of carcinoma and glioma-derived tumor cells, suggesting the potential use of phosphonium salts as tracers for tumor imaging. This study characterizes the in vivo uptake of [11C]TPMP in canine brain glioma using PET. METHODS: Dynamic paired PET studies of [11C]TPMP followed by [68Ga]ethylenediaminetetraacetic acid (EDTA) were performed 4 d before and 9 d after tumor cell inoculation. Graphical analysis was used to evaluate [11C]TPMP retention in tumor tissue. Distribution of tracer uptake was compared with tumor histological sections. RESULTS: [11C]TPMP exhibited enhanced uptake and prolonged retention in tumor cells. Patlak plot was linear over the 20- to 95-min postinjection period (r = 0.97 +/- 0.1). [68Ga]EDTA exhibited a gradual washout from the tumor tissue. The tumor-to-normal brain uptake ratio at 55 to 95 min postinjection was 47.5 for [11C]TPMP and 8.1 for [68Ga]EDTA. Qualitative comparison with histological sections indicated that [11C]TPMP enhanced uptake was restricted to the tumor area. CONCLUSION: The enhanced uptake and prolonged retention in tumor suggest [11C]TPMP as a promising means for imaging of gliomas in dogs. The need for studies in humans is indicated.