A Stress Protein-Based Suicide Prediction Score and Relationship to Reported Early-Life Adversity and Recent Life Stress.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24). METHODS: Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots. RESULTS: There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated "suicide risk score" using these measures had 71% sensitivity and 71% specificity. CONCLUSION: A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide.

Association of BDNF Val66Met Polymorphism and Brain BDNF Levels with Major Depression and Suicide.

Background: Brain-derived neurotrophic factor is implicated in the pathophysiology of major depressive disorder and suicide. Both are partly caused by early life adversity, which reduces brain-derived neurotrophic factor protein levels. This study examines the association of brain-derived neurotrophic factor Val66Met polymorphism and brain brain-derived neurotrophic factor levels with depression and suicide. We hypothesized that both major depressive disorder and early life adversity would be associated with the Met allele and lower brain brain-derived neurotrophic factor levels. Such an association would be consistent with low brain-derived neurotrophic factor mediating the effect of early life adversity on adulthood suicide and major depressive disorder. Methods: Brain-derived neurotrophic factor Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 nonsuicides. Additionally, brain-derived neurotrophic factor protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9), anterior cingulate cortex (Brodmann area 24), caudal brainstem, and rostral brainstem. The relationships between these measures and major depressive disorder, death by suicide, and reported early life adversity were examined. Results: Subjects with the Met allele had an increased risk for depression. Depressed patients also have lower brain-derived neurotrophic factor levels in anterior cingulate cortex and caudal brainstem compared with nondepressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower brain-derived neurotrophic factor levels in the anterior cingulate cortex were found in subjects who had been exposed to early life adversity and/or died by suicide compared with nonsuicide decedents and no reported early life adversity. Conclusions: This study provides further evidence implicating low brain brain-derived neurotrophic factor and the brain-derived neurotrophic factor Met allele in major depression risk. Future studies should seek to determine how altered brain-derived neurotrophic factor expression contributes to depression and suicide.

Radiosynthesis and in vivo evaluation of [11C]MOV as a PET imaging agent for COX-2.

Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40 ±â€¯10% yield and >99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1 mg/kg oral dose of COX-2 inhibitor valdecoxib.

In vivo evaluation of IGF1R/IR PET ligand [18F]BMS-754807 in rodents.

In vivo evaluation of [18F]BMS-754807 binding in mice and rats using microPET and biodistribution methods is described herein. The radioligand shows consistent binding characteristics, in vivo, in both species. Early time frames of the microPET images and time activity curves of brain indicate poor penetration of the tracer across the blood brain barrier (BBB) in both species. However, microPET experiments in mice and rats show high binding of the radioligand outside the brain to heart, pancreas and muscle, the organs known for higher expression of IGF1R/1R. Biodistribution analysis 2h after injection of [18F]BMS-754807 in rats show negligible [18F]defluorination as reflected by the low bone uptake and clearance from blood. Overall, the data indicate that [18F]BMS-754807 can potentially be a radiotracer for the quantification of IGF1R/IR outside the brain using PET.

Synthesis and in vitro evaluation of [18F]FECIMBI-36: A potential agonist PET ligand for 5-HT2A/2C receptors.

Radiosynthesis and in vitro evaluation of [(18)F]-2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-(2-fluoroethoxy)benzyl)ethanamine, ([(18)F]FECIMBI-36) or ([(18)F]1), a potential agonist PET imaging agent for 5-HT2A/2C receptors is described. Syntheses of reference standard 1 and the corresponding des-fluoroethyl radiolabeling precursor (2) were achieved with 75% and 65% yields, respectively. In vitro pharmacology assay of FECIMBI-36 by [(3)H]-ketanserin competition binding assay obtained from NIMH-PDSP showed high affinities to 5-HT2AR (Ki = 1nM) and 5-HT2CR (Ki=1.7 nM). Radiolabeling of FECIMBI-36 was achieved from the boc-protected precursor 2 using [(18)F]-fluoroethyltosylate in presence of Cs2CO3 in DMSO followed by removal of the protective group. [(18)F]1 was isolated using RP-HPLC in 25 ± 5% yield, purity > 95% and specific activity 1-2Ci/µmol (N = 6). In vitro autoradiography studies demonstrate that [(18)F]1 selectively label 5-HT2A and 5-HT2C receptors in slide-mounted sections of postmortem human brain using phosphor imaging. Our results indicate the potential of [(18)F]1 for imaging 5-HT2A/2C receptors in the high affinity state in vivo using PET imaging.

Radiosynthesis of [18F]ATPFU: a potential PET ligand for mTOR.

Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation, and recent evidence suggests that an altered mTOR signaling pathway plays a central role in the pathogenesis of aging, tumor progression, neuropsychiatric, and major depressive disorder. Availability of a mTOR-specific PET tracer will facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. Towards this we have developed the radiosynthesis of [(18)F]1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-(2-fluoroethyl)urea [(18)F]ATPFU ([(18)F]1) as an mTOR PET ligand. Synthesis of reference 1 and the precursor for radiolabeling, 4-(4-8-oxa-3-azabicyclo[3.2.1]-octan-3yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6yl)aniline (10), were achieved from beta-chloroaldehyde 3 in 4 and 5 steps, respectively, with an overall yield of 25-28%. [(18)F]Fluoroethylamine was prepared by heating N-[2-(toluene-4-sulfonyloxy)ethyl]phthalimide with [(18)F]fluoride ion in acetonitrile. [(18)F]1 was obtained by slow distillation under argon of [(18) F]FCH2CH2NH2 into amine 10 that was pre-treated with triphosgene at 0-5 °C. The total time required for the two-step radiosynthesis including semi-preparative HPLC purification was 90 min, and the overall radiochemical yield of [(18)F]1 for the process was 15 ± 5% based on [(18)F]fluoride ion (decay corrected). At the end of synthesis (EOS), the specific activity was 37-74 GBq/µmol (N = 6).

Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R.

Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170°C at high radiochemical purity and specific activity (1-2Ci/µmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R.

Synthesis and in vivo evaluation of [(18)F]2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione ([(18)F]FECUMI-101) as an imaging probe for 5-HT1A receptor agonist in nonhuman primates.

The 5-HT1AR partial agonist PET radiotracer, [(11)C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki=0.1nM; Emax=77%; EC50=0.65nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [(18)F]fluoroethyltosylate in DMSO in the presence of 1.6equiv of K2CO3 in 45±5% yield (EOS). PET shows [(18)F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [(18)F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100635. These findings indicate that [(18)F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET.

Synthesis and in vitro evaluation of [18F](R)-FEPAQ: a potential PET ligand for VEGFR2.

Synthesis and in vitro evaluation of [(18)F](R)-N-(4-bromo-2-fluorophenyl)-7-((1-(2-fluoroethyl)piperidin-3-yl)methoxy)-6-methoxyquinazolin-4-amine ((R)-[(18)F]FEPAQ or [(18)F]1), a potential imaging agent for the VEGFR2, using phosphor image autoradiography are described. Synthesis of 2, the desfluoroethyl precursor for (R)-FEPAQ was achieved from t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3) in five steps and in 50% yield. [(18)F]1 was synthesized by reaction of sodium salt of compound 2 with [(18)F]fluoroethyl tosylate in DMSO. The yield of [(18)F]1 was 20% (EOS based on [(18)F]F(-)) with >99% radiochemical purity and specific activity of 1-2 Ci/µmol (n=10). The total synthesis time was 75 min. The radiotracer selectively labeled VEGFR2 in slide-mounted sections of human brain and higher binding was found in surgically removed human glioblastoma sections as demonstrated by in vitro phosphor imager studies. These findings suggest [(18)F]1 may be a promising radiotracer for imaging VEGFR2 in brain using PET.

PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density?

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 [11C]R121920 and [11C]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 [11C]R121920 and [11C]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 (Bmax) of 63.3 and 147.3 fmol/mg protein, respectively, and in human cerebellar cortex yielded Bmax 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, Bmax and K(D) were not measurable. Autoradiographic results were consistent except there was also detectable CRF1-specific binding in baboon cerebellum. CONCLUSION: Neither [11C]R121920 nor [11C]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 and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin- 1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione: a novel 5-HT1A receptor agonist positron emission tomography ligand.

Antagonist 5-HT(1A) PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-(11)C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (10), a potential high affinity (K(i) = 1.36 nM) 5-HT(1A) agonist PET tracer is described. Piperazine 10 is a 5-HT(1A) agonist with an EC(50) comparable to serotonin, based on cAMP formation and GTP(gamma)S binding assays. Radiosynthesis of [(11)C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [(11)C]CH(3)OTf in 25 +/- 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [(11)C]10 were >99% with a specific activity 1500 +/- 300 Ci/mmol (n =15). PET studies in anesthetized baboon demonstrate [(11)C]10 specific binding in brain regions rich in 5-HT(1A) receptors. Binding of [(11)C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V(T)) of [(11)C]10 in baboon correlate with [(11)C]WAY100635 V(T) in baboons. These data provide evidence that [(11)C]10 is the first promising agonist PET tracer for the 5-HT(1A) receptors.

Synthesis and in vivo evaluation of [O-methyl-11C](2R,4R)-4-hydroxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine as a 5-HT2A receptor PET ligand.

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.

In vitro and in vivo evaluation of [11C]MPEPy as a potential PET ligand for mGlu5 receptors.

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.

Autoradiographic Evaluation of [(18)F]FECUMI-101, a High Affinity 5-HT1AR Ligand in Human Brain.

[(18)F]FECUMI-101 ([(18)F]1) is a 5HT1AR ligand demonstrating specific binding in brain regions corresponding to the distribution of 5-HT1AR in baboons. However, we detected moderate uptake of [(18)F]1 in baboon thalamus, a brain region lacking 5-HT1AR. We sought to investigate the relative binding of [(18)F]1 to 5-HT1AR, α1R, and 5-HT7R in vitro. Using autoradiography in human brain sections, specific binding of [(18)F]1 to 5-HT1AR was confirmed. However, [(18)F]1 also showed 26% binding to α1R in PFC. The hippocampal formation exhibited 51% and 92% binding of [(18)F]1 to α1R and 5-HT1AR, respectively. Thalamus and cerebellum showed very little binding. There is no measurable specific binding of [(18)F]1 to 5-HT7R and no effect of temperature on [(18)F]1 specific binding to 5-HT1AR or α1R. These results indicate that, while [(18)F]FECUMI-101 is not a completely selective 5-HT1AR ligand for receptor quantification, it may be useful for occupancy measurements of drugs acting at 5-HT1AR in vivo.

Biodistribution and radiation dosimetry of 11C-WAY100,635 in humans.

UNLABELLED: Serotonin 1A receptors have been implicated in a variety of conditions including depression, suicidal behavior, and aggression. Dose estimates for current human studies are based on data from rat dosimetry studies. We report the biodistribution and dosimetry of the PET serotonin 1A antagonist 11C-WAY100,635 in humans. METHODS: PET studies of 6 healthy human volunteers (3 male, 3 female) were acquired after a bolus injection of 11C-WAY100,635. Transmission scans of 3.5 min were obtained at each bed position before injection, and emission scans then were collected in 2-dimensional mode over 8 bed positions. Regions of interest were drawn around the brain, left and right lungs, heart, liver, stomach wall, gallbladder, left and right kidneys, spleen, and urinary bladder. Because no fluid was removed from the subjects, whole-body radioactivity was calculated using the injected dose and a calibration factor determined from a cylinder phantom. The area under the curve for each region of interest was determined by trapezoidal integration of the first 3 points, with subsequent points fit by a decreasing monoexponential. The area under the curve was then divided by counts in the whole body, and the resulting residence times were entered into the MIRDOSE3 program. RESULTS: Primary elimination was via kidneys to the urinary bladder. There were no sex differences in organ residence times. The urinary bladder wall was the organ with the highest estimated radiation dose (1.94 x 10(-1) +/- 3.57 x 10(-2) mGy/MBq). Except for the kidney and bladder wall, correlation was good between human dosimetry estimates and estimates reported previously from rats. The human dosimetry was 6.6 and 60.6 times higher in the kidneys and urinary bladder wall, respectively, than estimates from rats. CONCLUSION: The urinary bladder wall is the critical organ for 11C-WAY100,635 in humans. In the United States, according to Radioactive Drug Research Committee guidelines a single dose cannot exceed 300 MBq in a man and 227 MBq in a woman, with up to 3 such injections permitted per annum.

Amyloid plaque imaging agent [C-11]-6-OH-BTA-1: biodistribution and radiation dosimetry in baboon.

BACKGROUND: The amyloid neuritic plaque is considered to be a toxic collection of amyloid-ss 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.

Synthesis and initial evaluation of 17-(11)C-heptadecanoic acid for measurement of myocardial fatty acid metabolism.

UNLABELLED: Fatty acid oxidation defects are being increasingly identified as causes of abnormal heart function and sudden death in children. Children with medium-chain acyl-coenzyme A (acyl-CoA) dehydrogenase defects can metabolize fatty acids labeled in the carboxylic acid end of the compound. Accordingly, our goal was to label a long-chain fatty acid in the omega-position and evaluate its myocardial kinetics. METHODS: Heptadecanoic acid, a 17-carbon fatty acid, was labeled in the C-17 position with (11)C by the general process of coupling (11)C-methyliodide to t-butyl-15-hexadecanoate. Yield was approximately 5%-10% end-of-bombardment. Subsequently, evaluation studies were performed on isolated perfused rat hearts and in intact, anesthetized dogs. The myocardial uptake and efflux of 17-(11)C-heptadecanoic acid were compared with those of 1-(11)C-palmitate. RESULTS: With the exception of delayed efflux of tracer reflecting the temporal delay for beta-oxidation, the washout of 17-(11)C-heptadecanoic acid from the heart mirrored that of 1-(11)C-palmitate in isolated rat hearts and in intact dogs with PET. CONCLUSION: 17-(11)C-Heptadecanoic acid may be a useful tracer for the identification of defects in fatty acid metabolism in subjects with medium- and short-chain fatty acid oxidation defects.

Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635.

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 (P<0.05) 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.

Biodistribution and radiation dosimetry of [11C]DASB in baboons.

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

Autoradiographic evaluation of [3H]CUMI-101, a novel, selective 5-HT1AR ligand in human and baboon brain.

[11C]CUMI-101 is the first selective serotonin receptor (5-HT1AR) partial agonist radiotracer for positron emission tomography (PET) tested in vivo in nonhuman primates and humans. We evaluated specific binding of [3H]CUMI-101 by quantitative autoradiography studies in postmortem baboon and human brain sections using the 5-HT1AR antagonist WAY-100635 as a displacer. The regional and laminar distributions of [3H]CUMI-101 binding in baboon and human brain sections matched the known distribution of [3H]8-OH-DPAT and [3H]WAY-100635. Prazosin did not measurably displace [3H]CUMI-101 binding in baboon or human brain sections, thereby ruling out [3H]CUMI-101 binding to α1-adrenergic receptors. This study demonstrates that [11C]CUMI-101 is a selective 5-HT1AR ligand for in vivo and in vitro studies in baboon and human brain.