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Ronald L Van Heertum,1 Robert Scarimbolo,1 John G Wolodzko,1 Barbara Klencke,2 Richard Messmann,3 Feza Tunc,4 Levi Sokol,4 Rajan Agarwal,5 James A Strafaci,1 Michael O’Neal1 1Medical Affairs, Bioclinica, Inc., Princeton, NJ, 2Medical Affairs, Sierra Oncology, Brisbane, CA, 3Medical Affairs, Apexian Pharmaceuticals, Indianapolis, IN, 4Radiology, University Radiology at RWJ University Hospital, New Brunswick, NJ, 5Radiology, Abington Hospital, Abington, PA, USA Abstract: An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59–0.87; P=

Background Positron emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D 2/3 receptor binding and decreased presynaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior. Methods Heroin-dependent and healthy control subjects were scanned with [ 11 C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D 2/3 receptor binding and presynaptic dopamine release. After the PET scans, the heroin-dependent subjects performed heroin self-administration sessions. Results Both striatal D 2/3 receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin. Conclusions These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D 2/3 receptor binding and low presynaptic dopamine. However, neither of these outcome measures was associated with the choice to self-administer heroin.

Amyloid load in the brain using Pittsburgh compound B (11C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using fluorodeoxyglucose (18F-FDG) PET were evaluated in patients with mild Alzheimer disease (AD, n = 18), mild cognitive impairment (MCI, n = 24), and controls (CTR, n = 18). 11C-PIB binding potential (BPND) was higher in prefrontal cortex, cingulate, parietal cortex, and precuneus in AD compared to CTR or MCI and in prefrontal cortex for MCI compared to CTR. For 18F-FDG, regional cerebral metabolic rate for glucose (rCMRGlu) was decreased in precuneus and parietal cortex in AD compared to CTR and MCI, with no MCI—CTR differences. For the AD—CTR comparison, precuneus BPND area under the receiver operating characteristic (ROC) curve (AUC) was 0.938 and parietal cortex rCMRGlu AUC was 0.915; for the combination, AUC was 0.989. 11C-PIB PET BPND clearly distinguished diagnostic groups and combined with 18F-FDG PET rCMRGlu, this effect was stronger. These PET techniques provide complementary information in strongly distinguishing diagnostic groups in cross-sectional comparisons that need testing in longitudinal studies.

Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects.Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole.Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum.The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.

Interventional nuclear brain imaging incorporates a variety of radiopharmaceutical techniques to enhance the functional assessment of the central nervous system. Many interventional nuclear brain imaging techniques initially were used in research protocols. In recent years, however, these same challenge paradigms are being increasingly applied with clinical imaging studies. At present, clinical interventional brain imaging techniques include pharmaceutical manipulations with drug administration or withdrawal, physical provocation, electrical stimulation, cognitive activation, and targeting of neurocircuitries with specific molecular receptor-ligand interactions. This review highlights how these approaches have resulted in more accurate measurement of regional cerebral metabolism, delineation of neurocircuitries, presurgical patient selection, and treatment management.

Vesicular monoamine transporter type 2 abundance quantified using the radiotracer [(11)C]-dihydrotetrabenazine (DTBZ) has been used to study diagnosis and pathogenesis of dementia and psychiatric disorders in humans. In addition, it may be a surrogate marker for insulin-producing pancreatic beta cell mass, useful for longitudinal measurements using positron emission tomography to track progression of autoimmune diabetes. To support the feasibility of long-term repeated administrations, we estimate the biodistribution and dosimetry of [(11)C]-DTBZ in humans.Five baboon studies were acquired using a Siemens ECAT camera. After transmission scanning, 165-210 MBq of [(11)C]-DTBZ were injected, and dynamic whole body emission scans were conducted. Time-activity data were used to obtain residence times and estimate absorbed radiation dose according to the MIRD model.Most of the injected tracer localized to the liver and the lungs, followed by the intestines, brain, and kidneys. The highest estimated absorbed radiation dose was in the stomach wall.The largest radiation dose from [(11)C]-DTBZ is to the stomach wall. This dose estimate, as well as the radiation dose to other radiosensitive organs, must be considered in evaluating the risks of multiple administrations.

Monoamine oxidase A is a mitochondrial enzyme which is responsible for the metabolism of catecholamines such as dopamine, norepinephrine, as well as serotonin. This study describes the biodistribution and dosimetry of 11C-harmine, a tracer designed to specifically bind to monoamine oxidase A for positron emission tomography imaging.Three baboon studies were acquired using a Seimens ECAT camera. Dynamic whole-body emission scans were collected in two-dimensional mode over a 2 h period after 223-255 MBq of 11C-harmine was injected. Regions of interest were drawn on transmission corrected images to encompass the entire activity in visible organs at each time point. Time-activity data were used to obtain residence times and absorbed radiation dose to various organs and to the entire body.Tracer uptake was greatest in the lungs, followed by kidney, small intestine, liver and brain. The largest absorbed dose based on averaged residence times was found in the lungs (reference adult/female 3.99x10(-2)/5.03x10(-2) mSv x MBq(-1)).The lungs are the critical organs for administration of 11C-harmine. For example, in the United States, the absorbed dose to the lungs would limit a single 11C-harmine administration for a research subject with the approval of a Radioactive Drug Research Committee to 1258/999 MBq (34/27 mCi) in the adult male/female. Quantitative measurement of monoamine oxidase A activity in the brain and elsewhere may aid in understanding the pathophysiology of several disease processes including neuroendocrine neoplasms and depression.

Aim Overstimulation of the CRF type 1 receptor (CRF1) is implicated in anxiety and depressive disorders. The aim of this study was to investigate the in vivo binding characteristics of [ 11 C]R121920 and [ 11 C]DMP696 in the nonhuman primate for application in positron emission tomography (PET) studies of CRF1. Methods PET imaging with the two novel CRF1 radioligands was performed in baboon. In vitro binding studies for CRF1 were performed in postmortem brain tissue of baboon and human to assess sufficiency of receptor density for PET. Results Both [ 11 C]R121920 and [ 11 C]DMP696 distributed rapidly and uniformly throughout the brain. Washout was comparable across brain regions, without differences in volume of distribution between regions reported to have high and low in vitro CRF1 binding. Membrane-enriched tissue homogenate assay using [ 125 I]Tyr 0 -sauvagine and specific CRF1 antagonists CP154,526 and SN003 in human occipital cortex yielded maximal binding ( B max ) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded B max of 103.6 and 64.6 fmol/mg protein, respectively. Dissociation constants ( K D ) were subnanomolar. In baboon, specific binding was not detectable in the same regions; therefore, B max and K D were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum. Conclusion Neither [ 11 C]R121920 nor [ 11 C]DMP696 demonstrated quantifiable regional binding in vivo in baboon. In vitro results suggest CRF1 density in baboon may be insufficient for PET. Studies in man may generate more promising results due to the higher CRF1 density compared with baboon in cerebral cortex and cerebellum.

Synthesis of [18F]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ([18F]celecoxib), a selective COX-2 inhibitor, is achieved via a bromide to [18F]F- exchange reaction. Synthesis of the precursor for radiolabeling was achieved from 4'-methylacetophenone in four steps with 22% overall yield. Under non-radioactive conditions, fluorination was achieved using TBAF in DMSO at 135 degrees C in 80% yield. Synthesis of [18F]celecoxib was achieved using [18F]TBAF in DMSO at 135 degrees C in 10+/-2% yield (EOS) with >99% chemical and radiochemical purities. The specific activity was 120+/-40 mCi/micromol (EOB). [18F]celecoxib was found to be stable in ethanol, however, de[18F]fluorination (6.5%) was observed after 4 h in 10% ethanol-saline solution. Rodent PET studies show bone labeling indicating in vivo de[18F]fluorination of [18F]celecoxib. PET studies in baboon indicated a lower rate of de[18F]fluorination than rat and retention of radioactivity in brain regions consistent with the known distribution of COX-2. A radiolabeling method that can generate consistent high specific activity is needed for routine human use.

Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter's role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates.Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test-retest and blocking conditions using 1 mg/kg nisoxetine.MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine.Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [(11)C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.

This case demonstrates the effect of exercise on the clearance of Tc-99m MAG3 in a patient with renal insufficiency status post-liver transplant. Even after furosemide administration, the tracer was retained in the kidneys after exercise. This is in contrast to normal clearance demonstrated on a baseline study performed 3 days previously.

Excessive activation via the metabotropic glutamate receptor subtype 5 (mGluR 5 ) has been implicated in depression, neuropathic pain and other psychiatric, neurological and neurodegenerative diseases. A mGluR 5 radioligand for in vivo quantification by positron emission tomography (PET) would facilitate studies of the role of this receptor in disease and treatment. 3-Methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity antagonist at the mGluR 5 receptor was selected as a candidate ligand; a recent publication by Yu et al. [ Nucl Med Biol 32 (2005) 631–640] presented initial micro-PET results for [ 11 C]MPEPy with enthusiasm. Building on their efforts, we report as unique contributions (1) an improved chemical synthesis method, (2) the first data using human tissue, (3) phosphor images for rat brain preparations, (4) a novel comparison of anesthetic agents and (5) in vivo data in baboon. In vitro phosphor imaging studies of this ligand using human and rat brain tissue demonstrated high specific binding in the hippocampus, striatum and cortex with minimal specific binding in the cerebellum. In contrast, in vivo micro-PET studies in rats using urethane anesthesia, PET studies in baboons using isoflurane anesthesia and ex vivo micro-PET studies in unanesthetized rats each showed little specific binding in the brain. Despite the promising in vitro results, the low signal-to-noise ratio found in vivo does not justify the use of [ 11 C]MPEPy as a PET radiotracer in humans.

Synthesis and evaluation of [O-methyl-11C](4-methoxy-2-methylphenyl)[1-(1-methoxymethylpropyl)-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4-yl]amine or [11C]SN003 ([11C]6), as a PET imaging agent for CRF1 receptors, in baboons is described. 4-[1-(1-Methoxymethylpropyl)-6-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-4-ylamino]-3-methylphenol (5), the precursor molecule for the radiolabeling, was synthesized from 2,4-dichloro-6-methyl-3-nitropyridine in seven steps with 20% overall yield. The total time required for the synthesis of [11C]SN003 is 30 min from EOB using [11C]methyl triflate in the presence of NaOH in acetone. The yield of the synthesis is 22% (EOS) with >99% chemical and radiochemical purities and a specific activity of >2000 Ci/mmol. PET studies in baboon show that [11C]6 penetrates the BBB and accumulates in brain. No detectable specific binding was observed, likely due to the rapid metabolism or low density of CRF1 receptors in primate brain.

The serotonin2A (5-HT2A) receptor is implicated in the pathophysiology of schizophrenia and mood disorders, and in vivo studies of this receptor would be of value in studying the pathophysiology of these disorders and in measuring the relationship of clinical response to receptor occupancy for 5-HT2A antagonists such as atypical antipsychotics. Therefore, (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)-phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine (MPM) (13), a selective and high-affinity (K(i)=0.79 nM) 5HT2A antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue (2R,4R)-4-hydroxy-2-[2-[2-[2-(3-hydroxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine (12) with [11C]methyltriflate in order to determine the suitability of [11C]MPM to quantify 5-HT2A in living brain using PET. Desmethyl-MPM 12 and standard MPM were prepared, starting from 3-hydroxymethylphenol (2), in excellent yield. The yield obtained for radiolabeling was 40+/-5% (EOB), and the total synthesis time was 30 min at EOS. PET studies with [11C]MPM in baboon showed a distribution in the brain consistent with the known distribution of 5-HT2A receptors. The time-activity curves for the high-binding regions peaked at approximately 45 min after injection. Blocking studies with M100907 demonstrated not only 38-57% blocking of tracer binding in brain regions known to have 5-HT2A receptors but also 38% blocking in cerebellum, which has a low 5-HT2A receptor concentration. Although [11C]MPM exhibits appropriate kinetics in baboon for imaging 5-HT2A receptors, its specific binding in cerebellum and higher proportion of nonspecific binding limit its usefulness for the in vivo quantification of 5-HT2A receptors with PET.

Synthesis and in vivo evaluation of 2-{4-[4-(3-methoxyphenyl)piperazin-1-yl]-butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (5 or MMT), a high affinity and selective serotonin 5-HT1AR agonist PET tracer, are described. GTPγS assay shows that MMT is an agonist with an EC50 comparable to 5-HT. Radiolabeling of 5 was achieved in 30% yield (EOS) from desmethyl-MMT (4) with >99% chemical and radiochemical purities and a specific activity >1000 Ci/mmol. PET studies in baboon show that [11C]5 penetrates the blood–brain barrier but, because of low specific binding and fast clearance of radioactivity it is not a suitable PET tracer for the in vivo quantification of 5-HT1AR.

The authors examined effects of a triallelic functional polymorphism of the human serotonin-transporter-linked promoter region (5-HTTLPR) on in vivo expression of serotonin transporter in the brain in healthy volunteers and subjects with major depressive disorder.Twenty-five medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and 42 healthy volunteers were clinically evaluated and genotyped. Serotonin transporter binding potential (f(1)B(max)/K(d)) was determined by using positron emission tomography with the radiotracer [(11)C]McN 5652 and metabolite-corrected arterial input functions.There was no difference in serotonin transporter binding potential by genotype in healthy volunteers or in subjects with major depressive disorder. Allelic frequencies did not differ between subjects with major depressive disorder and healthy volunteers.Associations of the 5-HTTLPR polymorphism to clinical phenotypes appear to be due to developmental effects of 5-HTTLPR on expression and not due to its direct effect on serotonin transporter binding in adulthood.

OBJECTIVE: CSF analysis, neuroendocrine challenges, serotonin depletion studies, and treatment studies implicate the serotonergic system in the pathophysiology of major depressive disorder. On the basis of postmortem and imaging studies, the authors hypothesized that subjects with major depressive disorder in a major depressive episode have fewer serotonin transporter sites, compared with healthy subjects. METHOD: Serotonin transporter binding potential (f1Bmax/Kd) was determined using positron emission tomography with [11C]McN 5652 in six brain regions in 25 medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and in 43 healthy volunteer comparison subjects. All subjects had arterial lines placed to determine metabolite-corrected arterial input functions. RESULTS: Serotonin transporter binding potential differed significantly by brain region and group. Post hoc analysis revealed lower binding potential in subjects with major depressive disorder, relative to the...

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide (AC90179, 4), a highly potent and selective competitive 5-HT2A antagonist, was labeled by [11C]-methylation of the corresponding desmethyl analogue 5 with [11C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p-tolylmethylamine in three steps with 46% overall yield. [11C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [11C]4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [11C]4 cannot be used as PET ligand for imaging 5-HT2A receptors. Copyright © 2006 John Wiley & Sons, Ltd.

Background The anxious phenotype of the 5-HT 1A receptor knockout mouse and the anxiolytic properties of 5-HT 1A agonists suggest that the 5-HT 1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT 1A binding. Methods Positron emission tomography with [carbonyl- 11 C]WAY-100635 was used to estimate regional 5-HT 1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT 1A BP. Results Higher psychic (β ≥ .63) and lower somatic (β ≤ –.70) anxiety predicted over 50% of the variance in 5-HT 1A BP in multiple cortical regions, but not in amygdala, hippocampus, or autoreceptors of the raphe nuclei. The psychic and somatic anxiety components were not related to depression severity. Comorbid panic disorder was associated with lower cortical and subcortical 5-HT 1A BP. Conclusions The 5-HT 1A receptor in the same brain regions has different relationships to psychic anxiety versus somatic anxiety. Lower 5-HT 1A BP in panic disorder may be accounted for by higher somatic and lower psychic anxiety. Further study of the pathobiology of these anxiety components may identify distinct therapeutic targets or mechanisms.

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps

A general one-pot method has been developed for the conversion of an aryl thiol moiety masked as the butyrate ester to the corresponding 11C-labeled methylsulfone group. The potential of this methodology has been demonstrated by the successful radiosynthesis of carbon-11 analogues of several highly selective cyclooxygenase-2 (COX-2) inhibitors such as Rofecoxib, Etoricoxib, and 3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethyl isoxazole in high yield. The chemical and radiochemical purities obtained for the 11C-labeled COX-2 inhibitors are >99% with a specific activity >1000 Ci/mmol.

Background The amyloid neuritic plaque is considered to be a toxic collection of amyloid-s protein found in brain tissue in Alzheimer's disease. A neutral analogue of the amyloid-binding thioflavin-T (BTA), has been radiolabeled as [C-11]-6-OH-BTA-1. It crosses the blood brain barrier, and is a promising tracer for imaging plaques in vivo using positron emission tomography. We now report the biodistribution and dosimetry of [C-11]-6-OH-BTA-1 in baboons. Methods Four 2-hour whole body studies were acquired in an ECAT ACCEL camera in two baboons after the bolus injection of [C-11]-6-OH-BTA-1. After 3.5 minute transmission scans performed per bed position prior to injection, emission scans were collected in 2-D mode over five bed positions. Regions of interest (ROI) were drawn around the brain, left and right lungs, heart, liver, gall bladder, left and right kidneys, spleen and urinary bladder. Since no fluid was removed from the baboons, total body radioactivity was calculated using the injected dose and a calibration factor determined from a cylinder phantom. The area under the curve (AUC) for each ROI was determined by trapezoidal integration of the first few points with subsequent points fit by a decreasing monoexponential. The AUC was then divided by counts in the total body, and resulting residence times were entered into the MIRDOSE3 program. Results The animals tolerated the procedure well. The ligand was eliminated via the hepatobiliary and renal systems. In the adult male and female reference the gallbladder received the highest estimated radiation dose and was the critical organ (3.9E–02 mGy/MBq and 4.3E–02 mGy/MBq respectively). Conclusion In the United States, the absorbed dose to the gallbladder would limit [C-11]-6-OH-BTA-1 administered with the approval of a Radioactive Drug Research Committee (RDRC) to a single injection of 1295 MBq (35 mCi) in the adult male, and 1314 MBq (35 mCi) in the adult female.

Previous neuroimaging studies of major depression have not controlled for the presence of personality disorders characterized by impulsive aggressive behavior, such as borderline personality disorder (BPD). Using positron emission tomography (PET), we studied regional glucose uptake in response to fenfluramine (FEN) in depressed subjects with BPD (n=11) and depressed patients without Cluster B Axis II disorders (n=8). Subjects were scanned while medication-free after a single blind placebo administration and after FEN on a second day. Brain responses were measured by PET imaging of [18F]fluorodeoxyglucose (FDG) and serial prolactin levels. Scans were compared at a voxel level using statistical parametric mapping. Correlations of changes in relative regional cerebral uptake (rCMRglu) with clinical measures were assessed. Depressed borderline patients had greater relative activity in parietotemporal cortical regions (BA 40, BA 22, and BA 42) before and after FEN activation compared to those without BPD. They also had less relative uptake in the anterior cingulate cortex (BA 32) at baseline compared to depressed patients without BPD and FEN abolished this difference. Impulsivity was positively correlated with rCMRglu in superior and middle frontal cortex (BA 6 and 44). Hostility was positively correlated with rCMRglu in temporal cortical regions (BA 21 and 22). In conclusions, borderline pathology in the context of a Major Depressive Disorder is associated with altered activity in parietotemporal and anterior cingulate cortical regions. Controlling for the presence of BPD in future imaging studies of mood disorders may elucidate similarities and differences in regional serotonergic function in these two often comorbid disorders.

Two measures used in brain imaging are binding potential (BP) and the specific to nonspecific equilibrium partition coefficient ( V3“). V3” determined using the 5-HT1A ligand [11C]WAY-100635 is sensitive to changes in the free and nonspecific binding of the ligand in the reference region ( V2). Healthy female volunteers have higher 5-HT1A BP but not V3“ compared with men, because V2 is higher in women. While there could be several explanations for this observation, we hypothesized that women have more 5-HT1A receptors in the cerebellum. We explore the cerebellum to define a subregion that more accurately represents the free and nonspecific binding, potentially allowing the use of V3”. A quantitative autoradiogram in human brain using [3H]WAY-100635 identified a cerebellar subregion devoid of 5-HT1A receptors. In vivo 5-HT1A receptors were evaluated using [11C]WAY-100635 in 12 healthy women and 13 healthy men. Each subject had a metabolite-corrected arterial input function. The autoradiogram demonstrates the lowest concentration of 5-HT1A receptors in the cerebellar white matter (CW) and highest concentration in the cerebellar vermis (CV). The CW volume of distribution ( VT) is lower than CV. Cerebellar white matter is adequately modeled by a one-tissue compartmental model, while a two-tissue model is necessary to model CV or the total cerebellum (CT). Women have a higher CW VT compared with men, suggesting a difference in V2. Use of CW improves identifiability and time stability of BP in cortical regions. Cerebellar white matter might be a better reference region for use in future 5-HT1A studies using [11C]WAY-100635. With CW as a reference region, V3“ cannot be used to detect differences in 5-HT1A receptors between men and women, suggesting the need for arterial input functions to determine BP.

[11C]Labeling of celecoxib, a COX-2 selective inhibitor and prescription drug for arthritis and pain has been achieved. The precursor molecule for the radiolabeling was synthesized from 4-bromoacetophenone in 4 steps with 23% overall yield. Stille reaction of N-[bis-(4-methoxyphenyl)phenylmethyl]-4-[5-(4-tributylstannylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonamide (5) with methyl iodide in presence of catalytic amounts of Pd2(dba)3, tri-o-tolylphosphine, CuCl and excess of K2CO3 in DMF followed by deprotection of the sulfonamide with 20% trifluoroaceticacid yielded 4-(5-p-tolyl-3-trifluoromethylpyrazol-1-yl)benzenesulfonamide or celecoxib (6) in 30% yield. However, under identical conditions, synthesis of [11C]celecoxib ([11C]6) was unsuccessful. Instead, trapping [11C]CH3I in an argon purged solution of catalytic amounts of Pd2(dba)3 and tri-o-tolylphosphine followed by the addition of the precursor 5 in DMF under argon and heating the mixture at 135°C for 4 min resulted in the incorporation of [11C]CH3 group. Removal of the dimethoxytrityl (DMT) with 20% trifluoroacetic acid afforded [11C]celecoxib in 40 min (EOB) and 8±2% yield (EOB) along with a specific activity of 1080±180 Ci/mmol (n=6) (EOB). Copyright © 2005 John Wiley & Sons, Ltd.

Background Schizophrenia is etiologically heterogeneous. It is anticipated, but unproven, that subgroups will differ in neuropathology and that neuroimaging may reveal these differences. The optimal imaging condition may be at rest, where greater variability is observed than during cognitive tasks, which more consistently reveal hypofrontality. We previously demonstrated symptom and physiologic differences between familial and sporadic schizophrenia patients and hypothesized that the groups would show different resting regional cerebral blood flow (rCBF) patterns. Methods Ten familial and sixteen sporadic schizophrenia patients and nine comparison subjects had single photon emission computed tomography imaging during passive visual fixation. Images were spatially normalized into Talairach coordinates and analyzed for group rCBF differences using SPM with a Z value threshold of 2.80, p Results The subgroups had similar age, gender, illness duration, and medication treatment. Sporadic patients had hypofrontality (anterior cingulate, paracingulate cortices, left dorsolateral and inferior-orbitofrontal), whereas familial patients had left temporoparietal hypoperfusion; all of these regions show resting activity in healthy subjects. Both groups hyperperfused the cerebellum/pons and parahippocampal gyrus; additional hyperperfusion for sporadic patients was observed in the fusiform; familial patients also hyperperfused the hippocampus, dentate, uncus, amygdala, thalamus, and putamen. Conclusions Familial and sporadic schizophrenia patients had different resting rCBF profiles, supporting the hypothesis that certain subgroups have distinct neural underpinnings. Different neuropathologic processes among subgroups of schizophrenia patients may account for the prior contradictory results of resting imaging studies.

A number of very significant advances in the field of positron emission tomography (PET) imaging are now beginning to have an impact on clinical PET brain imaging. Among the most significant advances are further improvements in PET scanner detectors and computers. Increasingly, more sophisticated methods of image analysis and quantitation are also beginning to emerge. In addition, there has been a very rapid introduction of newer PET radiotracers that will ultimately work their way into the clinical environment. Finally, there is an expanding interest in the potential of PET brain imaging in the evaluation of a wide variety of clinical neuropsychiatric conditions.

Ginkgolide B, a terpene trilactone constituent of Gingko biloba extracts and an antagonist for the platelet activating factor (PAF) receptor, was radiolabeled with the positron emitter 18F for visualizing its in vivo behavior using positron emission tomography (PET). The 7-[18F]fluoro analog of ginkgolide B (7-18FGB) was synthesized via nucleophilic displacement of the triflate group at C7 with [18F]fluoride. The reaction was complete in 5–10 min, affording 7-18FGB in an average radiochemical yield of approximately 16% (decay corrected). The average specific activity at E.O.S. was approximately 40 GBq/µmol, and the radiochemical and chemical purity was greater than 95%. Copyright © 2004 John Wiley & Sons, Ltd.

Background Previous imaging studies demonstrated that schizophrenia is associated with increased amphetamine-induced dopamine (DA) release in the striatum, most pronounced during episodes of illness exacerbation. Schizotypal personality disorder (SPD) is a schizophrenia spectrum disorder, genetically related to schizophrenia. The goal of this study was to investigate striatal DA function in patients with SPD. Methods In our study, 13 SPD patients and 13 matched healthy control subjects underwent single photon emission computed tomography (SPECT) scan during bolus plus constant infusion of the D2/3 radiotracer [123I]iodobenzamide (IBZM). Striatal specific to nonspecific equilibrium partition coefficient (V3′′) was measured at baseline and following amphetamine administration (.3 mg/kg). Results No significant differences were observed in baseline V3′′ between groups. Amphetamine induced a larger decrease in [123I]IBZM V3′′ in SPD patients (−12 ± 5%) compared with control subjects (−7 ± 5%, p = .03). Conclusions The reduction in [123I]IBZM V3′′ induced by amphetamine in SPD was similar to that observed in remitted schizophrenia patients (−10 ± 9%, n = 17), but significantly lower than that observed during illness exacerbation (−24 ± 13%, n = 17). This suggests that DA dysregulation in schizophrenia spectrum disorders might have a trait component, present in remitted patients with schizophrenia and in SPD, and a state component, associated with psychotic exacerbations but not SPD.

Synthesis of [O-methyl-11C]-4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolo-1,3,5-triazine ([11C]DMP696), a highly selective CRF1 antagonist has been achieved. The total time required for the synthesis of [11C]DMP696 is 30 min from EOB using [11C]methyl triflate in THF, with a 16% yield (EOS) and >99% chemical and radiochemical purities along with a specific activity of >2000 Ci/mmol (EOS). Copyright © 2004 John Wiley & Sons, Ltd.

In subjects with mood disorders, positron emission tomography (PET) with [(18)F]fluorodeoxyglucose has shown prefrontal cortical metabolism deficits, including in a subgenual region in subjects with familial illness. The authors applied a dl-fenfluramine challenge method to study metabolic response in this region to serotonergic challenge in familial major depression.The study group consisted of 19 depressed subjects with major depressive disorder or bipolar disorder, all of whom had at least one first-degree relative with history of major depression, and 10 healthy volunteers with similar age and gender distributions. PET images were acquired under placebo and challenge conditions, and volumetric MRI scans were also obtained. Group comparisons of metabolic and volumetric data were performed. Ratings of acute mood change during serotonergic challenge were compared with the imaging data.Within Brodmann's area 32, a glucose metabolism deficit in the depressed subjects on placebo day was observed by voxel-level analysis, but no volumetric deficit was found in the subgenual regions examined. Under challenge, both groups suppressed metabolism similarly. Within the patient group, the correlation between acute mood improvement during challenge and greater metabolic suppression approached significance.In familial mood disorders, a ventromedial prefrontal cortical deficit in baseline metabolism is not due to altered structural volume, and the response to serotonergic challenge appears predictive of acute mood response. The potential to predict treatment response can be tested by a combined challenge and treatment study.

A convenient synthesis of [N-methyl-11C]-3-[(6-dimethylamino)pyridin-3-yl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidine-7-amine (R121920), a highly selective CRF1 antagonist has been developed as a potential PET ligand. 3 - [(6 - methylamino)pyridin - 3 - yl]-2,5-dimethyl-N,N-dipropylpyrazolo [1,5-a]pyrimidine-7-amine (7), the precursor for radiolabelling was synthesized through a novel palladium catalyzed Suzuki coupling of aryl bromide 5 with heteroaryl boronate ester 4. The requisite boronate ester 4 was synthesized in four steps from 2-amino-4-bromopyridine in 50% overall yield. Although the synthesis of cold R121920 proceeded in 93% yield by sodium hexamethyl-disilazide (NaHMDS) mediated N-methylation of the desmethylamine 7 at −78°C, the attempted radiosynthesis under various conditions using conventional bases were not successful. However, the radiolabeling of [11C]R121920 was successfully carried out with [11C]MeOTf in acetone at −20°C in the absence of added basic reagents. The radiotracer was purified by RP-HPLC followed by RP-solid phase extraction. The yield of the reaction was 5% (at EOB) and the specific activity was >1000 Ci/mmol (at EOB) with a radiochemical purity >99%. Copyright © 2003 John Wiley & Sons, Ltd.

The role of PET and SPECT brain imaging in the initial assessment and differential diagnosis of dementia is beginning to evolve rapidly. Numerous studies confirm the value of functional brain imaging, particularly with FDG-PET imaging, as a potentially cost-effective means of establishing an earlier diagnosis of Alzheimer's disease. Such an approach should allow for a more objective means of establishing which patients will benefit from treatment with cholinesterase inhibitors. In the future, neuroreceptor and plaque burden imaging studies should further enhance the sensitivity and specificity of dementia detection and patient management.

Serotonin (5-HT) 1A receptors have been implicated in a variety of conditions including, depression, suicidal behavior, and aggression. Post-mortem brain studies and in vivo imaging studies report a variety of age and sex effects on brain 5-HT(1A) binding. Behavioral data from 5-HT(1A) specific pharmacological challenges suggest a role for 5-HT(1A) receptors in aggression. The goal of the present study was to determine age, sex, and severity of life-time aggression effects on 5-HT(1A) binding potential (BP) in vivo using positron emission tomography (PET) and the high affinity 5-HT(1A) antagonist, [carbonyl-C-11]WAY-100635 in 12 healthy females (ages 41.0+/-15.7 years) and 13 healthy males (ages 39.6+/-15.5 years). Regions of interest included the dorsal raphe, anterior cingulate cortex, cingulate body, hippocampus, amygdala, medial prefrontal cortex (PFC), and orbital PFC. No significant correlation between age and BP was detected in any brain region. MANOVA of the first three principle components demonstrated a significantly higher BP in females compared with males (P=0.0127). Post-hoc tests confirmed sex differences (P0.05) in the following regions: dorsal raphe, amygdala, anterior cingulate, cingulate body, medial PFC, and orbital PFC. The cerebellar volume of distribution was also significantly higher in females. There is a significant negative correlation between binding in several regions and lifetime aggression. We have replicated our post-mortem finding of higher 5-HT(1A) binding in females compared to males. We did not detect an age dependent decrease in binding in males or females. Lower 5-HT(1A) binding in more aggressive individuals is consistent with pharmacological challenge studies. Future studies should determine whether the binding is a state or trait effect.

Previous brain imaging studies with [(11)C]raclopride have suggested that the psychotogenic effects of the noncompetitive N-methyl-D-aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [(11)C]raclopride. No significant differences were observed in [(11)C]raclopride specific-to-nonspecific activity ratios (V(")(3)) measured during an early interval (30-50 min) and late interval (70-90 min), confirming that a state of sustained equilibrium had been established from 30-90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V(")(3) measured before ketamine (30-50-min interval) was compared to [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [(11)C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration.

Widely available SPECT allows imaging of certain critical components of neurotransmission, providing clinically and experimentally significant information. Future efforts may be directed toward developing innovative techniques to delineate dynamic neurochemical changes in vivo.

Background: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D 2 receptor availability and amphetamineinduced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. Methods: The striatal equilibrium specific to nonspecific partition coefficient (V 3 ″) of the D 2 receptor antagonist [ 123 I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. Results: No significant differences were observed in preamphetamine D 2 receptor availability between depressed patients (0.73 ± 0.08) and control subjects (0.78 ± 0.10, p = .23). Amphetamine-induced reduction in [ 123 I]IBZM V 3 ″ (ΔV 3 ″) was similar in depressed patients (−9.8 ± 5.5%) and control subjects (−7.8 ± 2.5%, p = .32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [ 123 I]IBZM ΔV 3 ″. Conclusions: This study did not replicate previously reported alterations in striatal D 2 receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.

A wide variety of diagnostic imaging modalities, including ultrasonography (US), CT, MR imaging, angiography, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic US (EUS), have been used in the evaluation of pancreatic disorders and tumors. These imaging techniques are often very helpful in the evaluation of pancreatic tumors. Unfortunately, these methods are not always successful in establishing a definitive diagnosis or identifying disease early, when tumor can be removed surgically. Newer radiopharmaceuticals have been used with positron and single photon emission CT (PET and SPECT) imaging techniques for the assessment of pancreatic tumors. These radiotracers have been reported to have a significant impact on the management of patients suspected or known to have tumors of the pancreas. This article is devoted to a discussion of radiolabeled compounds used to image pancreatic tumors, the rationale for their use, current imaging protocols used, and the results obtained in patients with endocrine and nonendocrine pancreatic tumors.

Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. 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 during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.

Background: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N -methyl-d-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. Methods: In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D 2 receptor antagonist [ 123 I]IBZM. Results: Ketamine significantly enhanced the amphetamine-induced decrease in [ 123 I]IBZM BP, from −5.5% ± 3.5% under control conditions to −12.8% ± 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p = .023). Conclusions: The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.

Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow (rCBF) was assessed by the planar 133 Xenon inhalation technique after a medication washout and following 6– 9 weeks of antidepressant treatment. At baseline, the depressed sample had reduced rCBF in frontal cortical regions when compared with 20 matched normal-control subjects. After treatment, Responders and Nonresponders differed in the expression of a specific topographic alteration, with Responders manifesting reduced perfusion in frontal regions. These findings are consistent with this group's previous report of reduced rCBF after response to electroconvulsive therapy (ECT) and suggest a common mechanism of action.

Binding competition between endogenous dopamine (DA) and the D2 receptor radiotracer [123I]IBZM allows measurement of the change in synaptic DA following amphetamine challenge with SPECT in the living human brain. Previous investigations using this technique in healthy subjects have shown that the magnitude of amphetamine effect on [123I]IBZM binding potential (BP) is small (range between 5 to 15% decrease), and that a large between-subject variability in this effect is observed. Therefore, it was unclear how much of the apparent between-subject variability was due to a low signal-to-noise ratio in the measurement, vs. true between-subject differences in the magnitude of the response. The goals of this investigation were to test the within-subject reproducibility and reliability of amphetamine-induced decrease in [123I]IBZM BP with a test/retest paradigm, and to establish the presence or absence of tolerance or sensitization to single administration ofi.v. amphetamine. Six healthy male subjects, never previously exposed to psychostimulants, twice underwent measurement of striatal amphetamine-induced DA release (between-measurement interval 16 +/- 10 days) using SPECT and the [123I]IBZM constant infusion technique. Results demonstrated an excellent within-subject reproducibility of amphetamine-induced DA release: amphetamine-induced decreases in [123I]IBZM BP were significant on each day, and had an intraclass correlation coefficient (ICC) of 0.89. Moreover, values from the second experiment were not significantly different from first experiment, suggesting the absence of either sensitization or tolerance to the effect of amphetamine on DA release in these experimental conditions. The subjective activation, as rated by the subjects on analog scales, was also highly reproducible. In conclusion, this scanning technique provides a reliable measurement of amphetamine-induced reduction of [123I]IBZM BP and enables detection of between-subject differences that appear stable over time.

LY274601, R-(+)-8-thiomethyl-2-(di-n-propylamino)tetralin, a serotonin (5-HT) 1A receptor full agonist with high affinity (Ki: 0.6nM) and selectivity, was labeled with 11 C for imaging 5-HT 1A receptor sites in vivo by positron emission tomography (PET). [ 11 C]LY274601 was synthesized by S-methylation of the normethyl precursor unmasked via hydrolysis of the butyrate thioester of LY274601. The methylation reaction with [ 11 C]iodomethane proceeded quickly and efficiently in DMF at 40°C, yielding the radiotracer in an average overall radiochemical yield of 35.7±9.8%, The synthesis time including HPLC purification and formulation for injection was approximately 30 min. The specific activity was 630±78mCi/μmol at the end of synthesis (E.O.S.). This labeling procedure was also employed in the preparation of [ 3 H]LY274601, R-(+)-8-[ 3 H]methylthio-2-(di-n-propyl-amino)tetralin, from [ 3 H]iodomethane.

OBJECTIVE AND IMPORTANCE: Focal neurological deficits after carotid endarterectomy may result from ischemia or hyperperfusion. The usefulness of single photon emission computed tomography (SPECT) for differentiating between these two mechanisms has not been previously emphasized. CLINICAL PRESENTATION: An 83-year-old man experienced dysarthria and left-sided weakness immediately after undergoing endarterectomy of the right internal carotid artery. The results of computed tomography of the head were normal, and transcranial Doppler sonography showed symmetrically elevated velocities in both middle cerebral arteries. On the 1st postoperative day, the patient's deficits worsened in parallel with spontaneous increases in blood pressure, and blood pressure reduction with labetalol resulted in clinical improvement. INTERVENTION: On the 2nd postoperative day, technetium-99-hexametazime SPECT demonstrated markedly increased flow in the right basal ganglia and inferior frontal cortex, confirming the diagnosis of cerebral hyperperfusion. The patient's deficits continued to improve with antihypertensive therapy, and SPECT performed 7 and 48 days after surgery showed gradual normalization of the focal hyperemia. CONCLUSION: SPECT can be used to diagnose and monitor cerebral hyperperfusion after carotid endarterectomy and may be of particular value for differentiating hyperperfusion from ischemia when characteristic computed tomographic and transcranial Doppler sonographic findings are absent.

Sterile, apyrogenic [123I]IBZM was prepared in a sealed, capped ‘V’ vial, followed by SEP-PAK C-18 cartridge purification, and then was placed under sealed vial condensation. The quantity of BZM present in the final product ranged from 3.3–5.9 μg, as measured by a UV spectrophotometer at 254 and 308 nm. Animal biodistribution studies revealed that the [123I]IBZM prepared by this method which contained 5.9 μg of BZM, compared to the standard preparation method containing 0 μg of BZM, resulted in identical brain uptakes at 15, 30, 60, and 120 min post-injection. The in vitro and in vivo studies demonstrated that a small amount of BZM presence in the final product did not affect the radiochemical purity, nor the D2 receptor binding capacity in the rat brain of [123I]IBZM. The preparation time can be shortened to 1.5 h compared with at least 2–4 h needed for the standard method of preparation. This factor may be important in routine clinical application.

Differentiating neuropsychiatric Lyme disease from a primary psychiatric disorder can be a daunting task. This article describes how functional brain imaging and neuropsychological testing can be particularly valuable in helping to make diagnostic distinctions. In addition to a review of the relevance of functional imaging to neuropsychiatry in general, recent findings are presented regarding the use of single photon emission computed tomographic (SPECT) imaging in Lyme disease.