High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals.

Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched (72)Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure (72)As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming (72)Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation.

A dual-tracer study of extrastriatal 6-[18F]fluoro-m-tyrosine and 6-[18F]-fluoro-L-dopa uptake in Parkinson's disease.

6-[(18)F]-Fluoro-L-dopa (FDOPA) has been widely used as a biomarker for catecholamine synthesis, storage, and metabolism--its intense uptake in the striatum, and fainter uptake in other brain regions, is correlated with the symptoms and pathophysiology of Parkinson's disease (PD). 6-[(18)F]fluoro-m-tyrosine (FMT), which also targets L-amino acid decarboxylase, has potential advantages over FDOPA as a radiotracer because it does not form catechol-O-methyltransferase (COMT) metabolites. The purpose of the present study was to compare the regional distribution of these radiotracers in the brains of PD patients. Fifteen Parkinson's patients were studied with FMT and FDOPA positron emission tomography (PET) as well as high-resolution structural magnetic resonance imaging (MRI). MRI's were automatically parcellated into neuroanatomical regions of interest (ROIs) in Freesurfer (http://surfer.nmr.mgh.harvard.edu); region-specific uptake rate constants (Kocc) were generated from coregistered PET using a Patlak graphical approach. The essential findings were as follows: (1) regional Kocc were highly correlated between the radiotracers and in agreement with a previous FDOPA studies that used different ROI selection techniques; (2) FMT Kocc were higher in extrastriatal regions of relatively large uptake such as amygdala, pallidum, brainstem, hippocampus, entorhinal cortex, and thalamus, whereas cortical Kocc were similar between radiotracers; (3) while subcortical uptake of both radiotracers was related to disease duration and severity, cortical uptake was not. These results suggest that FMT may have advantages for examining pathologic changes within allocortical loop structures, which may contribute to cognitive and emotional symptoms of PD.

Moderate-level prenatal alcohol exposure induces sex differences in dopamine d1 receptor binding in adult rhesus monkeys.

BACKGROUND: We examined the effects of moderate prenatal alcohol exposure and/or prenatal stress exposure on (D1 R) binding in a non human primate model. The dopamine D1 R is involved in executive function, and it may play a role in cognitive behavioral deficits associated with prenatal alcohol and/or stress exposure. Little is known, however, about the effects of prenatal alcohol and/or stress exposure on the D1 R. We expected that prenatal insults would lead to alterations in D1 R binding in prefrontal cortex (PFC) and striatum in adulthood. METHODS: Rhesus macaque females were randomly assigned to moderate alcohol exposure and/or mild prenatal stress as well as a control condition during pregnancy. Thirty-eight offspring were raised identically and studied as adults by noninvasive in vivo neuroimaging using positron emission tomography with the D1 antagonist radiotracer [(11) C]SCH 23390. Radiotracer binding in PFC and striatum was evaluated by 2 (alcohol) × 2 (stress) × 2 (sex) analysis of variance. RESULTS: In PFC, a significant alcohol × sex interaction was observed with prenatal alcohol exposure leading to increased [(11) C]SCH 23390 binding in male monkeys. No main effect of prenatal alcohol or prenatal stress exposure was observed. CONCLUSIONS: These results suggest that prenatal alcohol exposure results in long-term increases in prefrontal dopamine D1 R binding in males. This may help explain gender differences in the prevalence of neurodevelopmental disorders consequent to prenatal alcohol exposure.

A within-subject comparison of 6-[18F]fluoro-m-tyrosine and 6-[18F]fluoro-L-dopa in Parkinson's disease.

Progression of Parkinson's disease symptoms is imperfectly correlated with positron emission tomography biomarkers for dopamine biosynthetic pathways. The radiopharmaceutical 6-[(18) F]fluoro-m-tyrosine is not a substrate for catechol-O-methyltransferase and therefore has a more favorable uptake-to-background ratio than 6-[(18) F]fluoro-L-dopa. The objective of this study was to evaluate 6-[(18) F]fluoro-m-tyrosine relative to 6-[(18) F]fluoro-L-dopa with partial catechol-O-methyltransferase inhibition as a biomarker for clinical status in Parkinson's disease. Twelve patients with early-stage Parkinson's disease, off medication, underwent Unified Parkinson Disease Rating Scale scoring, brain magnetic resonance imaging, and 3-dimensional dynamic positron emission tomography using equivalent doses of 6-[(18) F]fluoro-m-tyrosine and 6-[(18) F]fluoro-L-dopa with tolcapone, a catechol-O-methyltransferase inhibitor. Images were realigned within subject, after which the tissue-derived uptake rate constant was generated for volumes of interest encompassing the caudate nucleus, putamen, and subregions of the putamen. We computed both bivariate (Pearson) and partial (covariate of age) correlations between clinical subscores and tissue-derived uptake rate constant. Tissue-derived uptake rate constant values were correlated between the radiopharmaceuticals (r = 0.8). Motor subscores were inversely correlated with the contralateral putamen 6-[(18) F]fluoro-m-tyrosine tissue-derived uptake rate constant (|r| > 0.72, P < .005) but not significantly with the 6-[(18) F]fluoro-L-dopa tissue-derived uptake rate constant. The uptake rate constants for both radiopharmaceuticals were also inversely correlated with activities of daily living subscores, but the magnitude of correlation coefficients was greater for 6-[(18) F]fluoro-m-tyrosine. In this design, 6-[(18) F]fluoro-m-tyrosine uptake better reflected clinical status than did 6-[(18) F]fluoro-L-dopa uptake. We attribute this finding to 6-[(18) F]fluoro-m-tyrosine's higher affinity for the target, L-aromatic amino acid decarboxylase, and the absence of other major determinants of the uptake rate constant. These results also imply that L-aromatic amino acid decarboxylase activity is a major determinant of clinical status.

Improved production of 76Br, 77Br and 80mBr via CoSe cyclotron targets and vertical dry distillation.

INTRODUCTION: The radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76Br, 77Br, and 80mBr. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein. METHODS: 76Br, 77Br, and 80mBr were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co76Se, Co77Se, and Co80Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination. RESULTS: Cyclotron production yields were 103 ±â€¯10 MBq∙µA-1∙h-1 for 76Br, 88 ±â€¯10 MBq∙µA-1∙h-1 for 80mBr at 16 MeV and 17 ±â€¯1 MBq∙µA-1∙h-1 for 77Br at 13 MeV. Radiobromide isolation yields were 76 ±â€¯11% in a small volume of aqueous solution. The synthesized 77Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/µmol at end of synthesis. CONCLUSIONS: A novel selenium alloy target enabled clinical-scale production of 76Br, 77Br, and 80mBr with high apparent molar activities, which was used to for the production of a new 77Br-labeled inhibitor of PARP-1. ADVANCES IN KNOWLEDGE: New methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77Br by a factor of three and 76Br by a factor of six compared with previous methods. IMPLICATIONS FOR PATIENT CARE: Preclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co77Se.

PET Measures of D1, D2, and DAT Binding Are Associated With Heightened Tactile Responsivity in Rhesus Macaques: Implications for Sensory Processing Disorder.

Sensory processing disorder (SPD), a developmental regulatory condition characterized by marked under- or over-responsivity to non-noxious sensory stimulation, is a common but poorly understood disorder that can profoundly affect mood, cognition, social behavior and adaptive life skills. Little is known about the etiology and neural underpinnings. Clinical research indicates that children with SPD show greater prevalence of difficulties in complex cognitive behavior including working memory, behavioral flexibility, and regulation of sensory and affective functions, which are related to prefrontal cortex (PFC), striatal, and midbrain regions. Neuroimaging may provide insight into mechanisms underlying SPD, and animal experiments provide important evidence that is not available in human studies. Rhesus monkeys (N = 73) were followed over a 20-year period from birth into old age. We focused on a single sensory modality, the tactile system, measured at 5-7 years, because of its critical importance for nourishment, attachment, and social reward in development. Positron emission tomography imaging was conducted at ages 12-18 years to quantify the availability of the D1 and D2 subtypes of the DA receptor (D1R and D2R), and the DA transporter (DAT). Heightened tactile responsivity was related to (a) elevated D1R in PFC overall, including lateral, ventrolateral, medial, anterior cingulate (aCg), frontopolar, and orbitofrontal (OFC) subregions, as well as nucleus accumbens (Acb), (b) reduced D2R in aCg, OFC, and substantia nigra/ventral tegmental area, and (c) elevated DAT in putamen. These findings suggest a mechanism by which DA pathways may be altered in SPD. These pathways are associated with reward processing and pain regulation, providing top-down regulation of sensory and affective processes. The balance between top-down cognitive control in the PFC-Acb pathway and bottom-up motivational function of the VTA-Acb-PFC pathway is critical for successful adaptive function. An imbalance in these two systems might explain DA-related symptoms in children with SPD, including reduced top-down regulatory function and exaggerated responsivity to stimuli. These results provide more direct evidence that SPD may involve altered DA receptor and transporter function in PFC, striatal, and midbrain regions. More work is needed to extend these results to humans.

Positron-emitting resin microspheres as surrogates of 90Y SIR-Spheres: a radiolabeling and stability study.

Commercially available resin microspheres and SIR-Spheres were labeled with metallic positron emitters and evaluated as positron emission tomography (PET) imaging surrogates of (90)Y SIR-Spheres. Radiolabeling was performed using a batch method, and in vitro stability over 24 h was evaluated in saline at physiological pH at 37 degrees C. The activity per microsphere distribution, as evaluated by autoradiography, showed the activity per microsphere to be proportional to the square radius of the spheres, suggesting surface binding. The in vivo stability of radiolabeling was evaluated in rats by micro-PET imaging after the intravenous injection of labeled microspheres. The different resin microspheres and radionuclides evaluated in this study all showed good radiolabeling efficiency and in vitro stability. However, only resins labeled with (86)Y and (89)Zr proved to have the in vivo stability required for clinical applications.

Sensory processing disorders in a nonhuman primate model: evidence for occupational therapy practice.

Evaluation of sensory processing function serves as a critical component of treatment planning and implementation of intervention in pediatric occupational therapy practice. We developed a Sensory Processing Scale for Monkeys (SPS-M), based on human tests, that measures behavioral responses to a series of tactile stimuli. This assessment has been used to assess sensory processing in adult rhesus monkeys exposed to prenatal alcohol, stress, or postnatal lead. Control monkeys from undisturbed pregnancies showed a habituation pattern, prenatally stressed monkeys showed sensitization, and prenatal alcohol-exposed monkeys showed relatively high responsiveness without habituation across trials. Lead-exposed monkeys showed sensitization compared to nonlead-exposed controls, and chelation reduced the sensitization in lead-exposed animals. Aversive responsiveness was associated with up-regulated striatal dopamine receptor binding measured with positron emission tomography.

Chemical Consequences of Radioactive Decay and their Biological Implications.

The chemical effects of radioactive decay arise from (1) transmutation, (2) formation of charged daughter nuclei, (3) recoil of the daughter nuclei, (4) electron "shakeoff" phenomenon and (5) vacancy cascade in decays via electron capture and internal conversion. This review aims to reiterate what has been known for a long time regarding the chemical consequences of radioactive decay and gives a historical perspective to the observations that led to their elucidation. The energetics of the recoil process in each decay mode is discussed in relation to the chemical bond between the decaying nucleus and the parent molecule. Special attention is given to the biological effects of the Auger process following decay by electron capture and internal conversion because of their possible utility in internal radiotherapy.

Intrinsic and Stable Conjugation of Thiolated Mesoporous Silica Nanoparticles with Radioarsenic.

The development of new image-guided drug delivery tools to improve the therapeutic efficacy of chemotherapeutics remains an important goal in nanomedicine. Using labeling strategies that involve radioelements that have theranostic pairs of diagnostic positron-emitting isotopes and therapeutic electron-emitting isotopes has promise in achieving this goal and further enhancing drug performance through radiotherapeutic effects. The isotopes of radioarsenic offer such theranostic potential and would allow for the use of positron emission tomography (PET) for image-guided drug delivery studies of the arsenic-based chemotherapeutic arsenic trioxide (ATO). Thiolated mesoporous silica nanoparticles (MSN) are shown to effectively and stably bind cyclotron-produced radioarsenic. Labeling studies elucidate that this affinity is a result of specific binding between trivalent arsenic and nanoparticle thiol surface modification. Serial PET imaging of the in vivo murine biodistribution of radiolabeled silica nanoparticles shows very good stability toward dearsenylation that is directly proportional to silica porosity. Thiolated MSNs are found to have a macroscopic arsenic loading capacity of 20 mg of ATO per gram of MSN, sufficient for delivery of chemotherapeutic quantities of the drug. These results show the great potential of radioarsenic-labeled thiolated MSN for the preparation of theranostic radiopharmaceuticals and image-guided drug delivery of ATO-based chemotherapeutics.

Mathematical modeling of positron emission tomography (PET) data to assess radiofluoride transport in living plants following petiolar administration.

BACKGROUND: Ion transport is a fundamental physiological process that can be studied non-invasively in living plants with radiotracer imaging methods. Fluoride is a known phytotoxic pollutant and understanding its transport in plants after leaf absorption is of interest to those in agricultural areas near industrial sources of airborne fluoride. Here we report the novel use of a commercial, high-resolution, animal positron emission tomography (PET) scanner to trace a bolus of [(18)F]fluoride administered via bisected petioles of Brassica oleracea, an established model species, to simulate whole plant uptake of atmospheric fluoride. This methodology allows for the first time mathematical compartmental modeling of fluoride transport in the living plant. Radiotracer kinetics in the stem were described with a single-parameter free- and trapped-compartment model and mean arrival times at different stem positions were calculated from the free-compartment time-activity curves. RESULTS: After initiation of administration at the bisected leaf stalk, [(18)F] radioactivity climbed for approximately 10 minutes followed by rapid washout from the stem and equilibration within leaves. Kinetic modeling of transport in the stem yielded a trapping rate of 1.5 +/- 0.3%/min (mean +/- s.d., n = 3), velocity of 2.2 +/- 1.1 cm/min, and trapping fraction of 0.8 +/- 0.5%/cm. CONCLUSION: Quantitative assessment of physiologically meaningful transport parameters of fluoride in living plants is possible using standard positron emission tomography in combination with petiolar radiotracer administration. Movement of free fluoride was observed to be consistent with bulk flow in xylem, namely a rapid and linear change in position with respect to time. Trapping, likely in the apoplast, was observed. Future applications of the methods described here include studies of transport of other ions and molecules of interest in plant physiology.

Time profile of cerebral [18F]6-fluoro-L-DOPA metabolites in nonhuman primate: implications for the kinetics of therapeutic L-DOPA.

At least two rates of dopamine turnover have been demonstrated in vivo, including a slow turnover rate that is associated with synaptic vesicles, and a faster rate that leads to rapid production of dopamine metabolites. Similarly, [18F]6-fluorodopamine (FDA), the decarboxylation product of the PET tracer [18F]6-fluoro-L-DOPA (FDOPA), may have multiple turnover rates which could substantially affect the interpretation of FDOPA uptake. To better characterize FDA turnover in vivo, we measured the formation of FDOPA metabolites in primate brain following bolus FDOPA injection with carbidopa pretreatment. FDOPA was allowed to circulate for either 30 minutes or 90 minutes, prior to removal of brain samples. The primary metabolites in striatum were [18F]6-fluoro-3-methyl-L-DOPA (3-OMFD), FDA, [18F]6-fluoro- L-3,4-dihydroxyphenylacetic acid (FDOPAC), and [18F]6-fluorohomovanillic acid (FHVA). The percentages of total radioactivity in striatum at 30 minutes and 90 minutes were: FDOPA(5%, 2%), FDA (39%, 23%), FDOPAC (12%, 3%), FHVA (14%, 34%), and 3-OMFD (29%, 39%). In cortex and cerebellum most of the activity (73%, 80%) was 3-OMFD. These data were compared against the metabolite profiles predicted by two compartmental models of FDOPA metabolism. A model that assumes only a single slow rate of FDA turnover predicted much lower concentrations of FDA metabolites (FDOPAC, FHVA) in striatum than were found in the brain assay, while a model that includes both slow and fast FDA turnover was in much better agreement. These findings extend and confirm previous observations of FDOPA metabolites. The implications for the interpretation of FDOPA PET, particularly in terms of the availability of dopamine synthesized from therapeutic L-DOPA, are discussed.

The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model.

The question of whether psychosocial stress during pregnancy (alone or in combination with fetal alcohol exposure) has negative consequences for offspring has not been clearly established in human studies. In this article, we present an overview of three prospective longitudinal studies. Using rhesus monkeys as subjects, a noise or hormone stressor, alone or in combination with moderate level alcohol solution, was presented daily during different stages of pregnancy. Prenatal stress resulted in lighter birth weights in two of three studies, and males from the alcohol plus noise stress condition had reduced birth weights. There were no significant effects of any of the prenatal treatments on gestation duration. Both prenatal stress and moderate fetal alcohol exposure reduced attention span and neuromotor capabilities of offspring during the first month of life, while early gestation prenatal stress, during the period of neuronal migration, emerged as a period of enhanced vulnerability for these effects. Under conditions of challenge, prenatally stressed monkeys showed more disturbance behaviors and reduced locomotion and exploration as well as altered hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. Fetal alcohol exposed monkeys also showed increased HPA axis activity in response to stressful conditions. Finally, altered patterns of alcohol consumption during adolescence were associated with prenatal stress.

PET Measurement of rCBF in the presence of a neurochemical tracer.

Functional neurochemical imaging can indicate neurotransmitter release by detecting changes in receptor occupancy. A dual tracer positron emission tomography (PET) technique is presented here to extend such studies by simultaneously measuring changes in regional cerebral blood flow (rCBF). This would permit correlations of task or drug induced changes in rCBF and neurochemical function. In this proposed method, the rapidly varying signal from a blood flow tracer is distinguished from the slowly changing signal due to a long-lived neurochemical tracer. As a proof of principle, baseline studies were carried out in rhesus monkeys. Two monkeys were anesthetized with isoflurane, and [18F]fallypride (t1/2=110 min), a dopamine D2 receptor antagonist, was injected. Starting 99-137 min after injection, PET images were acquired every 10 s while the blood flow tracer [17F]fluoromethane (t1/2=65 s) was administered by inhalation in a repeating pattern of 45 s on/45 s off. The observed time-activity curves for 2 ml brain regions were fit with a three compartment lung-body-brain model of fluoromethane kinetics with whole brain perfusion fixed. Comparing consecutive 6 min scans, reproducibility of relative rCBF and striatal [18F]fallypride concentration were 9 and 8%, respectively.

Prenatal stress induces increased striatal dopamine transporter binding in adult nonhuman primates.

BACKGROUND: To determine the effects in adult offspring of maternal exposure to stress and alcohol during pregnancy, we imaged striatal and midbrain dopamine transporter (DAT) binding by positron emission tomography in rhesus monkeys (Macaca mulatta). We also evaluated the relationship between DAT binding and behavioral responses previously found to relate to dopamine D2 receptor density (responsivity to tactile stimuli, performance on a learning task, and behavior during a learning task). METHODS: Subjects were adult offspring derived from a 2 × 2 experiment in which pregnant monkeys were randomly assigned to control, daily mild stress exposure (acoustic startle), voluntary consumption of moderate-level alcohol, or both daily stress and alcohol. Adult offspring (n = 38) were imaged by positron emission tomography with the DAT ligand [(18)F]2ß-carbomethoxy-3ß-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT). RESULTS: Results showed that prenatal stress yielded an overall increase of 15% in [(18)F]FECNT binding in the striatum (p = .016), 17% greater binding in the putamen (p = .012), and 13% greater binding in the head of the caudate (p = .028) relative to animals not exposed to prenatal stress. Striatal [(18)F]FECNT binding correlated negatively with habituation to repeated tactile stimulation and positively with tactile responsivity. There were no significant effects of prenatal alcohol exposure on [(18)F]FECNT binding. CONCLUSIONS: Maternal exposure to mild daily stress during pregnancy yielded increases in striatal DAT availability that were apparent in adult offspring and were associated with behavioral characteristics reflecting tactile hyperresponsivity, a condition associated with problem behaviors in children.

Synthesis of [64Cu]Cu-NOTA-Bn-GE11 for PET imaging of EGFR-rich tumors.

Epidermal growth factor receptors (EGFR) are over-expressed in many different types of cancer, thus, are logical targets for both diagnosis and therapy. Antibodies and antibody fragments targeting the extracellular EGF receptor and small molecules targeting the intracellular tyrosine kinase (TK) part of EGFR have been developed as possible diagnostic EGFR imaging agents. Recently, a 12-amino acid peptide, GE11, was identified using phage display screening to have high affinity for EGFR (Kd=22nM). Reported in vitro and in vivo characteristics of GE11 suggest that positron-labeled GE11 may be a useful PET imaging agent in selecting patients with EGFR-rich tumors who can most benefit from anti- EGFR therapy. To enable the exploration of this possibility, positron emitting [64Cu]Cu-NOTA-Bn-GE11 was prepared for further evaluation as PET EGFR imaging agent.

Production of 34m Cl and 38 Cl via the (d,α) reaction on 36 Ar and nat Ar gas at 8.4 MeV.

Production of (38)Cl and (34m)Cl via the (d, α) reaction on natural argon and (36)Ar reveal medical cyclotrons' ability to supply these isotopes in small quantities. (38)Cl provides an inexpensive developmental tool, while (34m)Cl is a positron emitter of interest in PET imaging. Production yields, cyclotron target development, cryo-recovery of enriched gases, and nucleophilic chemistry of a model compound are described.

Assessment of fetal brain uptake of paraquat in utero using in vivo PET/CT imaging.

Prenatal in utero conditions are thought to play a role in the development of adult diseases including Parkinson's disease (PD). Paraquat is a common herbicide with chemical structure similar to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine, a neurotoxin known to induce parkinsonism. In order to assess the role of in utero paraquat exposure in PD, uptake in maternal and fetal brains were measured using positron emission tomography (PET)/computed tomography (CT) imaging. Two anesthetized pregnant rhesus macaques in the late second trimester of pregnancy were given bolus iv injections of ¹¹C-paraquat, and whole-body PET/CT imaging was performed. Using maternal ventricular blood pool as the input function, the unidirectional influx rate constants (K(i)s), a measure of the irreversible transport of paraquat from plasma to brain, were calculated for the maternal and fetal brains using Patlak graphical analysis. Results indicate minimal uptake of paraquat by both maternal and fetal brains with average K(i)s of 0.0009 and 0.0016 per minute, respectively. The highest regional cerebral uptake in the maternal brain (0.0009% injected dose) was seen in the pineal gland, a structure known to lack a blood brain barrier. The finding of minimal paraquat uptake in maternal and fetal brains is similar to previous findings in adult male macaques and extends the contention that a single acute paraquat exposure, prenatally or postnatally, is unlikely to play a role in PD.

A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson's disease.

Although [(18)F]fluoro-L: -dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function.

Fetal dose estimates for (18)F-fluoro-L-thymidine using a pregnant monkey model.

UNLABELLED: Estimating the radiation dose received by the fetus from nuclear medicine procedures is important because of the greater sensitivity of rapidly developing fetal tissues to ionizing radiation. (18)F-fluoro-L-thymidine (FLT) uptake is related to cellular proliferation and is currently used to monitor tumor progression and response to therapy. This study was undertaken to estimate-on the basis of biodistribution data obtained by PET/CT in pregnant rhesus monkeys-radiation absorbed dose to a human fetus administered (18)F-FLT. METHODS: Three pregnant rhesus macaques (gestational age, 113 +/- 8 d) were administered (18)F-FLT and imaged for 2 h on a PET/CT scanner. Time-activity curves for maternal and fetal organs were generated in anatomic regions of interest identified via CT. Doses were estimated using OLINDA/EXM and the 6-mo-pregnant human model. RESULTS: The extrapolated whole-body maternal dose obtained, 11.4 microGy/MBq, is similar to the previously reported adult female dose of 15.6 microGy/MBq. The estimated total-body dose to a human fetus is 24 microGy/MBq. Significant long-term (18)F-FLT accumulation in fetal liver resulted in a fetal liver dose of 53 microGy/MBq. CONCLUSION: The fetal dose estimate in a 6-mo-pregnant human using (18)F-FLT is slightly greater than that reported for (18)F-FDG. (18)F-FLT trapping in the fetal liver should be considered in the risk-benefit analysis of (18)F-FLT PET examination in pregnant patients.