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The dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness.Dsub2/3/subreceptor radiotracer [sup11/supC]FLB457 BPsubND/sub(binding potential relative to nondisplaceable uptake) was measured in 14 off-medication subjects with SCH and 14 healthy control (HC) subjects at baseline and after the administration of 0.5 mg/kg oral d-amphetamine. The amphetamine-induced change in BPsubND/sub(ΔBPsubND/sub) was calculated as the difference between BPsubND/subin the postamphetamine condition and BPsubND/subin the baseline condition and expressed as a percentage of BPsubND/subat baseline. DA release in the striatum using the radiotracer [sup11/supC]NPA was also measured in these subjects.[sup11/supC]FLB457 ΔBPsubND/subwas greater in the HC group compared with the SCH group (Fsub1,26/sub = 5.7; p = .02) with significant differences in [sup11/supC]FLB457 ΔBPsubND/subseen across cortical brain regions. Only in the SCH group was a significant negative correlation observed between [sup11/supC]FLB457 ΔBPsubND/subin the dorsolateral prefrontal cortex and [sup11/supC]NPA ΔBPsubND/subin the dorsal caudate (r = -0.71, p = .005).Subjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH.

Docosahexaenoic acid (DHA) shows anti-inflammatory/proresolution effects in the brain. Higher red blood cell (RBC) DHA in humans is associated with improved cognitive performance and a lower risk for suicide. Here, we hypothesized that binding to the 18 kDa translocator protein (TSPO), a proxy for microglia levels, will be higher in individuals with low DHA relative to high DHA levels. We also postulated that higher TSPO would predict poor cognitive performance and impaired stress resilience.RBC DHA screening was performed in 320 healthy males. [sup11/supC]PBR28 positron emission tomography was used to measure binding to TSPO in 38 and 32 males in the lowest and highest RBC DHA quartiles. Volumes of distribution expressed relative to total plasma ligand concentration (VsubT/sub) was derived using an arterial input function-based kinetic analysis in 14 brain regions.[sup11/supC]PBR28 VsubT/subwas significantly lower (by 12% and 20% in C/T and C/C rs6971 genotypes) in males with low RBC DHA than in males with high RBC DHA. Regional VsubT/subwas correlated positively and negatively with RBC DHA and serum triglycerides, respectively. No relationships between VsubT/suband cognitive performance or stress resilience measures were present.Contrary to our hypothesis, we found lower TSPO binding in low-DHA than in high-DHA subjects. It is unclear as to whether low TSPO binding reflects differences in microglia levels and/or triglyceride metabolism in this study. Future studies with specific targets are necessary to confirm the effect of DHA on microglia. These results underscore the need to consider lipid parameters as a factor when interpreting TSPO positron emission tomography clinical findings.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogenMycobacterium tuberculosis(Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalianMtbdisaccharide trehalose – 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) – can act as a mechanism-based enzyme reporter in vivo. Use of [18F]FDT in the imaging ofMtbin diverse models of disease, including non-human primates, successfully co-optsMtb-specific processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-specific, clinical diagnostic candidate. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either bespoke radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [3H]CBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [3H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [3H]flortaucipir (45 nM) or [3H]MK-6240 (>50 nM). [18F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [3H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

Introduction Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-β (Aβ) deposits in living people. However, this technique cannot distinguish between Aβ deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aβ immunotherapies in AD patients, such as CAA. Methods A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aβ fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. Results Compound 1 displays characteristics of Aβ binding dyes, such as thioflavin-S, in that it labels both parenchymal Aβ plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aβ amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aβ deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. Conclusion We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aβ deposits in the vascular wall (i.e., “delivery selectivity”).

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials.

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, (18)F-flortaucipir and (18)F-MK-6240, in the same subjects. Methods: (18)F-flortaucipir and (18)F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I–VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80–100 min ((18)F-flortaucipir) or 70–90 min ((18)F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated (r(2) > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for (18)F-MK-6240 than for (18)F-flortaucipir. Cerebellar SUVs were similar for (18)F-MK-6240 and (18)F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with (18)F-flortaucipir and most often in the meninges with (18)F-MK-6240. Conclusion: Both (18)F-MK-6240 and (18)F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. (18)F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes.

OBJECTIVE: An imbalance between neuropeptides that promote stress and resilience, such as corticotrophin-releasing factor (CRF) and nociceptin, has been postulated to underlie relapse in addiction. The objective of this study was to develop a paradigm to image the in vivo interaction between stress-promoting neuropeptides and nociceptin receptors (NOP) in humans. METHODS: [(11)C]NOP-1A PET was used to measure the binding to NOP receptors at baseline (BASE) and following an intravenous hydrocortisone challenge (POST-CORT) in 19 healthy controls. Hydrocortisone was used as a challenge because in microdialysis studies it has been shown to increase CRF release in extrahypothalamic brain regions such as the amygdala. [(11)C]NOP-1A total distribution volume (V(T)) in eleven regions (ROIs) were measured using a two-tissue compartment kinetic analysis. The primary outcome measure was hydrocortisone-induced ΔV(T) calculated as (V(T POST-CORT) - V(T BASE)) / V(T BASE). RESULTS: Hydrocortisone led to an acute increase in plasma cortisol levels. Regional [(11)C]NOP-1A V(T) was on average 11 to 16% higher in the POST-CORT compared to BASE condition (linear mixed model, condition, p = 0.005; region, p < 0.001, condition*region, p < 0.001). Independent t-tests in all ROIs were statistically significant and survived multiple comparison correction. Hydrocortisone-induced ΔV(T) was significantly negatively correlated with baseline V(T) in several ROIs. CONCLUSIONS: Hydrocortisone administration increases NOP receptor availability. Increased NOP in response to elevated cortisol might suggest a compensatory mechanism in the brain to counteract CRF/stress. The [(11)C]NOP-1A and hydrocortisone imaging paradigm should allow for the examination of interactions between stress-promoting neuropeptides and NOP in addictive disorders. (In Vivo Imaging of Corticotropin-releasing Factor - Nociceptin Receptor Interactions, https://clinicaltrials.gov/ct2/show/NCT03302416 ClinicalTrials.gov Identifier: )

Background The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. Methods Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. Results Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. Conclusions The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [(3)H]CBD-2115 had a K(D) value of 6.9 nM and a nominal B(max) of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [(3)H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [(3)H]Flortaucipir (45 nM) or [(3)H]MK-6240 (>50 nM). [(18)F]CBD-2115 was reliably synthesized (3–11% radiochemical yield with molar activity of 27 – 111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats and non-human primate and all species showed initial brain uptake of 0.5–0.65 standardized uptake value with fast clearance from normal tissues. [(3)H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

Nociceptin/orphanin FQ (N/OFQ) is an antistress neuropeptide transmitter in the brain that counteracts corticotropin-releasing factor (CRF)-mediated stress and anxiety symptoms during drug and alcohol withdrawal. It also inhibits the release of a wide array of neurotransmitters, including dopamine and glutamate, which allows for it to block the rewarding properties of cocaine. Chronic cocaine administration in rodents has been shown to decrease N/OFQ and increase nociceptive opioid peptide (NOP) receptors in the nucleus accumbens. No previous studies have reported on the in vivo status of NOP in chronic cocaine-abusing humans.[A significant increase in [Increased NOP in cocaine use disorder suggests an adaptive response to decreased N/OFQ, or increased CRF transmission, or both. Future studies should examine the interactions between CRF and NOP to elucidate their role in negative reinforcement and relapse. NOP agonist medications to enhance N/OFQ should be explored as a therapeutic to treat cocaine use disorder.

Objective:Nociceptin/orphanin FQ (N/OFQ) is an antistress neuropeptide transmitter in the brain that counteracts corticotropin-releasing factor (CRF)-mediated stress and anxiety symptoms during dru...

Background Posttraumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and antistress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an antistress neuropeptide in the brain that promotes resilience in animal models of PTSD. Methods [11C]NOP-1A positron emission tomography was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [11C]NOP-1A data from 18 healthy control subjects were also included to provide a contrast with the sexual violence group. [11C]NOP-1A total distribution volume (VT) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional VT and Clinician-Administered PTSD Scale for DSM-5 total symptom and subscale severity were examined using correlational analyses. Results No differences in [11C]NOP-1A VT were noted between the sexual violence and control groups. VT in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month before positron emission tomography. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their VT with that in control subjects showed no group differences. Conclusions Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.

Increased vascular cell adhesion (hyperadhesion) to the endothelium is responsible for the hallmark acute pain episodes, or vaso-occlusive crises (VOC), of sickle cell disease. The integrin αvβ3 plays an important role in VOC since it mediates sickle red blood cell adhesion to the endothelium, a process that leads to ischemia and painful bone infarction. In the pilot study presented herein, we hypothesized that real-time imaging of hyperadhesion could quantify VOC severity and identify the most vulnerable anatomical sites. We also hypothesized that harnessing hyperadhesion as a proximate event in VOC would provide sensitive, objective evidence of VOC before pain has developed. Specifically, we tested whether positron emission tomography (PET) imaging of integrin αvβ3 using the PET tracer 68Ga-PRGD2 would successfully image hyperadhesion associated with VOC in a patient with sickle cell disease. We observed persistently higher tracer uptake in the femurs during VOC compared to baseline. In the vessel, after an initial and transient increase during VOC, blood pool activity was similar between baseline and VOC. These findings suggest that PET imaging of integrin αvβ3 may be a valuable strategy for imaging of VOC.

Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm.The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT).[(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power.This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Phosphodiesterase-10a (PDE10a) is located exclusively in medium spiny neurons (MSN). Rodent studies show an increase in striatal MSN spine density following exposure to cocaine. These increases in MSN spine density are suggested to underlie neurobiological changes which contribute to cocaine self-administration. No postmortem or imaging studies have confirmed this finding in humans. Here, we hypothesized an increase in the MSN marker PDE10a in subjects with cocaine use disorder ("cocaine users") compared to controls. PDE10a availability was measured with [11 C]IMA107 and positron emission tomography in 15 cocaine users and 15 controls matched for age, gender, and nicotine status. Cocaine users with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient-monitored abstinence. [11 C]IMA107 binding potential relative to nondisplaceable uptake (BPND ) in the regions of interest was derived with the simplified reference tissue method. No significant effect of diagnosis on BPND was demonstrated using linear mixed modeling with [11 C]IMA107 BPND as the dependent variable and regions of interest as a repeated measure. There were no significant relationships between BPND and clinical rating scales. To the extent that PDE10a is a valid proxy for MSN spine density, these results do not support its increase in recently abstinent cocaine users.

SEP-227162 [R(-)-O-desmethylvenlafaxine] is an enantiomer of the venlafaxine metabolite O-desmethylvenlafaxine (ODV, Pristiq™, Wyeth). This study compared the serotonin transporter (SERT) occupancy achieved by SEP-227162 and ODV, at daily doses of 25, 50, 100, and 150 mg using [11 C]DASB positron emission tomography (PET). Sixteen healthy male subjects participated in one of four dose groups (N = 4 per group) during which they were administered two doses of the study drug (SEP-227162 or ODV). For each study drug, total daily doses of 25, 50, 100, and150 mg were studied. Subjects underwent three PET scans with [11 C]DASB. A baseline, off-medication, scan was performed prior to dosing and a [11 C]DASB PET scan was performed after 72 hr at each dose level. [11 C]DASB binding potential (BPND ) was calculated using the simplified reference tissue method. SERT occupancy was calculated as the change in BPND (ΔBPND ) from baseline scan to the on-medication scan relative to the baseline BPND value. SEP-227162 and ODV significantly reduced regional distribution volumes and region BPND values in a dose-dependent manner. Across all doses ODV produced significantly greater SERT occupancy than SEP-227162 (ANOVA F = 21.8, df = 1,23, p < .001). The total daily dose required to provide 50% SERT occupancy was 24.8 mg for SEP-227162 and 14.4 mg for ODV. In vitro data suggests a ratio of 3.3:1 for binding at human SERT for SEP-227162 relative to ODV. Our study suggests a ratio of 1.7:1, highlighting the value of in vivo imaging in the drug development process.

Background Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH. Methods D2/3 agonist positron emission tomography radiotracer [11C]N-propyl-norapomorphine ([11C]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg–1 oral D-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. Results A trend-level increase was observed in comparing baseline [11C]NPA BPND (repeated-measures analysis of variance, F1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (repeated-measures analysis of variance, F1,26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 ± 5.3 vs. 23.7 ± 4.1, paired t test, p Conclusions This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.

BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's anti-stress system. Nociceptin exerts its anti-stress effect by counteracting the functions of corticotropin releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. METHODS: Here, we used [(11)C]NOP-1A and PET to measure the in vivo binding to NOP receptors in 15 DSM-IV alcohol-dependent humans and 15 healthy controls matched for age, gender, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient monitored abstinence (confirmed with 3×/week urine alcohol metabolite testing). [(11)C]NOP-1A distribution volume (V(T)) in regions of interest (including the amygdala, hippocampus, midbrain, striatal, and prefrontal cortical subdivisions) were measured with kinetic analysis using the arterial input function. RESULTS: Regional [(11)C]NOP-1A V(T) in alcohol-dependence was not significantly different compared to healthy controls. No relationship between [(11)C]NOP-1A V(T) and other clinical measures (including duration and severity of alcohol abuse, craving, anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. CONCLUSIONS: The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.

The development of positron emission tomography (PET) radioligands for the non-invasive imaging of amyloid-β plaque burden has been the focus of intense research efforts over the last decade. A variety of structural backbones have been investigated and several radiolabeled molecules have been evaluated in phase I (and later) clinical studies. These efforts have been driven by the desire not only to develop a suitable diagnostic imaging agent but also to develop a means to evaluate potential therapies for Alzheimer's disease. This review focuses on the development of these ligands, as well as the radiochemistry and current regulatory status of these PET radioligands. Particular attention is given to those ligands that have progressed to the later stages of drug development (phase II/III clinical trial studies) or approved New Drug Application status.

Section 121 of the 1997 FDA Modernization Act (FDAMA) required that PET drugs be prepared according to U.S. Pharmacopeia (USP) compounding standards and PET drug monographs until the Food and Drug Administration (FDA) established appropriate approval processes and good manufacturing practice (GMP)

For 100 years, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) have been recognized as the neuropathological hallmarks of Alzheimer's disease (AD), and their presence or absence could only be assessed postmortem using stains and dyes that identified these microscopic structures. Approximately 10 years ago, the first successful Aβ plaque-specific positron emission tomography (PET) imaging study was conducted in a living human subject clinically diagnosed with probable AD using the (11)C-labeled radiopharmaceutical Pittsburgh Compound B (PiB). Laboratory studies and preclinical evaluations to design PiB began a decade earlier than the first human PiB PET study and involved chemical modifications of different well-known dyes that bound specifically to the extended β-pleated sheets that comprise the fibrils of amyloid proteins such as Aβ plaques, NFTs, α-synuclein deposits, and prions. These preclinical studies were conducted in our laboratories at the University of Pittsburgh, starting with Congo red derivatives, followed by Chrysamine G derivatives, followed by X-series compounds, and finally with neutral derivatives of thioflavin-T. The in vitro and in vivo evaluations of the different derivatives as candidate PET radioligands for imaging Aβ plaques and neurofibrillary tangles in human brain are described in this review, along with the specific evaluation criteria by which the candidate radioligands were judged. Out of these studies came PiB, a PET radioligand that binds selectively and with high affinity to only fibrillar forms of Aβ. PiB has been used in many different human research protocols throughout the world and has demonstrated the usefulness of assessing the Aβ plaque status of subjects many years before the clinical diagnosis of probable AD. Recently, longer-lived (18)F-radiolabeled Aβ-selective radiopharmaceuticals have been developed. It is likely that the full clinical impact of these imaging agents will be realized by identifying presymptomatic subjects who would benefit from early drug treatments with future disease-modifying AD therapeutics.

There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [(11)C]WAY100635 and [(18)F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V(T)) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age(2), sex, and hormone concentrations, with post hoc regional significance set at p0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex-hormone-serotonin receptor relationships.

Studies in nonhuman primates and humans have demonstrated that amphetamine-induced dopamine release in the cortex can be measured with [(11)C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg(−1)) did not lead to a significant reduction in [(11)C]FLB 457 BP(ND) (i.e., binding potential relative to non-displaceable uptake). Two factors that likely contributed to the inability to displace [(11)C]FLB 457 BP(ND) in this cohort relative to successful cohorts are: (1) the acquisition of the baseline and post-amphetamine scans on different days as opposed to the same day and (2) the initiation of the post-amphetamine [(11)C]FLB 457 scan at ~ 5 hours as opposed to ~ 3 hours following oral amphetamine. Furthermore, we show [(11)C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BP(ND) when the test and re-test scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.

In a recent PET study, we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the relatively high affinity dopamine D2/3 radioligand [11C]FLB 457 (Narendran et al., [2009] Synapse 63:447–461). The aim of this study was to evaluate the reproducibility and reliability of [11C]FLB 457 in the same imaging paradigm we used to measure amphetamine-induced DA transmission. Six healthy human subjects (three males/three females) were studied twice with [11C]FLB 457, once at baseline and again 3 h following the end of the baseline scan. D2/3 receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test–retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BPP), and binding potential relative to nondisplaceable uptake (BPND) of [11C]FLB 457. The test–retest variability of [11C]FLB 457 VT, BPP, and BPND were ≤15%, consistent with the published test–retest variability for this ligand in other brain regions (Sudo et al., [2001] Nucl Med Commun 22:1215–1221; Vilkman et al., [2000] Eur J Nucl Med 27:1666–1673). In addition, no significant decrease in [11C]FLB 457 BPND was observed in the second scan compared to the first one. This suggests that the contribution of carryover mass of [11C]FLB 457 to the measured reduction in [11C]FLB 457 BPND following amphetamine was relatively low. These data support the further validation of [11C]FLB 457 as a tool to measure amphetamine-induced dopamine release in the human cortex. Synapse 65:35–40, 2011. © 2010 Wiley-Liss, Inc.

We measured the whole-body distribution of intravenously injected (11)C-N-propylnorapomorphine ((11)C-NPA), a dopamine agonist PET tracer, in human subjects and determined the resulting absorbed radiation doses.Six subjects (3 women, 3 men) were injected with (11)C-NPA (nominal dose, 370 MBq). A total of 9 consecutive whole-body PET scans were obtained for each subject. In addition, time-activity curves for 12 organs were determined, and residence times were computed for each subject. Dosimetry was determined for the various body organs and the whole body.The average NPA whole-body radiation dose was 3.17 x 10(-3) mSv per MBq of injected (11)C-NPA. The organ receiving the highest dose was the gallbladder wall, with an average of 2.81 x 10(-2) mSv.MBq(-1).On the basis of averaged dosimetry results, an administration of less than 1,780 MBq (48 mCi) of (11)C-NPA yields an organ dose of under 50 mSv (5 rem) to all organs.

Activated microglia are an important feature of many neurological diseases and can be imaged in vivo using 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a ligand that binds the peripheral benzodiazepine receptor (PBR). N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl) acetamide (DAA1106) is a new PBR-specific ligand that has been reported to bind to PBR with higher affinity compared with PK11195. We hypothesized that this high-affinity binding of DAA1106 to PBR will enable better delineation of microglia in vivo using positron emission tomography. [3H]DAA1106 showed higher binding affinity compared with [3H](R)-PK11195 in brain tissue derived from normal rats and the rats injected intrastriatally with 6-hydroxydopamine or lipopolysaccharide at the site of the lesion. Immunohistochemistry combined with autoradiography in brain tissues as well as correlation analyses showed that increased [3H]DAA1106 binding corresponded mainly to activated microglia. Finally, ex vivo autoradiography and positron emission tomography imaging in vivo showed greater retention of [11C]DAA1106 compared with [11C](R)-PK11195 in animals injected with either lipopolysaccaride or 6-hydroxydopamine at the site of lesion. These results indicate that DAA1106 binds with higher affinity to microglia in rat models of neuroinflammation when compared with PK11195, suggesting that [11C]DAA1106 may represent a significant improvement over [11C](R)-PK11195 for in vivo imaging of activated microglia in human neuroinflammatory disorders.

The Radiotracer [11C]OMAR was developed for positron emission tomography (PET) imaging of cannabinoid type-1 receptors (CB1R). The objectives of the present study were to evaluate kinetic analysis methods, determine test–retest reliability, and assess gender differences in receptor availability. Dynamic PET data were acquired in 10 human subjects, and analyzed with one-tissue (1T) and two-tissue (2T) compartment models and by the Logan and multilinear analysis (MA1) methods to estimate regional volume of distribution ( VT). The 2T model inclusive of a vascular component (2TV) and MA1 were the preferred techniques. Test–retest reliability of VT was good (mean absolute deviation ~ 9%; intraclass correlation coefficient ~ 0.7). Tracer parent fraction in plasma was lower in women ( P < 0.0001). Cerebral uptake normalized by body weight and injected dose was higher in men by 17% ( P < 0.0001), but VT was significantly greater in women by 23% ( P < 0.0001). These findings show that [11C]OMAR binding can be reliably quantified by the 2T model or MA1 method and demonstrate the utility of this tracer for in vivo imaging of CB1R. In addition, results from the present study indicate that gender difference in receptor binding should be taken into consideration when [11C]OMAR is used to quantify CB1R availability in neuropsychiatric disorders.

Purpose: We investigated 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) positron emission tomography (PET) imaging of apoptosis posttherapy to determine optimal timing for predicting chemotherapy response in a mouse head/neck xenograft cancer model. Procedures: BALB/c nude mice (4-8 weeks old) were implanted with UM-SCC-22B tumors. The treatment group received 2 doses of doxorubicin (10 mg/kg, days 0, 2). Small animal 18F-ML-10 PET/computed tomography was performed before and on days 1, 3, and 7 postchemotherapy. Using regions of interest around tumors, 18F-ML-10 uptake change was measured as %ID/g and uptake relative to liver. Terminal Uridine Nick-End Labeling (TUNEL) immunohistochemistry assay was performed using tumor samples of baseline and on days 1, 3, and 7 posttreatment. Results: Treated mice demonstrated increased 18F-ML-10 uptake compared to baseline and controls, and 10 of 13 mice showed tumor volume decreases. All control mice showed tumor volume increases. Tumor-to-liver (T/L) ratios from the control group mice did not show significant change from baseline (P > .05); however, T/L ratios of the treatment group showed significant 18F-ML-10 uptake differences from baseline compared to days 3 and 7 posttreatment (P < .05), but no significant difference at 1 day posttreatment. Conclusion: 2-(5-Fluoro-pentyl)-2-methyl-malonic acid PET imaging has the potential for early assessment of treatment-induced apoptosis. Timing and image analysis strategies may require optimization, depending on the type of tumor and cancer treatment.

In an effort to develop selective, high-affinity radioligands for the 5-HT-3 receptor, a series of homologues of 5-chloro-2,3-dimethoxy- N -(1-azabicyclo[2.2.2]oct-3-yl)benzamide (2b) was prepared in which individual methoxy groups were replaced by ethoxyl, (2-fluoroethoxyl), allyloxyl, propargyloxyl, or (3-iodoallyl)oxyl groups. Affinities for the 5-HT-3 receptor were determined by displacement of the binding of [ 125 I]MIZAC (2a), a selective 5-HT-3 receptor antagonist radioligand, in rat brain homogenates. The 3-substituted homologues were more potent than the lead compound, 2b. The homologue having the largest 3-substituent, i.e., E-(S)- N -(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-3-(3-iodo-2-propenyl)oxy-2-methoxybenzamide (3b, THIZAC), had one of the highest affinities, K i 0.08 nM. The 2-substituted homologues were equipotent with 2b, having K i 0.2–0.3 nM, regardless of the size of the substituent. The corresponding iodoallyl derivative, E-(S)- N -(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-(3-iodo-2-propenyl)oxy-3-methoxybenzamide (4, LIZAC), displayed a K i of 0.29 nM. Saturation binding of [ 125 I]-4 gave a K D of 0.31 ± 0.04 nM and a B max of 2.36 ± 0.10 fmol/mg of entorhinal cortex. In vivo biodistribution of [ 125 I]-4 in the rat brain showed increased accumulation in hippocampus relative to that in cerebellum. Both the high-affinity ligands [ 125 I]-3b and [ 125 I]-4 are potentially useful radioligands for studying the 5-HT-3 receptor.

A stereoconservative synthetic route for the preparation of the precursors of [11C](+)-McN 5652 and [11C](−)-McN 5652, also known as [11C]McN-5652-X and [11C]McN-5652-W, is reported. The key steps involved the transformation of the (+)-trans-4-bromophenyl or (−)-trans-4-bromophenyl analogues of (+)-McN 5652 or (−)-McN 5652 to triisopropylsilyl-protected thioethers and conversion of the thioethers to benzoyl thioesters via a one-pot deprotection and esterification sequence. Subsequent formation of a tartrate salt of the benzoyl thioesters provided stable, convenient precursors for the routine radiosynthesis of [11C](+)-McN 5652 and [11C](−)-McN 5652. The radiosyntheses were accomplished by S-methylation with high specific activity [11C]methyl iodide of the phenylsulfides, which were generated in situ from the tartrate salt of the benzoyl thioesters. HPLC analyses of the final products demonstrated that all of the reactions were stereoconservative, with no detectable isomerization or racemization taking place in any of the reaction sequences. [11C](+)-McN 5652 and [11C](−)-McN 5652 were obtained with end of synthesis (EOS) yields of ∽120 mCi and EOS specific activities of ∽4000 Ci/mmol following radiosynthesis and purification procedures that required approximately 25 min. The chemical and radiochemical purities of the final products were greater than 95%. © 1998 John Wiley & Sons, Ltd.

We report an improved synthesis of unlabeled (S)-iodozacopride, the radiolabeling of (S)-[125I]iodozacopride via deschloro-(S)-zacopride, and a re-evaluation of its affinity for the 5-HT3 receptor. Unlabeled (S)-iodozacopride was prepared in seven steps from 4-aminosalicylic acid via alkaline hydrolysis of its 4-acetamide derivative. Catalytic hydrogenation of (S)-iodozacopride gave deschloro-(S)-zacopride, identical to the obtained from (S)-3-amino-quinuclidine and 4-amino-2-methoxybenzoic acid via its corresponding 1-imidazole derivative. Radioiodination to produce (S)-[125I]idozacopride was accomplished by treatment of deschloro-(S)-zacopride with 5 mCi sodium 125iodide and chloramine-T in hydrochloric acid. Purification of the reaction products using an HPLC system capable of detecting chlorinated side-products revealed a mixture of 2.1 mCi (1.3 nmol) (S)-[125I]idozacopride and (S)-zacopride (1.5 nmol). Saturation analysis of the binding of the purified (S)-[125I]iodozacopride to whole rat brain homogenates gave an estimated KD of 1.10±0.07 nM. As anticipated, this is approximately half the KD reported for binding of racemic [125I]iodozacopride, and differs from the previosuly reported values by an order of magnitude. Analysis of the apparent binding affinity of a 1 : 1 mixture of (S)-[125I]iodozacopride and (S)-zacopride suggests that the previous result may have been confounded by contamination of the product with unlabeled (S)-zacopride. Competition analysis of the displacement of the displacement of (S)-[125I]iodozacopride binding by unlabeled (S)-iodozacopride and (S)-zacopride gave Ki values of 0.95 and 0.21 nM, respectively.

The development of positron emission tomography (PET) radioligands for the non-invasive imaging of amyloid-β plaque burden has been the focus of intense research efforts over the last decade. A variety of structural backbones have been investigated and several radiolabeled molecules have been evaluated in phase I (and later) clinical studies. These efforts have been driven by the desire not only to develop a suitable diagnostic imaging agent but also to develop a means to evaluate potential therapies for Alzheimer’s disease. This review focuses on the development of these ligands, as well as the radiochemistry and current regulatory status of these PET radioligands. Particular attention is given to those ligands that have progressed to the later stages of drug development (phase II/III clinical trial studies) or approved New Drug Application status.

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.

This study evaluated the utility of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3-dimethoxybenzamide ([18F]fluoropropylepidepride), [18F]5-FPrEpid, as a ligar d for PET studies of cerebral dopamine D2 receptors. The in vitro affinity for the rat striatal dopamine D2 receptor, KD 138 pM, was determined by Scatchard analysis of in vitro binding to rat striatal homogenate. The apparent lipophilicity, log kw 1.6, was measured with reverse phase HPLC at pH 7.5. The receptor specificity was determined by competitive displacement of [18F]5-FPrEpid by a variety of neurotransmitter ligands. Only dopamine D2 ligands displaced [18F]5-FPrEpid with high affinity. Positron tomographic imaging studies in primates of [18F]5-FPrEpid demonstrated a stable striatal uptake. of 0.02% injected dose/ml for up to 5 h after injection. The striatal: cerebellar ratio increased from 2 at 15 min, to 7 at 200 min, and to 10 at 300 min. Striatal uptake was displaceable by haloperidol (1 mg/kg) or raclopride (2.5 mg/kg) to cerebellar levels with a t1/2 of washout of 9 or 15 min. Striatal uptake was mildly susceptible to displacement by d-amphetamine (1–2 mg/kg) released endogenous dopamine; d-amphetamine administration produced a 10%/h increase in the rate of striatal washout. Although uptake in the striatum is reversible, an equilibrium between receptor bound [18F]5-FPrEpid in striatum and [18F]5-FPrEpid in plasma is not reached within 5 h postinjection. © 1993 Wiley-Liss. Inc.

Biodegradable elastomers, which can possess favorable mechanical properties and degradation rates for soft tissue engineering applications, are more recently being explored as depots for biomolecule delivery. The objective of this study was to synthesize and process biodegradable, elastomeric poly(ester urethane)urea (PEUU) scaffolds and to characterize their ability to incorporate and release bioactive insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF).Porous PEUU scaffolds made from either 5 or 8 wt% PEUU were prepared with direct growth-factor incorporation. Long-term in vitro IGF-1 release kinetics were investigated in saline or saline with 100 units/ml lipase to simulate in vivo degradation. Cellular assays were used to confirm released IGF-1 and HGF bioactivity.IGF-1 release into saline occurred in a complex multi-phasic manner for up to 440 days. Scaffolds generated from 5 wt% PEUU delivered protein faster than 8 wt% scaffolds. Lipase-accelerated scaffold degradation led to delivery of90% protein over 9 weeks for both polymer concentrations. IGF-1 and HGF bioactivity in the first 3 weeks was confirmed.The capacity of a biodegradable elastomeric scaffold to provide long-term growth-factor delivery was demonstrated. Such a system might provide functional benefit in cardiovascular and other soft tissue engineering applications.

This longitudinal, case-control pilot study examined amygdala growth in rhesus macaque infants receiving the complete US childhood vaccine schedule (1994-1999). Longitudinal structural and functional neuroimaging was undertaken to examine central effects of the vaccine regimen on the developing brain. Vaccine-exposed and saline-injected control infants underwent MRI and PET imaging at approximately 4 and 6 months of age, representing two specific timeframes within the vaccination schedule. Volumetric analyses showed that exposed animals did not undergo the maturational changes over time in amygdala volume that was observed in unexposed animals. After controlling for left amygdala volume, the binding of the opioid antagonist [(11)C]diprenorphine (DPN) in exposed animals remained relatively constant over time, compared with unexposed animals, in which a significant decrease in [(11)C]DPN binding occurred. These results suggest that maturational changes in amygdala volume and the binding capacity of [(11)C]DPN in the amygdala was significantly altered in infant macaques receiving the vaccine schedule. The macaque infant is a relevant animal model in which to investigate specific environmental exposures and structural/functional neuroimaging during neurodevelopment.

In a recent PET study, we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the relatively high affinity dopamine D₂/₃ radioligand [¹¹C]FLB 457 (Narendran et al., [2009] Synapse 63:447-461). The aim of this study was to evaluate the reproducibility and reliability of [¹¹C]FLB 457 in the same imaging paradigm we used to measure amphetamine-induced DA transmission. Six healthy human subjects (three males/three females)were studied twice with [¹¹C]FLB 457, once at baseline and again 3 h following the end of the baseline scan. D₂/₃ receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BP(P)), and binding potential relative to non-displaceable uptake (BP(ND)) of [¹¹C]FLB 457. The test-retest variability of [¹¹C]FLB 457 VT, BPP, and BP(ND) were ≤15%, consistent with the published test-retest variability for this ligand in other brain regions (Sudo et al., [2001] Nucl Med Commun 22:1215-1221; Vilkman et al., [2000] Eur J Nucl Med 27:1666-1673). In addition, no significant decrease in [¹¹C]FLB457 BP(ND) was observed in the second scan compared to the first one. This suggests that the contribution of carryover mass of [¹¹C]FLB 457 to the measured reduction in[¹¹C]FLB 457 BP(ND) following amphetamine was relatively low. These data support the further validation of [¹¹C]FLB 457 as a tool to measure amphetamine-induced dopamine release in the human cortex.

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine D(2/3) receptor agonist, and [(11)C]NPA is a suitable radiotracer to image D(2/3) receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study, the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic dopamine was assessed with PET in healthy humans and compared with that of the reference D(2/3) receptor antagonist radiotracer [11C]raclopride. Ten subjects (eight females and two males) were studied on two separate days, a minimum of 1 week apart, both with [11C]raclopride and [11C]NPA at baseline and after the administration of 0.5 mg x kg(-1) oral d-amphetamine. Kinetic modeling with an arterial input function was used to derive the binding potential relative to nonspecific uptake (BPND) in the ventral striatum (VST), caudate (CAD), and putamen (PUT). [11C]Raclopride BPND was significantly reduced by 9.7 +/- 4.4, 8.4 +/- 4.2, and 14.7 +/- 4.8% after amphetamine administration in the VST, CAD, and PUT. [11C]NPA BPND was also reduced significantly, by 16.0 +/- 7.0, 16.1 +/- 6.1, and 21.9 +/- 4.9% after the same dose of amphetamine in the VST, CAD, and PUT. Although these results suggest that [11C]NPA is more vulnerable to endogenous competition by dopamine compared with [11C]raclopride by a factor of 1.49 to 1.90, the same data for a related outcome measure, binding potential relative to plasma concentration, was not significant. Nevertheless, these data add to the growing literature that suggests D(2/3) agonist radiotracers are more vulnerable to endogenous competition by dopamine than existing D(2/3) antagonist radiotracers.

Unsaturated analogues of androst-4-en-17 beta-ol-3-one, each with a 17 alpha-iodoethynyl or 17 alpha-(2-iodoethenyl) substituent, were prepared, and their relative binding affinities (RBAs) for androgen-binding protein (ABP) were compared with those of 5 alpha-androstan-17 beta-ol-3-one, androst-4-en-17 beta-ol-3-one, androsta-4,6-dien-17 beta-ol-3-one, and androsta-1,4,6-trien-17 beta-ol-3-one. These binding studies indicate that the iodine[125I] analogues of 17 alpha-iodoethynyl and 17 alpha-[(E)-2-iodoethenyl] derivatives of androsta-4,6-dien-17 beta-ol-3-one and androsta-1,4,6-trien-17 beta-ol-3-one will have RBAs at least twice as great as that of 5 alpha-androstan-17 beta-ol-3-one. They can be prepared from 17 alpha-ethynylandrosta-4-en-17 beta-ol-3-one, the final synthetic step using N-[125I]iodosuccinimide, and are potential radioiodinated, active site-directed photoaffinity ligands for ABP and testosterone-binding globulin.

17α-[125I]Iodoethynyl-4,6-androstadien-17β-ol-3-one with a specific radioactivity of 24 Ci/mmol was prepared as an active-site-directed photoaffinity radiolabel for androgen-binding proteins. The iodinated steroid was formed by the silver nitrate-catalyzed reaction of N-[125I]iodosuccinimide and 17α-ethynyl-4,6-androstadien-17β-ol-3-one in acetone. N-[125I]Iodosuccinimide was prepared by reaction of silver succinimide with iodine-125 in dioxane, the latter being formed by oxidation of sodium iodide-125 with sodium nitrite-nitric acid in water-hexane.

Inflammation of the central nervous system (CNS) is a nearly ubiquitous consequence of neuropathologic processes involved in a spectrum of brain disorders, including brain trauma, ischemia, infection, and autoimmune and neurodegenerative diseases. CNS inflammation has seemingly paradoxical roles, responsible for both exacerbating and resolving tissue damage resulting from CNS insult. It is not only the primary mechanism by which tissue pathogens are sequestered and neutralized but also that which mitigates tissue repair and regeneration. CNS inflammation is characterized by