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Objective: To determine whether technetium Tc 99m exametazime (HMPAO) single-photon emission computed tomography (SPECT) can distinguish between human immunodeficiency virus (HIV)-positive homosexual men with normal neuropsychologic test results and HIV-positive homosexual men with abnormal neuropsychologic test results. Design: Neurologic, neuropsychologic, magnetic resonance imaging, and Tc 99m HMPAO SPECT examinations were performed on 10 HIV-positive homosexual men without cognitive impairment and five HIV-positive homosexual men with cognitive impairment. Patients: Human immunodeficiency virus—positive homosexual men from New York City were recruited for the study. Main Outcome Measures: Findings on SPECT scans were evaluated qualitatively for focal defects, heterogeneity of the cortical margin, white matter hypoperfusion, and decreased global cortical uptake. All SPECT focal defects were coregistered with magnetic resonance images; SPECT heterogeneity and global cortical uptake were also measured quantitatively. Results: Coregistration with magnetic resonance imaging revealed that 63% of the focal SPECT defects corresponded to brain gyri and 37% corresponded to sulci. There was no significant difference in the frequency of qualitative or quantitative SPECT abnormalities between HIV-positive homosexual men with and without cognitive impairment. However, after examining individual neuropsychologic test factors, impaired motor speed performance was associated with decreased quantitative global cerebral uptake. Conclusions: Qualitative SPECT abnormalities are not increased in frequency in HIV-positive homosexual men with global cognitive impairment compared with those in HIV-positive homosexual men without cognitive impairment. Impaired motor speed performance may be associated with decreased quantitative global cerebral uptake.

Using sodium acetate, [1- 14 C] as a starting material, a total of seven steps were required to synthesize the title compound. This involved acylation of ortho-dichlorobenzene to form dichloroacetophenone, [2. 14 C] (I). The 2-phenyl-4-quinoline carboxylic acid, [2- 14 C] (II) was prepared by the Pfitzinger reaction from (I) and dichloroisatin. Compound II was converted to the acid chloride (III) by reaction with SOCl 2 in benzene. Grignard condensation reaction of (III) yielded 4-quinolylmethylketone, [2- 14 C] (IV) which was then converted to the bromomethylketone (V). Compound V was reacted with NaBH 4 to form the ethylene oxide (VI). Alkylation of the oxide yielded the title compound (VII). The overall radiochemical yield was 10.1% and the specific activity was 3.0 mCi/mmol, with a radiochemical purity of >99.5%

Objective: To determine whether technetium Tc 99m exametazime single-photon computed emission tomography (SPECT) can distinguish gay human immunodeficiency virus (HIV)—positive subjects, both with and without mild cognitive impairment, from gay HIV-negative control subjects. Design: Twenty HIV-positive subjects (12 without cognitive impairment and eight with mild cognitive impairment) and 10 HIV-negative subjects underwent neurological, neuropsychological, magnetic resonance imaging, and technetium Tc 99m exametazime SPECT examinations. Setting: Subjects were recruited from a natural history study of gay men with HIV infection. Patients: Subjects from the cohort who had previously participated in a magnetic resonance imaging study were selected for the SPECT study. Main Outcome Measures: The SPECT scans were rated as abnormal if focal defects, confirmed by a horizontal profile analysis, were seen. Results: Sixty-seven percent of HIV-positive subjects without cognitive impairment, 88% of HIV-positive subjects with mild cognitive impairment, and 20% of HIV-negative subjects had abnormal SPECT scans (P Conclusion: Compared with gay HIV-negative control subjects, focal SPECT defects are seen with an increased frequency in HIV-positive gay men without cognitive impairment and in HIV-positive gay men with mild cognitive impairment.

1-Methyl-4-[4-(7-chloro-4-quninolyl-[3- 14 C]-amino)-benzoyl]piperazine (V) was prepared for pharmacokinetic and pharmacodynamic evaluation. The synthesis of V was accomplished first by a modified Claisen ester condensation reaction of diethyl-[2- 14 C]-malonate, triethyl orthoformate, and acetic anhydride in the presence of ZnCl 2 to form ethyl ethoxymethylene-[2- 14 C]-malonate (1), which was further condensed with m-chloroaniline to yield 7-chloro-4-hydroxy-3-[ 14 C]-quinoline-ethyl-carboxylate (II). Saponification of II yielded the corresponding carboxylic acid (III). Decarboxylation of the acid group upon heating and a substitution of the 4-OH group of compound 111 into chlorine atom with POCl 3 produced 4,7-dichloro-[3- 14 C]-quinoline (IV), which then was reacted with 1 -methyl-4-(p-amino-benzoyl)piperazine to form the title compound V. There were a total of five steps of reaction, with a overall yield of 34.3%. The specific activity was 1,74 mCi/mmol

Bulimia nervosa (BN) has been characterized as similar to an addiction, though the empirical support for this characterization is limited. This study utilized PET imaging to determine whether abnormalities in brain dopamine (DA) similar to those described in substance use disorders occur in BN.PET imaging with [(11) C]raclopride, pre/post methylphenidate administration, to assess dopamine type 2 (D(2)) receptor binding (BP(ND)) and striatal DA release (ΔBP(ND)).There was a trend toward lower D(2) receptor BP(ND) in two striatal subregions in the patient group when compared with the control group. DA release in the putamen in the patient group was significantly reduced and, overall, there was a trend toward a difference in striatal DA release. Striatal DA release was significantly associated with the frequency of binge eating.These data suggest that BN is characterized by abnormalities in brain DA that resemble, in some ways, those described in addictive disorders.

Objective: Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, positron emission tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is linked to cocaine-seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. The authors hypothesized that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. Method: Prior to treatment, cocainedependent subjects underwent two PET scans using [11 C]raclopride, before and after the administration of a stimulant (methylphenidate), for measurement of striatal dopamine D 2/3 receptor binding and presynaptic dopamine release. Results: Both of the outcome measures were lower in the volunteers who did not respond to treatment than in those who experienced a positive treatment response. Conclusions: These findings provide in sight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.

SUMMARY Five steps were required to synthesize the title compound. This involved a catalytic exchange reaction, nitration, hydrolysis, and condensation. The overall radiochemical yield was 28.87% and the specific activity was 12.4 mCi/mmol, with a radiochemical purity of more than 95.7%

PURPOSE The participation in concussive susceptible sports such as boxing may cause chronic traumatic brain injury. The objective of this study was to determine whether there are unique patterns of reduced brain glucose metabolism in professional and amateur boxers. METHOD We compared the fluorine-18 fluorodeoxyglucose (F-18 FDG) PET brain scans of boxers (group) (N=19) with those of controls (group) (N=7) using both statistical parametric mapping and region of interest analysis. RESULTS Boxers showed decreased F-18 FDG uptake by 8-15% in the following brain areas: posterior cingulate cortex, parieto-occipito, frontal lobes (Broca's area) bilaterally, and the cerebellum (P

Objective To examine the utility of single-photon emission computed tomography (SPECT) to predict conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). Design Longitudinal, prospective study. Setting University-based memory disorders clinic. Participants One hundred twenty seven patients with MCI and 59 healthy comparison subjects followed up for 1–9 years. Measurements Diagnostic evaluation, neuropsychological tests, social/cognitive function, olfactory identification, apolipoprotein E genotype, magnetic resonance imaging, and brain 99m Tc hexamethyl-propylene-aminoxime SPECT scan with visual ratings, and region of interest (ROI) analyses were done. Results Visual ratings of SPECT temporal and parietal blood flow did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), but the global rating predicted conversion (41.9% sensitivity and 82.3% specificity, Fisher's exact test p=0.013). Blood flow in each ROI was not predictive, but when dichotomized at the median value of the patients with MCI, low flow increased the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% confidence interval: 1.16–7.53, p=0.023) and medial temporal regions (hazard ratio: 3.12, 95% confidence interval: 1.14–8.56, p=0.027). In the 3-year follow-up sample, low parietal (p Conclusions SPECT visual ratings showed limited utility in predicting MCI conversion to AD. The modest predictive utility of quantified low parietal and medial temporal flow using SPECT may decrease when other stronger predictors are available.

[(18)F]Fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [(18)F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE).[(18)F]FDG-PET scans of 46 adult patients with pharmacoresistant unilateral TLE (25 RTLE and 21 LTLE) were subjected to SPM analysis.Forty-six patients were diagnosed with nonlesional TLE, 16 of whom had hippocampal sclerosis (HS). The average duration of epilepsy was 17.4 +/- 12.3 years (3-46 years),5 years in 10 patients andor=10 years in 30 patients. Visual analysis of [(18)F]FDG-PET scans revealed hypometabolism in the epileptogenic temporal cortex in 31 (67%) patients. After SPM analysis of all [(18)F]FDG-PET images, hypometabolism was unilateral and reported in lateral and mesial structures of the epileptogenic temporal cortex in addition to the ipsilateral fusiform and middle occipital gyrus. Subsequent analysis revealed that temporal lobe hypometabolism was present only in patients with longer epilepsy duration (or=10 years) in parahippocampal gyrus, uncus, and middle and superior temporal gyrus (P0.05 corrected). Epilepsy duration was inversely correlated with decreased glucose uptake in the inferior temporal gyrus, hippocampus, and parahippocampal gyrus of the epileptogenic temporal cortex (P0.05). Age at seizure onset did not affect the correlation between epilepsy duration and glucose uptake except in the inferior temporal gyrus (P0.05).Voxel-based mapping supports the assertion that glucose hypometabolism of the epileptogenic temporal lobe cortex and other neighboring cortical regions increases with longer epilepsy duration in TLE.

The purpose of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of brain perfusion SPECT studies using 99mTc radiopharmaceuticals. SPECT of the brain is a technique for obtaining tomographic images of the 3-dimensional distribution of a radiopharmaceutical, which reflects regional cerebral perfusion. ### A. Patient Preparation 1. Before arrival, patients should be instructed to avoid, if possible, caffeine, alcohol, or other drugs known to affect cerebral blood flow. 2. Before injection: 1. The most important aspect of patient preparation is to evaluate the patient for ability to cooperate. 2. A consistent environment must be maintained at the time of injection and uptake: 1. Place the patient in a quiet, dimly lit room. 2. Instruct the patient to keep eyes and ears open. 3. Ensure that the patient is seated or reclining comfortably. 4. Place intravenous access at least 10 min before injection to permit accommodation. 5. Instruct the patient not to speak or read. 6. Have no interaction with the patient before, during, or for 5 min after injection. ### B. Information Pertinent to Performing the Procedure Relevant patient data suggested for optimal interpretation of scans includes patient history (including any past drug use or trauma), neurologic examination, psychiatric examination, mental status examination (e.g., Folstein mini-mental examination or other neuropsychologic tests), recent morphologic imaging studies (e.g., CT, MRI), and current medications and when last taken. ### C. Precautions 1. Demented patients must be closely monitored at all times. 2. Patients with neurologic deficits may require special care and monitoring. 3. If sedation is required, it should be given after injection of the radiopharmaceutical, when possible. ### D. Radiopharmaceutical 1. Radiopharmaceutical types: 1. Unstabilized 99mTc-exametazime (HMPAO) 2. Stabilized 99mTc-HMPAO 3. 99mTc-bicisate (ethyl cystine dimer [ECD]) Dosimetry for these radiopharmaceuticals is presented in Tables 1 and 2. 2. Radiopharmaceutical preparation: 1. Use fresh generator eluate (

D. P. Devanand, M.D., Ronald L. Van Heertum, M.D., Lawrence S. Kegeles, M.D., Ph.D., Xinhua Liu, Ph.D., Zong Hao Jin, Gnanavalli Pradhaban, M.B.B.S., Henry Rusinek, Ph.D., Mali Pratap, M.B.B.S., Gregory H. Pelton, M.D., Isak Prohovnik, Ph.D., Yaakov Stern, Ph.D., J. John Mann, M.D., and Ramin Parsey, M.D., Ph.D. Divisions of Geriatric Psychiatry and Molecular Imaging, New York State Psychiatric Institute, College of Physicians and Surgeons, Columbia University; the Gertrude H. Sergievsky Center and the Departments of Neurology and Radiology, College of Physicians and Surgeons, Columbia University and the Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University, New York; Department of Biostatistics, Mailman School of Public Health, Columbia University, New York; New York University Medical Center, New York; and the Departments of Psychiatry and Radiology, Mount Sinai Medical Center, New York, NY

Type 2 vesicular monoamine transporter (VMAT2), found in the brain, is also expressed by P-cells of the pancreas in association with insulin. Preclinical experiments suggested that C-11-dihydrotetrabenazine PET-measured VMAT2 binding might serve as a biomarker of P-cell mass. We evaluated the feasibility of C-11- dihydrotetrabenazine PET quantification of pancreatic VMAT2 binding in healthy subjects and patients with long-standing type 1 diabetes. Methods: C-11-Dihydrotetrabenazine PET was performed on 6 patients and 9 controls. VMAT2 binding potential (BPND) was estimated voxelwise by using the renal cortex as reference tissue. As an index of total pancreatic VMAT2, the functional binding capacity (the sum of voxel BPND x voxel volume) was calculated. Pancreatic BPND, functional binding capacity, and stimulated insulin secretion measurements were compared between groups. Results: The pancreatic mean BPND was decreased in patients (1.86 +/- 0.05) to 86% of control values (2.14 +/- 0.08) (P = 0.01). In controls, but not in patients, BPND correlated with stimulated insulin secretion (r(2) = 0.50, P = 0.03). The average functional binding capacity was decreased by at least 40% in patients (P = 0.001). The changes in functional binding capacity and BPND were less than the near-complete loss of stimulated insulin secretion observed in patients (P = 0.001). Conclusion: These results suggest that C-11-dihydrotetrabenazine PET allows quantification of VMAT2 binding in the human pancreas. However, BPND and functional binding capacity appear to overestimate beta-cell mass given the near-complete depletion of p-cell mass in long-standing type 1 diabetes, which may be due to higher nonspecific binding in the pancreas than in the renal cortex.

Context: There is controversy regarding whether objective neurobiological abnormalities exist after intensive antibiotic treatment for Lyme disease. Objectives: To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR). Design: Case-controlled study. Setting: A university medical center. Participants: A total of 35 patients and 17 healthy volunteers (controls). Patients had well-documented prior Lyme disease, a currently reactive IgG Western blot, prior treatment with at least 3 weeks of intravenous cephalosporin, and objective memory impairment. Main Outcome Measures: Patients with persistent Lyme encephalopathy were compared with age-, sex-, and education-matched controls. Fully quantified assessments of rCBF and rCMR for glucose were obtained while subjects were medication-free using positron emission tomography. The CBF was assessed in 2 resting room air conditions (without snorkel and with snorkel) and 1 challenge condition (room air enhanced with carbon dioxide, ie, hypercapnia). Results: Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (P < .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements. Conclusions: Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.

Cerebral single photon emission computed tomography (SPECT), a method of functional brain imaging, measures cerebral blood flow and metabolism. This paper describes the imaging procedure and several cases where cerebral SPECT was of use in the differential diagnosis of medically ill patients who also presented with psychopathology. SPECT patterns in cerebrovascular disease, dementia, focal epilepsy, and AIDS are at present the best described and seem to be the most specific. Often changes in regional cerebral blood flow are seen before structural changes become apparent on CT or MRI. Cerebral SPECT can add valuable diagnostic information in assessing psychopathology in the medically ill and can often lead to changes in treatment.

Background Previous positron emission tomography (PET) imaging studies in nonhuman primates have shown that striatal dopamine type 2/3 (D 2/3 ) receptors correlate with social hierarchy in monkeys and that dominant animals exhibit higher levels of D 2/3 receptor binding. The goal of the present study was to examine this phenomena in human subjects using PET and the radiotracer [ 11 C]raclopride. Methods Fourteen healthy volunteers were scanned with [ 11 C]raclopride to measure D 2/3 receptor binding potential (BP). Social status was assessed using the Barratt Simplified Measure of Social Status. In addition, participants were asked to assess their level of social support using the Multidimensional Scale of Perceived Social Support (MSPSS). Results A correlation was seen between social status and dopamine D 2/3 receptors, where volunteers with the higher status had higher values for [ 11 C]raclopride BP. A similar correlation was seen with the perceived social support, where higher [ 11 C]raclopride BP correlated with higher scores on the MSPSS. Conclusions The results of this study support the hypothesis that social status and social support is correlated with D 2/3 receptor binding.

Neuroreceptor PET studies consisting of long dynamic data acquisitions result in data with low signal-to-noise ratio and limited spatial resolution. To address these problems we have developed a 3D wavelet-based image processing tool (wavelet filter, WF), containing both denoising and enhancement functionality. The filter is based on multi-scale thresholding and cross-scale regularization. These operations are data-driven, which may lead to non-linearity effects and hamper quantification of dynamic PET data. The aim of the present study was to investigate these effects using both phantom and human PET data. A phantom study was performed with a cylindrical phantom, filled with 18F, containing a number of spherical inserts filled with 11C. Human studies were performed on 9 healthy volunteers after injection of the serotonine transporter tracer [11C]DASB. Images from both phantom and human studies were reconstructed with filtered backprojection and post-processed by WF with a series of different denoising and enhancement parameter values. The phantom study was analyzed by computing the insert-to-background ratio as a function of time. The human study was analyzed with a 1-tissue compartment model for a series of brain regions. For the phantom study, linear relations were found between unprocessed and WF processed data for positive contrasts. However, for negative contrast, non-linearity effects were observed. For the human data, good correlation was obtained between results from unprocessed and WF processed data. Our results showed that, although non-linear effects may appear in low-contrast areas, it is possible to achieve accurate quantification with wavelet-based image processing.

Ronald L Van Heertum, Robert Scarimbolo, Robert Ford, Eli Berdougo, Michael O’Neal BioClinica Inc, Princeton, PA, USA Abstract: In the era of personalized medicine, diagnostic approaches are helping pharmaceutical and biotechnology sponsors streamline the clinical trial process. Molecular assays and diagnostic imaging are routinely being used to stratify patients for treatment, monitor disease, and provide reliable early clinical phase assessments. The importance of diagnostic approaches in drug development is highlighted by the rapidly expanding global cancer diagnostics market and the emergent attention of regulatory agencies worldwide, who are beginning to offer more structured platforms and guidance for this area. In this paper, we highlight the key benefits of using companion diagnostics and diagnostic imaging with a focus on oncology clinical trials. Nuclear imaging using widely available radiopharmaceuticals in conjunction with molecular imaging of oncology targets has opened the door to more accurate disease assessment and the modernization of standard criteria for the evaluation, staging, and treatment responses of cancer patients. Furthermore, the introduction and validation of quantitative molecular imaging continues to drive and optimize the field of oncology diagnostics. Given their pivotal role in disease assessment and treatment, the validation and commercialization of diagnostic tools will continue to advance oncology clinical trials, support new oncology drugs, and promote better patient outcomes. Keywords: companion diagnostics, molecular imaging, oncology trials, personalized medicine, diagnostic assays

Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons.In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH(3)OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (+/-)-8-OH-DPAT.MMP is a selective 5-HT1A receptor agonist (Ki 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 +/- 5% (n = 15) yield at EOS with a specific activity of 2,600 +/- 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (+/-)-8-OH-DPAT.We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.

Diabetes results from an absolute or relative reduction in pancreatic beta cell mass (BCM) leading to insufficient insulin secretion and hyperglycemia. Measurement of insulin secretory capacity is currently used as a surrogate measure of BCM. However, serum insulin concentrations provide an imprecise index of BCM, and no reliable noninvasive measure of BCM is currently available. Type 2 vesicular monoamine transporters (VMAT2) are expressed in human islet beta cells, as well as in tissues of the CNS. [11C]Dihydrotetrabenazine ([11C]DTBZ) binds specifically to VMAT2 and is a radioligand currently used in clinical imaging of the brain. Here we report the use of [11C]DTBZ to estimate BCM in a rodent model of spontaneous type 1 diabetes (the BB-DP rat). In longitudinal PET studies of the BB-DP rat, we found a significant decline in pancreatic uptake of [11C]DTBZ that anticipated the loss of glycemic control. Based on comparison of standardized uptake values (SUVs) of [11C]DTBZ and blood glucose concentrations, loss of more than 65% of the original SUV correlated significantly with the development of persistent hyperglycemia. These studies suggest that PET-based quantitation of VMAT2 receptors provides a noninvasive measurement of BCM that could be used to study the pathogenesis of diabetes and to monitor therapeutic interventions.

Pharmacological evidence suggests that schizophrenia is associated with increased stimulation of dopamine (DA) D2 receptors. Recently, several groups have demonstrated that amphetamine-induced DA release is increased in schizophrenia, providing direct evidence for dysregulation of DA systems in this condition. In healthy volunteers, pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine increases amphetamine-induced DA release to levels similar to those observed in patients with schizophrenia. Therefore, the dysregulation of DA function observed in schizophrenia might be secondary to NMDA hypofunction. In this study, the regulation of this response by glutamate (GLU) transmission was further characterized by using a metabotropic glutamate (mGlu) receptor group II agonist to inhibit GLU transmission. The amphetamine- (0.5 mg/kg intravenously (i.v.)) induced decrease in [11C]raclopride equilibrium-specific binding (V3″) was measured under control conditions and following pretreatment with the mGlu2/3 receptor agonist LY354740 (20 mg/kg i.v.) in four baboons. Amphetamine reduced [11C]raclopride V3″ by 28 ± 7% under control conditions. Following LY354740 pretreatment, amphetamine-induced reduction in [11C]raclopride V3″ was significantly enhanced (35 ± 7%, p = 0.002). The enhancement of the amphetamine-induced reduction in [11C]raclopride V3″ by LY354740 was not a simple additive effect, as LY354740 alone did not reduce [11C]raclopride V3″. In conclusion, the results of this study further document the involvement of GLU transmission in regulating the effect of amphetamine-induced DA release, and provide additional support to the hypothesis that the dysregulation of DA function revealed by the amphetamine challenge in schizophrenia might stem from a deficit in GLU transmission.

Antagonist 5-HT(1A) PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-(11)C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (10), a potential high affinity (K(i) = 1.36 nM) 5-HT(1A) agonist PET tracer is described. Piperazine 10 is a 5-HT(1A) agonist with an EC(50) comparable to serotonin, based on cAMP formation and GTP(gamma)S binding assays. Radiosynthesis of [(11)C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [(11)C]CH(3)OTf in 25 +/- 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [(11)C]10 were99% with a specific activity 1500 +/- 300 Ci/mmol (n =15). PET studies in anesthetized baboon demonstrate [(11)C]10 specific binding in brain regions rich in 5-HT(1A) receptors. Binding of [(11)C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V(T)) of [(11)C]10 in baboon correlate with [(11)C]WAY100635 V(T) in baboons. These data provide evidence that [(11)C]10 is the first promising agonist PET tracer for the 5-HT(1A) receptors.

Beta-cell mass (BCM) influences the total amount of insulin secreted, varies by individual and by the degree of insulin resistance, and is affected by physiologic and pathologic conditions. The islets of Langerhans, however, appear to have a reserve capacity of insulin secretion and, overall, assessments of insulin and blood glucose levels remain poor measures of BCM, beta-cell function and progression of diabetes. Thus, novel noninvasive determinations of BCM are needed to provide a quantitative endpoint for novel therapies of diabetes, islet regeneration and transplantation. Built on previous gene expression studies, we tested the hypothesis that the targeting of vesicular monoamine transporter 2 (VMAT2), which is expressed by beta cells, with [11C]dihydrotetrabenazine ([11C]DTBZ), a radioligand specific for VMAT2, and the use of positron emission tomography (PET) can provide a measure of BCM. In this report, we demonstrate decreased radioligand uptake within the pancreas of Lewis rats with streptozotocin-induced diabetes relative to their euglycemic historical controls. These studies suggest that quantitation of VMAT2 expression in beta cells with the use of [11C]DTBZ and PET represents a method for noninvasive longitudinal estimates of changes in BCM that may be useful in the study and treatment of diabetes.

3D acquisition mode in PET is a way to increase the sensitivity of the scanner. To reconstruct the 3D data it is necessary to use either a fully 3D reconstruction algorithm or, alternatively, a rebinning algorithm followed by 2D reconstruction. The advantages of the 2nd approach are higher speed and reduced data size. Rebinning algorithms may become more important in the future with time-of-flight PET due to the increased dimensionality of the projection data. Although two exact rebinning algorithms have been developed, the most commonly used method today is the approximate Fourier rebinning algorithm. These three methods are based on analytic solutions in the frequency domain and involve geometric approximations, which may be significant for some scanner geometries. They also require attenuation corrected data, which can lead to complications since some reconstruction algorithms work better with non-attenuation corrected data. We have developed a novel rebinning algorithm, called reprojection rebinning (RP-RB), which is free from theoretical and geometric approximations as well as from the requirement of attenuation correction. It is based on an initial reconstruction of a 2D data-subset, which results in a somewhat sub-optimal utilization of the oblique data. The results can be improved, however, by an iterative procedure. We have tested RP-RB using simulated phantom data, showing an SD reduction in the central transaxial plane after the 1st, 2nd and 3rd iteration by a factor of 3.0, 3.5 and 4.1, respectively, as compared to 2D data only. There was also a very good spatial accuracy in images reconstructed from noiseless data, even for scanner geometries with large acceptance angles.

The in vivo dynamic behavior of ginkgolide B (GB), a terpene lactone constituent of the Ginkgo biloba extracts, in the living animal was visualized by positron emission tomographic (PET) imaging using a GB analogue labeled with the positron emitter 18 F. The in vivo imaging studies, combined with ex vivo dissection experiments, reveal that GB exists in 2 forms in the body: the original GB with its lactone rings closed and a second form with one of the rings open. The original GB in plasma is taken up rapidly by various organs including the liver, the intestine and possibly the stomach. Consequently, in plasma, the proportion of the ionized form of GB increases dramatically with time. Thereafter the ratio between the 2 forms appears to shift slowly towards equilibrium. The results suggest that more attention needs to be focused on in vivo dynamics between the 2 forms of GB.

Background Serotonin 1A receptors (5-HT1A) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT1A and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT1A G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT1A than healthy volunteers (controls). We measure 5-HT1A in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. Methods Genotyped and determined 5-HT1A binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. Results No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. Conclusions AN have higher 5-HT1A than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT1A receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT1A.

To assess the value of [18F]fluoro-2-deoxy-d-glucose positron emission tomography (18FDG-PET) in defining aggressive cartilage neoplasms, particularly those with problematic or borderline histologic, imaging and clinical characteristics. From 2000 to 2003, 29 cartilage lesions were studied with whole-body 18FDG-PET scans (Siemens Ecat Exact, Knoxville, Tenn.). Analyses of data in 20 females and nine males, 11–85 years old, were based on maximum standard uptake values (SUVs) in regions of interest (ROIs) on axial 3.37 mm thick, 3×3 pixel images. A statistically significant maximum SUV cutoff of 2.0 was used to distinguish benign from malignant cartilage neoplasms and correlated with the postoperative histopathologic findings. In 26 operated cases the overall sensitivity of whole-body 18FDG-PET in separating benign and malignant lesions was 90.9% (10/11), specificity 100% (18/18) and accuracy 96.6%. Whole-body 18FDG-PET is a valuable adjunct in identifying primary, recurrent and metastatic cartilage malignancies. It supplements classic histology and morphologic imaging with functional data which may facilitate management in individual cases.

Objective The serotonin transporter has been implicated in a variety of conditions including mood disorders and suicidal behavior. In vivo human brain studies with positron emission tomography and the serotonin transporter antagonist [ 11 C]DASB ([ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) are ongoing in several laboratories with the maximum administered activity based on dosimetry collected in rodents. We report on the biodistribution and dosimetry of [ 11 C]DASB in the baboon as this species may be a more reliable surrogate for human dosimetry. Methods Four baboon studies (two studies in each of two baboons) were acquired in an ECAT ACCEL camera after the bolus injection of 183±5 MBq/2.3±1.0 nmol of [ 11 C]DASB. For each study, six whole-body emission scans were collected in 3D mode over 6/7 bed positions for 2 h. Regions of interest were drawn on brain, lungs, liver, gallbladder, spleen, kidneys, small intestine and bladder. Since no fluid was removed from the animal, total body radioactivity was calculated using the injected dose calibrated to the ACCEL image units. Results Uptake was greatest in lungs, followed by the urinary bladder, gallbladder, brain and other organs. The ligand was eliminated via the hepato-billiary and renal systems. The largest absorbed dose was found in the lungs (3.6×10 −2 mSv/MBq). The absorbed radiation doses in lungs and gallbladder were four and nine times larger than that previously estimated from rat studies. Conclusion Based on our baboon biodistribution and dose estimates, the lungs are the critical organs for administration of [ 11 C]DASB. In the United States, the absorbed dose to the lungs would limit [ 11 C]DASB administered with the approval of a Radioactive Drug Research Committee to 1400 MBq (37 mCi) in the adult male and 1100 MBq (30 mCi) in the adult female.

Background The objective of this study was to evaluate the sensitivity of [ 11 C]-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB) binding to the brain serotonin transporter (SERT) to changes in endogenous serotonin (5-hydroxytryptamine [5-HT]) levels. A ligand sensitive to endogenous competition (EC) would enable the measurement of fluctuations of intrasynaptic 5-HT. A ligand insensitive to EC can provide a measure of SERT unaffected by levels of 5-HT. Alternatively, serotonin depletion could accelerate internalization of SERT and reduce binding. Methods Eighteen (14 baseline and 9 tryptophan-depleted) positron emission tomography (PET) scans were carried out in two baboons (Papio anubis). A metabolite-corrected arterial input function was used to estimate the binding potential (BP = B max /K D ). Results Depletion of plasma tryptophan by a mean of 65% from the baseline ( p = .03) reduces [ 11 C]-DASB BP in the six brain regions of interest (ROI). Lower DASB binding correlated with lower plasma tryptophan levels in the ROIs with higher SERT density. Conclusions [ 11 C]-DASB binding to SERT in vivo rapidly declines in response to acute reduction in serotonin availability, contrary to what is predicted by a simple competition model. This rapid reduction in SERT availability may be due to accelerated transporter internalization.

Synthesis and in vitro evaluation of [O-methyl-(11)C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide ([(11)C]-1), a potential imaging agent for CB(1) receptors using PET is described. 1-(2-Chlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (5), the precursor for radiolabeling, was synthesized from 4-OTBDPS-propiophenone (2) in five steps with 30% overall yield. The reaction of alcohol 5 with [(11)C]MeOTf at 60 degrees C afforded [(11)C]-1 with an average radiochemical yield of 14.5% (EOS) and2000 Ci/mmol specific activity. The radiotracer was found to selectively label CB(1) receptors in slide-mounted sections of postmortem human brain containing prefrontal cortex as demonstrated by in vitro autoradiography using phosphor imaging.

This study examined brain functioning in patients with Lyme encephalopathy. Eleven patients underwent neuropsychological tests and Xenon(133)-regional cerebral blood flow (rCBF) studies, using an external detector system. Each rCBF scan was age- and sex-matched to two archival, normal controls. While few differences were noted on gray-matter flow indices (ISI, fg), Lyme patients demonstrated significant flow reductions in white matter index (k(2)) (p=.004), particularly in the posterior temporal and parietal lobes bilaterally (p=.003). Flow reductions in white matter areas were significantly associated with deficits in memory (r=.66, p=.027) and visuospatial organization (r=.62, p=.041). Results suggest that Lyme encephalopathy may be a disease primarily affecting the cerebral white matter.

Radiopharmaceutical brain imaging is clinically applied in planning resective epilepsy surgery. Cerebral sites of seizure generation-propagation are highly associated with regions of hyperperfusion during seizures, and with glucose hypometabolism interictally. For surgical planning in epilepsy, the functional imaging modalities currently established are ictal single photon emission computed tomography (SPECT) with [(99m)Tc]technetium-hexamethylpropyleneamine oxime (HMPAO) or with [(99m)Tc]technetium-ethylene cysteine dimer (ECD), and interictal positron emission tomography (PET) with 2-[(18)F]fluoro-2-deoxyglucose (FDG). Ictal SPECT and interictal FDG PET can be used in presurgical epilepsy evaluations to reliably: (1) determine the side of anterior temporal lobectomy, and in children the area of multilobar resection, without intracranial electroencephalographic recording of seizures; (2) select high-probability sites of intracranial electrode placement for recording ictal onsets; and, (3) determine the prognosis for complete seizure control following anterior temporal lobe resection. Coregistration of a patient's structural (magnetic resonance) and functional images, and statistical comparison of a patient's data with a normal data set, can increase the sensitivity and specificity of these SPECT and PET applications to the presurgical evaluation.

Background Lower serotonergic activity correlates with high-lethality suicide attempts in major depression. Postmortem studies of serotonin receptors in suicides localize changes to the ventral prefrontal cortex (PFC). We studied serotonergic response in ventral PFC in depressed patients surviving a high-lethality suicide attempt. Methods Depressed patients with a history of a high-lethality suicide attempt(n = 16) were compared with those with low-lethality attempts (n = 9) for level of depression, suicidal intent and ideation, impulsivity, aggression, and neuropsychological test performance. Subjects were scanned while medication free after a single-blind placebo and after fenfluramine hydrochloride administration on a second day. Brain responses were measured by positron emission tomography imaging of fludeoxyglucose F 18 and serial prolactin levels. Scans were compared by means of statistical parametric mapping. Correlations of changes in relative regional cerebral uptake (rCMRglu) with clinical and neuropsychological measures were assessed. Results Depressed high-lethality suicide attempters had lower rCMRglu in ventral, medial, and lateral PFC compared with low-lethality attempters. This difference was more pronounced after fenfluramine administration. Lower ventromedial PFC activity was associated with lower lifetime impulsivity, higher suicidal intent (planning), and higher-lethality suicide attempts. Higher verbal fluency was positively correlated with rCMRglu in the same regions. Conclusions Prefrontal localized hypofunction and impaired serotonergic responsivity are proportional to the lethality of the suicide attempt and may mediate the effects of suicide intent and impulsivity on lethality. Positron emission tomographic neuroreceptor studies are needed to determine whether postmortem serotonin receptor findings are also present in vivo and contribute to the abnormal rCMRglu responses.

Background: Regional cerebral blood flow (CBF), a good indirect index of cerebral pathologic changes in Alzheimer disease (AD), is more severely reduced in patients with higher educational attainment and IQ when controlling for clinical severity. This has been interpreted as suggesting that cognitive reserve allows these patients to cope better with the pathologic changes in AD. Objective: To evaluate whether premorbid engagement in various activities may also provide cognitive reserve. Design: We evaluated intellectual, social, and physical activities in 9 patients with early AD and 16 healthy elderly controls who underwent brain H2 15 O positron emission tomography. In voxelwise multiple regression analyses that controlled for age and clinical severity, we investigated the association between education, estimated premorbid IQ, and activities, and CBF. Results: In accordance with previous findings, we replicated an inverse association between education and CBF and IQ and CBF in patients with AD. In addition, there was a negative correlation between previous reported activity score and CBF in patients with AD. When both education and IQ were added as covariates in the same model, a higher activity score was still associated with more prominent CBF deficits. No significant associations were detected in the controls. Conclusions: At any given level of clinical disease severity, there is a greater degree of brain pathologic involvement in patients with AD who have more engagement in activities, even when education and IQ are taken into account. This may suggest that interindividual differences in lifestyle may affect cognitive reserve by partially mediating the relationship between brain damage and the clinical manifestation of AD. Arch Neurol. 2003;60:359-365

Cerebral 18F-fluorodeoxyglucose positron emission tomography in 14 patients with microcephaly, developmental delay, seizures, and mutations of the glucose transporter Glut1 (Glut1 deficiency syndrome) showed distinct abnormalities. Within a global context of diminished cortical uptake, more severe hypometabolism was found in the mesial temporal regions and thalami, accentuating a relative signal increase in the basal ganglia. In contrast, the structure of the brain appeared preserved in patients additionally investigated by magnetic resonance imaging. This metabolic footprint was relatively constant in all patients regardless of age, seizure history, or therapies and therefore constitutes a radiological signature of the disease. The full expression of the signature in the youngest patient (aged 19 months) indicates that the state of haploinsufficiency caused by Glut1 mutation leaves a permanent footprint on the nervous system from its earlier postnatal stages of development. The potential benefit of prompt diagnosis, aided by 18F-fluorodeoxyglucose positron emission tomography, and early initiation of available therapies is underscored by our results.

A portable ultrasound performed to evaluate abdominal pain in a 70-year-old hospitalized man showed cholelithiasis and sludge in the gallbladder but no ductal dilatation. Biliary scintigraphy revealed early filling of the gallbladder and subsequent delayed accumulation of radiotracer adjacent to the initial collection. Another portable sonogram showed an S-shaped gallbladder with narrowing at the midportion and proximal small calculus. The S shape was initially missed because of the superficial location of the fundus. The scintigraphic results are likely due to delayed filling of the fundus of the gallbladder from partial obstruction by the S-shaped structure, slight narrowing, and an adjacent small stone.

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D(1) receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D(1) receptor availability was measured with positron emission tomography and the selective D(1) receptor antagonist [(11)C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [(11)C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 ± 0.39 ml/gm) compared with control subjects (1.27 ± 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [(11)C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D(1) receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D(1) receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

To describe the technique, applications and advantages of 18FDG PET scanning in detection, analysis and management of musculoskeletal lesions. Forty-five patients (19 males,26 females) aged 9 to 81 years had radiographs, routine radionuclide scans, CT and/or MRI of clinically suspected active benign or malignant musculoskeletal lesions. 18FDG scans with a Siemens ECAT EXACT 921 dedicated PET unit (Knoxville, Tenn.) and FWH=6 mm images acquired as a 5–6 bed examination (6 min emission and 4 min transmission) used OSEM iterative reconstruction with segmented transmission attenuation correction and a Gaussian filter (cutoff 6.7 mm). Region of interest (ROI) 3×3 pixel image analysis based on transverse whole body images (slice thickness 3.37 mm) generated Maximum Standard Uptake Values (Max SUV) with a cutoff of 2.0 used to distinguish benign and malignant lesions. Thirty-nine studies were available for SUV ROI analysis. Overall sensitivity for differentiating malignant from benign osseous and non-osseous lesions was 91.7% (22/24), overall specificity was 100% (11/11) with an accuracy of 91.7%. All aggressive lesions had a Max SUV >2.0. Data separating benign from malignant lesions and aggressive from benign lesions were statistically significant (P

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D2 receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V3″) and binding potential (BP) of [11C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [11C]Raclopride V3″ in the VST (1.86 ± 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 ± 0.28) and dorsal putamen (DPU, 2.99 ± 0.26), an observation consistent with postmortem studies. The reproducibility of V3″ and BP were appropriate and similar in VST (V3″ test–retest variability of 8.2% ± 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% ± 5.1%, 0.77), DPU (6.0% ± 4.1%, 0.71), and striatum as a whole (6.3% ± 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% ± 5% of the specific binding measured in the VST originated from D2 receptors located in the VST, whereas 12% ± 3% and 18% ± 3% were contributed by D2 receptors in the DCA and DPU, respectively. Thus, accuracy of D2 receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D2 receptor measurement with [11C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D2 receptors in the VST using endogenous competition techniques.

Rationale. Although selective serotonin reuptake inhibitors (SSRIs) are widely used in the treatment of anxiety and depressive disorders, the occupancy of the serotonin reuptake transporter (SERT) achieved in humans at typical clinical doses by these agents remains poorly characterized. Objective. The purpose of this study was to determine the occupancy of the SERT achieved in vivo by the SSRI paroxetine in social phobia patients at typical antianxiety doses. Methods. Measures of SERT availability were obtained with positron emission tomography and the SERT radiotracer [11C](+)-McN 5652 in five patients with social phobia before and during treatment with paroxetine at usual therapeutic doses (20–40 mg per day). Results. Occupancy of the SERT by paroxetine was high in all subjects and in all regions measured after 3–6 months of continuous treatment. Conclusions. The results of this study in an anxiety disorder sample are consistent with previously reported results in a depressed sample and suggest that paroxetine at therapeutic doses achieves very high occupancy levels of the SERT.

Schizophrenia patients vary in right ear advantage (REA) on dichotic listening tests for assessing left hemispheric dominance for language processing. The authors examined if patients with low REA differed from other patients in symptoms and in resting brain metabolism. SPECT was conducted during visual fixation for 9 healthy control subjects and 16 schizophrenia patients: 8 with normal and 8 with diminished REA. REA-diminished patients had greater positive symptoms and lower mental status scores (all P

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine 1A (5-HT 1A ) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT 1A autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT 1A receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT 1A receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT 1A antagonist [ carbonyl - 11 C]WAY-100635 or [ carbonyl - 11 C] N -(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)- N -(2-pyridyl)cyclohexanecarboxamide abbreviated as [ 11 C]WAY-100635. Pindolol dose-dependently decreased [ 11 C]WAY-100635 BP. Combining all the regions, occupancy was 20 ± 8% at scan 2, 14 ± 8% at scan 3, and 44 ± 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT 1A receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT 1A receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT 1A autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT 1A agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.

Serotonin 5-HT1A receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT1A receptor parameters in the human brain with positron emission tomography (PET) and [ carbonyl-11C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT1A receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT1A receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 ± 0.14 (mean ± SD of 15 regions) and 0.84 ± 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 ± 0.28, 0.47 ± 0.28, and 0.55 ± 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test—retest reproducibility, lower vulnerability to experimental noise, and absence of bias.