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Background OBJECTIVE: Caregivers of patients with advanced cancer experience significant anxiety, depression, and distress. Caregivers have barriers to accessing in-person treatment to manage stress. Technology allows for the dissemination of evidence-based interventions in a convenient way. This study examined usage rates of Pep-Pal (an evidence-based mobilized intervention to help caregivers of patients with advanced cancer manage distress) and estimates of efficacy on anxiety, depression, stress, and sexual dysfunction. Methods Fifty-six primary caregivers of patients with advanced cancer were recruited through oncology clinics and randomized to either Pep-Pal (a mobilized psychoeducation and skills-based intervention for caregivers, n= 26) or treatment as usual (TAU, n= 30). All were screened for moderate anxiety on the HADS-A screening assessment (A ≥ 8) at baseline. Results Participants randomized to Pep-Pal experienced greater reductions in perceived stress (PSS F = 3.91, p=.05), greater increases in ability to learn and use stress management skills (F = 6.16, p = 0.01), and greater increases in sexual function (women only; F = 5.07, p = 0.03) compared to participants in TAU. Of Pep-Pal participants, only 10 (38.5%) watched at least 7/9 full-length sessions. The a priori hypothesis and criterion that participants would watch at least 75% full-length sessions were not met. Conclusions A brief, easily disseminated mobile intervention showed poor adherence, but had limited estimates of efficacy for secondary outcomes; perceived stress, learning stress management skills, and sexual functioning (women only). Future directions are discussed. This article is protected by copyright. All rights reserved.

Background Psychological interventions reduce caregiver distress (CG-distress). Less distress in caregivers may contribute to improved patient quality of life (QoL), but empirical evidence is lacking. Will a caregiver stress management intervention improve patient QoL? Methods In this replication study, we randomized 155 allogeneic hematopoietic stem cell transplant (Allo-HSCT) patients and caregivers to PsychoEducation, Paced Respiration, and Relaxation (PEPRR) or enhanced treatment as usual (eTAU). We provided PEPRR over 3 months following transplant. Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) evaluated patient QoL, and CG-distress was based on depressive, anxious, and stress symptoms. Hierarchical linear models tested intervention, time, and interactions as fixed effects with participant as random effects. Results Patients whose caregivers received PEPRR did not differ on FACT-BMT between baseline and 6 months (mean = +3.74; 95% CI, -3.54 to 11.02) compared with patients of caregivers in eTAU (mean = +3.16; 95% CI, -2.88 to 9.20) even though CG-distress was decreased by PEPRR (mean = -0.23; 95% CI, -0.448 to -0.010) compared with those receiving eTAU (mean = +0.27; 95% CI, 0.033-0.504) at 6 months. Conclusions PEPRR reduced CG-distress without affecting their patient's FACT-BMT score. The FACT-BMT may not have distinguished unique psychological changes associated with their caregiver receiving PEPRR.

[11 C]Carfentanil ([11 C]CFN) is a selective radiotracer for in vivo positron emission tomography imaging studies of the μ-opioid system that, in our laboratories, is synthesized by methylation of the corresponding carboxylate precursor with [11 C]MeOTf, and purified using a C2 solid-phase extraction cartridge. Changes in the commercial availability of common C2 cartridges have necessitated future proofing the synthesis of [11 C]CFN to maintain reliable delivery of the radiotracer for clinical imaging studies. An updated synthesis of [11 C]CFN is reported that replaces a now obsolete purification cartridge with a new commercially available version and also substitutes the organic solvents used in traditional production methods with ethanol.

(−)-[18F]Flubatine was selected for clinical imaging of α4β2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (−)-[18F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (−)-[18F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [18F]fluoride in an automated synthesis module. Subsequent deprotection of the Boc group with 1-M HCl yielded (−)-[18F]flubatine, which was purified by semi-preparative HPLC. (−)-[18F]Flubatine was prepared in 25% radiochemical yield (formulated for clinical use at end of synthesis, n = 3), >95% radiochemical purity, and specific activity = 4647 Ci/mmol (171.9 GBq/µmol). Doses met all quality control criteria confirming their suitability for clinical use. Evaluation of (−)-[18F]flubatine in rhesus macaques was performed with a Concorde MicroPET P4 scanner (Concorde MicroSystems, Knoxville, TN). The brain was imaged for 90 min, and data were reconstructed using the 3-D maximum a posteriori algorithm. Image analysis revealed higher uptake and slower washout in the thalamus than those in other areas of the brain and peak uptake at 45 min. Injection of 2.5 µg/kg of nifene at 60 min initiated a slow washout of [18F]flubatine, with about 25% clearance from the thalamus by the end of imaging at 90 min. Copyright © 2013 John Wiley & Sons, Ltd.

The vesicular transporters for the monoamine and acetylcholine have been successfully targeted for the development of radioligands for human brain imaging. The vesicular monoamine transporter type 2 ligands are based on the structure of tetrabenazine, a known clinically used drug. In contrast, the radioligands for vesicular acetylcholine transporter are based on vesamicol, a toxic xenobiotic. The similarities and differences in the development of these two classes of radioligands are discussed. Copyright © 2013 John Wiley & Sons, Ltd.

Allogeneic stem cell transplantation is a common form of treatment for many types of blood cancers and requires active caregiver involvement for 100 days or longer [1]. The stress of caregiving starts before transplantation when families are preparing for the adversities of the transplant process. Caregivers are often involved in patients’ treatment prior to transplantation since most caregivers are patients’ immediate family members. As the start of transplant nears, the realities of the decision to proceed to transplant and associated risks for morbidity and mortality become increasingly concrete to the patient and caregiver. Although there is potential for significant improvement in the patients’ disease status following transplant, there remains a high level of risk with the transplant procedure. Understanding caregiver adjustment to these peri-transplant stressors is important to identify support needs and develop interventions to help caregivers meet the caregiving challenge. Caregivers of cancer patients face considerable risk regarding their own well-being. The burden of caregiving can have a significant impact on emotional, physical and social functioning [2-7], as well as immune and neuroendocrine processes [8, 9]. The patient and caregiver are closely connected in their experiences of dealing with the cancer; patient physical and psychological well-being is related to caregiver emotional and psychological well-being [10, 11]. From a systems perspective, this relationship would be bidirectional. Thus, caring for the caregiver is important for the health of the caregiver as well as the health of the patient. Despite the critical role of caregivers, only limited research has focused on the caregiver experience and even fewer studies have focused on the caregiver during the allogeneic peri-transplant period. When allogeneic transplant patients and caregivers (n=40 and n=39, respectively) were compared on their pre-transplant psychosocial and psychological functioning, patients and caregivers reported significant distress prior to transplant [12]. Relatives of autologous and allogeneic transplant recipients reported stress significantly above the norm on the General Health Questionnaire, with stress greatest before and immediately following transplant [10]. Caregivers experienced greater anxiety and depression prior to transplant than five and 20 days post-transplant [13]. In a large study of autologous transplant caregivers (n=102), caregivers reported low levels of fatigue yet moderate levels of anxiety prior to transplant compared to population norms [14]. These studies suggest distress experienced by transplant caregivers is especially acute in the period preceding and immediately following transplantation of stem cells, i.e., the peri-transplant period. However, studies are limited by small sample sizes, restrictions in outcomes assessed, and heterogeneous patient groups consisting of both autologous and allogeneic transplant recipients or only autologous patient groups who present different caregiver challenges than allogeneic caregivers. The purpose of this study was to describe the peri-transplant psychological status in a sample of caregivers of allogeneic transplant patients using measures of mood, perceived stress, sleep, and caregiving burden while determining if demographic or patient illness characteristics prior to transplant predicted levels of caregiver distress. We predicted that caregiver sex, age and patient status would contribute to overall peri-transplant caregiver distress. We hypothesized that female caregivers and younger caregivers would experience more distress than male or older caregivers.

Background Patient navigation (PN) is a method for addressing racial–ethnic and socioeconomically based disparities in cancer-related care. Patient navigators provide logistic and emotional support to underserved patients to facilitate successful completion of diagnostic and treatment care. Yet, little is known about patient satisfaction with the relationship with a navigator due to a dearth of instruments measuring satisfaction. Objective The objective of this study was to validate the Patient Satisfaction with Interpersonal Relationship with Navigator (PSN-I) measure for patients undergoing diagnostic and/or therapeutic cancer care. Methods We administered the PSN-I to 783 participants from the nine different sites of the National Cancer Institute sponsored Patient Navigation Research Program. We evaluated the latent structure and internal consistency of the PSN-I using principal components analysis (PCA) and Cronbach coefficient alpha (α), respectively. We used correlation analyses to examine divergence and convergence of the PSN-I with the Patient Satisfaction with Cancer-related Care (PSCC), the Rapid Estimate of Adult Literacy in Medicine (REALM) Long Form, and patients' demographics. Results The PCA revealed a coherent set of items that explicates 76.6% of the variance in PSN-I. Reliability assessment revealed high internal consistency (α ranging from 0.95 to 0.96). The PSN-I had good face validity as well as convergent and divergent validities as indicated by moderate correlations with score on the PSCC (all ps 0.05). Conclusion The PSN-I is a valid and suitable measure of satisfaction with a patient navigator for the present sample. Copyright © 2011 John Wiley & Sons, Ltd.

The significant threats to the fewer than 30 wild Dicerorhinus sumatrensis harrissoni, the Bornean sub-species of the Sumatran rhinoceros, are obvious and include poaching, habitat loss, and environmental changes. Subtle effects on population survival, however, include nutritional or other diseases, which affect morbidity and reproductive success. To address these issues and focus on animals within their natural range, this feeding trial and analysis characterizes the diet fed to the only three captive D. s. harissoni in the world housed at the Sumatran Rhino Breeding Center (SRBC) in Sabah, Malaysia. The study provides an indication of the variance in nutrient composition in local browse, and a comparison with other captive feeding studies. Mean dry matter intake (DMI), comprising ∼90% native browse species, equaled 3.55% (range=2.8–4.1%) of body mass, with a dry matter digestibility averaging 82%. The mean crude protein content of native browses (n=8 spp.) averaged 11.2% (DM basis; range=5–23%, depending on plant part), with available protein measured at 7.8%. Leaves contained significantly (P

We recently reported the synthesis and binding affinity of ligands for the muscarinic acetylcholine receptor (mAChR) based on both the pyrrolidyl and piperidyl benzilate scaffold. One of these, (R)-3-pyrrolidyl benzilate, was successfully radiolabeled with [(11)C]methyl triflate and the resulting compound, (R)-N-[(11)C]methyl-3-pyrrolidyl benzilate (3-[(11)C]NMPYB), was evaluated as a reversible, acetylcholine-sensitive tracer for the mAChR (K(i) of unlabeled 3-NMPYB is 0.72 nM). This compound displayed high, receptor-mediated retention in regions of the mouse and rat brain known to have high concentrations of mAChRs. Moreover, bolus studies in a pigtail monkey showed that this compound had superior clearance from the brain when compared to muscarinic radiotracers previously employed in human PET studies. Infusion studies in the same monkey revealed that it was possible to achieve equilibrium of radiotracer distribution for 3-[(11)C]NMPYB in both the striatum and cortex. Sensitivity to endogenous acetylcholine levels was evaluated by injecting phenserine (5 mg/kg) into rats prior to administration of 3-[(11)C]NMPYB in an equilibrium infusion protocol. This pretreatment produced a modest, statistically significant decrease (9-11%) in the distribution volume ratios for muscarinic receptor rich regions of the rat brain as compared to controls.

In the course of developing microcalorimeters as detectors for astronomical X-ray spectroscopy, we have undertaken an empirical characterization of non-ideal effects in the doped semiconductor thermometers used with these detectors, which operate at temperatures near 50 mK. We have found three apparently independent categories of such behavior that are apparently intrinsic properties of the variable-range hopping conduction mechanism in these devices: 1/f fluctuations in the resistance, which seems to be a 2D effect; a departure from the ideal coulomb-gap temperature dependence of the resistance at temperatures below T 0 /24; and an electrical nonlinearity that has the time dependence and extra noise that are quantitatively predicted by a simple hot electron model. This work has been done largely with ion-implanted Si:P:B, but similar behaviors have been observed in transmutation doped germanium.

[11C]Paraquat was synthesized by the reaction of [11C]methyl triflate with the mono-triflate salt of 1-methyl-[4,4′]bipyridinyl. The product was selectively separated from the precursor by a microcolumn of Chelex 100 ion exchange resin. The method was applied to the synthesis of a variety of [N-methyl-11C]bisquaternary ammonium compounds. This is the first reported use of a chelating cation exchange resin for the selective purification of organic dications. Copyright © 2002 John Wiley & Sons, Ltd.

The nociceptin receptor (NOP) has been investigated as a potential therapeutic target for pain control. Nociceptin, the endogenous ligand for NOP, produces analgesia in rodents and primates when gi...

The current study investigated the impact of a severe environmental stressor and the role that declining social integration played in mediating its effect on loneliness and immune status. Increased loneliness and decreased social support in the months following the stressor (storm) were significantly associated with increased HHV-6 antibody titers, reflecting poorer control over the virus. Poorer social integration mediated the relationship between loneliness and HHV-6, even after controlling for nonspecific polyclonal B-cell activation, disease status (CD3+CD4+ cell counts), living arrangements, acute social losses (bereavement), and potential disruptions in social-support resources. These findings suggest that specific elements of social support may explain the oft-noted negative effects of loneliness on the immune system, and generalized to a medically vulnerable population.

Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examined the feasibility of utilizing ( 11 C)N-methyl-4- piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes associated with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examined the concentration of muscarinic receptors with ( 11 C)NMPB and PET using two- and three- compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was associ- ated with a reduction in muscarinic receptor binding in neocortical regions and thala- mus. In AD patients, the three-compartment model appeared capable of dissociating changes in tracer transport from changes in receptor binding, but suffered from statis- tical uncertainty, requiring normalization to a reference region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concentrations were observed in AD. Synapse 39:275-287, 2001. © 2001 Wiley-Liss, Inc.

Based on surrogate assays of peripheral red blood cells, reports state that widely prescribed doses of donepezil hydrochloride provide nearly complete inhibition of cerebral cortical acetylcholinesterase activity in the treatment of Alzheimer's disease (AD). To test this, direct positron emission tomography measures of cerebral acetylcholinesterase activity were made in AD patients before and after treatment with donepezil (5 and 10 mg/day) for at least 5 weeks and compared with similar measures in normal controls who were untreated or after acute administration of another AChE inhibitor, physostigmine salicylate (1.5 mg/hr). After physostigmine, acetylcholinesterase inhibition averaged 52% in normal cerebral cortex. After donepezil, cerebral cortical inhibition in AD brain averaged only 27%. Clinical trials of this donepezil dose schedule are not testing the effect of nearly complete cerebral cortical inhibition.

The dose- and time-dependent changes of in vivo radioligand binding to the neuronal membrane dopamine transporter (DAT) and vesicular monoamine trans- porter type 2 (VMAT2) were examined in mouse brain after MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) administrations. Regional brain distribution studies were done in male C57BL/6 mice using simultaneous injections of d-threo-( 3 H)methylpheni- date (DAT) and (1)-a-( 11 C)dihydrotetrabenazine (VMAT2). Single (55 mg/kg i.p.) or multiple (4 3 10 mg/kg i.p., 1-hour intervals) administration of MPTP caused significant reductions in ( 3 H)methylphenidate and ( 11 C)dihydrotetrabenazine specific striatal bind- ing, measured 14 days later. The single high dose of MPTP produced greater losses of ( 11 C)dihydrotetrabenazine binding than did the multiple MPTP dosing regimen. Using the single high dose of MPTP, changes of in vivo binding of the two radioligands were determined at 1, 3, and 14 days after neurotoxin injection. At 1 day, there are large losses of ( 3 H)methylphenidate binding (DAT) but no changes in ( 11 C)dihydrotetrabenazine binding to the VMAT2 site in the striatum. At 3 and 14 days, there were .50% losses of binding of both bot radioligands, but significantly (P , 0.001) greater losses of VMAT2 binding of ( 11 C)dihydrotetrabenazine. These studies indicate that the losses of the neuronal membrane and vesicular transporters are not always equal, and do not occur in the same time frame, after administration of the neurotoxin MPTP. Synapse 35:250

Deficits in Complex I (NADH-ubiquinone oxidoreductase) of the electron transport chain may play an important role in the inception and progression of neurodegenerative diseases such as Parkinson's disease. In vivo imaging of Complex I offers a unique method for evaluation of these changes in living human brain. Previous carbon-11 labeled rotenoids showed promising results, but were prepared as mixtures of stereoisomers at the 5'-position. We report here the stereospecific syntheses of (-)-6',7'-[ 11 C]dihydroroten-12α-ol ((-)-[ 11 C]DHROL), a modified rotenoid with in vitro affinity for Complex I. O-[ 11 C]methylation of the appropriate desmethyl precursor provided (-)-[ 11 C]DHROL in an average radiochemical yield, corrected to end of bombardment, of 27% (n = 4) and >99% radiochemical purity. In mice, (-)-[ 11 C]DHROL gave a high and uniform brain uptake similar to that obtained with prior radiolabeled rotenoids. Further in vivo evaluation of (-)-[ 11 C]DHROL in rats with unilateral quinolinic acid-induced striatal lesions showed significant losses of radioligand binding after neurotoxin treatment (lesion/unlesioned ratio of 0.66). As this reduction of in vivo radioligand binding is very similar to that obtained previously with the mixture of [ 11 C]DHROL isomers, the stereochemistry at the 5'-position of [ 11 C]DHROL does not significantly influence the in vivo applications of this radiotracer.

Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (-)-[18F] FEOBV,(-)-(2R,3R)-trans-2-hydroxy-3-(4-phenylpiperidino)-5-(2-[18F ]fluoroethoxy)-1,2,3,4-tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (-)-[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare-like effects of FEOBV were associated with the "(-)"-enantiomer exclusively. (-)-[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)-3-PPP, or E-2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or sigma receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (-)-[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (-)-[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET.

The effects of MPTP treatment (4 3 10 mg/kg, 2-h intervals) on in vivo striatal binding of (1)-a-( 3 H)dihydrotetrabenazine ((1)-( 3 H)DTBZ) to the vesicular monoamine transporter type 2 (VMAT2) were examined in wild type (1,1) and tottering (tg/tg) mice of the C57BL/6J strain. The tottering mutant has been previously character- ized as having hyperinnervation of noradrenergic terminals in the brain, with increased concentrations of norepinephrine and increased numbers of VMAT2 binding sites. In wild-type mice, MPTP caused a significant decrease in specific striatal (1)-( 3 H)DTBZ binding in both males (-71%) and females (-57%), consistent with dopaminergic terminal losses. In the tottering mice, the neurotoxic effects of MPTP were diminished, with smaller losses of (1)-( 3 H)DTBZ binding observed both in males (-45%) and females (-26%). These results are consistent with the hypothesis that vesicular storage (as a result of hyperinnervation) offers neuroprotection toward MPTP toxicity, although the confounding effects of increases in norepinephrine concentrations or changes in calcium ion channel function (both also characteristics of the tottering mutant) cannot be ruled out. The tottering mutant does, however, offer another animal model to examine the biochemical features responsible for MPTP toxicity. Synapse 30:205-210, 1998.

Chiral column liquid chromatography and enantiospecific enzymatic hydrolysis were utilized to separate the enantiomers of alpha- and beta-dihydrotetrabenazine and alpha-9-O-desmethyldihydrotetrabenazine, three benzo[a]quinolizines derived from the amine-depleting drug tetrabenazine. An X-ray crystal structure analysis of (-)-alpha-9-O-desmethyldihydrotetrabenazine gave an absolute structure of that compound as the 2S, 3S, 11bS isomer. Therefore, (-)-alpha-dihydrotetrabenazine also has the 2S, 3S, 11bS absolute configuration. (+)-alpha-Dihydrotetrabenazine, the single biologically active isomer from the metabolic reduction of tetrabenazine, thus has the absolute configuration of 2R, 3R, 11bR. For further in vitro and in vivo studies of the vesicular monoamine transporter, it is now possible to use the single enantiomer of radiolabeled alpha-dihydrotetrabenazine.

Two esters, N-[11C]methylpiperidyl acetate ([11C]AMP) and N-[11C]methylpiperidyl propionate ([11C]PMP), were synthesized in no-carrier-added forms and evaluated as in vivo substrates for brain acetylcholinesterase (AChE). After peripheral injection in mice, each ester showed rapid penetration into the brain and a regional retention of radioactivity (striatum > cortex, hippocampus > cerebellum) reflecting known levels of AChE activity in the brain. Regional brain distributions after [11C]PMP administration showed better discrimination between regions of high, intermediate, and low AChE activities. Chromatographic analysis of blood and brain tissue extracts showed rapid and nearly complete hydrolysis of [11C]PMP within 10 min after injection. For both [11C]AMP and [11C]PMP, retention of radioactivity in all regions was reduced by pretreatment with diisopropylfluorophosphate (DFP), a specific irreversible AChE inhibitor. DFP treatment also significantly increased the proportions of unhydrolyzed ester in both blood and brain. Radioactivity localization in brain after peripheral injection was thus dependent on AChE-catalyzed hydrolysis to the hydrophilic product N-[11C]methylpiperidinol. PET imaging of [11C]AMP or [11C]PMP distributions in monkey brain showed clear accumulation of radioactivity in areas of highest AChE activity (striatum, cortex). These esters are thus in vivo substrates for brain AChE, with potential applications as in vivo imaging agents of enzyme action in the human brain. [11C]PMP, the ester with a slower rate of hydrolysis, appears to be the better candidate radiotracer for further development.

We have synthesized the fluorine-18 labeled derivative of N-tert-butyl-α-phenylnitrone (PBN), a free radical spin trapping agent widely used with electron spin resonance (ESR). N-tert-Butyl-α-(4-[ 18 F]fluorophenyl)-nitrone ([ 18 F]FPBN) could be prepared with low radiochemical yield (3% decay corrected) by the direct aromatic nucleophilic substitution of N-tert-butyl-α-(4-nitrophenyl)nitrone with [ 18 F]fluoride. An alternate two step synthesis route consisted of the nucleophilic [ 18 F]fluoride substitution of 4-N,N,N-trimethylammoniumbenzaldehyde triflate to yield 4-[ 18 F]fluorobenzaldehyde, which was distilled into a vial containing N-tert-butylhydroxylamine in 2N NaOH. 4-[ 18 F]Fluorobenzaldehyde readily reacted with the hydroxylamine to form [ 18 F]FPBN. [ 18 F]FPBN was obtained in overall decay corrected yields of 24% in a total synthesis time

SUMMARY Prolyl endopeptidase (PEP: [E.C.3.4.21.26]) is a widely distributed serine peptidase that cleaves a variety of oligopeptides in the brain and peripheral tissues. Y-29794 ((2-(8-dimethylaminooctylthio)-6-isopropyl-3pyridyl-2-thienyl ketone) is a potent competitive reversible inhibitor of this enzyme. In order to study the biodistribution of PEP in vivu we have synthesized (N-" C]methyl)Y-29794, by [11C]alkylation of the Ndesmethyl precursor. The radiotracer was purified by silica gel Sep-Pak and was obtained in 10-17% yields (EOB: synthesis times shorter than 45 min) with >98% radiochemical purities and specific activities >550 Ci/mmol (EOS).

The synthesis of the 4-[11 C]methylamino derivative of N-{N-[4-(4-Aminophenyl)butyryl]-L-prolyl}pyrrolidine (SUAM-1221), is described as a potential marker for prolyl endopeptidase for in vivo positron emission tomography studies. Direct methylation of the 4-amino derivative of SUAM-1221 (1) with methyl iodide provided a mixture of the 4-monomethyl (2) and 4-dimethylamino (3) derivatives which were separated by chromatography. Methylation of 1 with [11 C]methyl iodide provided the 4-[11C]methylamino derivative of SUAM-1221, ([11C]2), in 18–30% decay corrected radiochemical yield after HPLC purification, with a specific activity > 1700 Ci/mmol and a 40 minute synthesis time from end of bombardment.

The design, synthesis and biological activities of several acyclonucleoside analogues related to misoni-dazole are described. The hydroxy-5, bromo-6, iodo-7, and fluoro-8 derivatives of ethoxymethylazomycin and iodopropenyloxymethylazomycin (12) have been prepared. Alkylation of silylated azomycin with haloethoxy-methylene chloride gave the corresponding acyclonucleosides. Similarly, propargyloxymethylene chloride gave propargyloxymethylazomycin (10), which after hydrostannylation and subsequent iododestannylation yielded iodopropenyloxymethylazomycin (12). The radiolabeled [125I] or [18F] compounds were prepared from the corresponding substrates. Biodistribution results of the radiolabeled analogues in mice showed that compound 7 had good tumor uptake (2.0% injected dose/g at 1 hour). The high radioactive levels in blood and stomach, however, were perhaps due to in vivo deiodination or metabolism. Compound [125I]-12 showed the highest tumor uptake (4.8 and 3.6% injected dose/g at 1 and 4 hours respectively) of all of the compounds tested. Relatively low thyroid uptake of radioactivity in mice dosed with compound [125I]-12 indicates significantly reduced in vivo deiodination in comparison to compound [125I]-7.

Full experimental details are given for the preparation of [18F]fluoroethoxy-benzovesamicol, (−)-(2R, 3R)-trans-2-hydroxy-3-(4-phenylpiperidino)-5-(2-[18F]fluoroethoxy)-1,2,3,4-tetralin, a new fluorine-18 labeled cholinergic neuron mapping agent for use in positron emission tomography (PET). This radiotracer was made by nucleophilic radiofluorination of tosyloxyethoxy-benzovesamicol, followed by reverse phase HPLC purification, in decay corrected radiochemical yield exceeding 60%.

SUMMARY The correlation between the 1%-NMR chemical shift of the aromatic ring carbon bearing the leaving group and the yield of nucleophilic aromatic displacement with no-carrier-added [ 18Flfluoride ion was evaluated. In comparison of structurally analogous compounds (fluoro, nitro and trimethylammonium substituted benzaldehydes, benzophenones and benzonitriles), the 13C-NMR chemical shift of the reactive aryl ring carbon correlated quite well with the [18F]fluorination yield (r2 = 0.87) for most but not all ring structures. Compounds with trimethylammonium leaving groups or methyl ring substituents were found to not fit the proposed correlation. Kinetic studies indicated clearly different rates of reaction for these compounds, with much higher than expected reactivity for the ccompounds with the cationic leaving group. Competition experiments suggest that low reactivity of methylsubstituted rings may be due to conversion of [18F[fluoride to an unreactive form. Our results indicate that the correlation between [W'Jfluorination yields for nucleophilic aromatic substitution reactions and the 1% NMR chemical shift of the aryl ring carbon bearing the leaving group is applicable to numerous structurally analogous compounds, but cannot be simply generalized to aromatic rings with different leaving groups or ring substituents.

SUMMARY Fluorine-18 labeled l,l-difluoro-2,2-dichloroethyl aryl ethers have been prepared by a facile 18F-for-19F isotopic exchange reaction. The isotopic exchange proceeds in good to excellent yields (up to 85%), and is dependent on reaction time, temperature, and concentration of reactants (aryl ether or fluoride ion). Substitution even occurs at room temperature in DMSO, and at elevated temperature (100 to 155 OC) in DMSO or acetonitrile containing up to 20% water. Specific activities of 0.5-55 Ci/mol have been achieved, with the products obtained in pure radiochemical and chemical form.

We studied the binding of [18F]GBR 13119 (1-[[(4-[18F]fluorophenyl) (phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine) to rat brain with autoradiography after intravenous injection. The rank order of binding was dorsal striatum greater than nucleus accumbens = olfactory tubercle greater than substantia nigra = ventral tegmental area greater than other areas. Binding was blocked by prior injection of dopamine uptake blockers but not by injection of dopamine receptor antagonists or drugs that bind to the dialkylpiperazine site. Unilateral 6-hydroxy-dopamine lesions of dopamine neurons caused a marked decrease in striatal and nigral binding on the side of the lesion. We conclude that intravenous injection of [18F]GBR 13119 provides a useful marker of presynaptic dopamine uptake sites.

Preparation of no-carrier-added fluorine-18 labeled GBR 12909 (1-[2-(bis(4-fluorophenyl)methoxy)ethyl]-4-(3-phenylpropyl)piperazine), a specific and high affinity inhibitor of dopamine reuptake, is described. 4-Fluoro-4′-[18F]fluorobenzophenone was prepared by [18F]fluoride ion substitution of the corresponding trimethylammonium trifluoromethanesulfonate salt. The [18F]benzophenone was reduced to the benzhydrol, chlorinated, then used to alkylate 1-(2-hydroxyethyl)-4-(3-phenyl-propyl)piperazine to yield [18F]GBR 12909 in high specific activity (≥2000 Ci/mmol) and overall yields of 10–16% (corrected, 140 min synthesis).