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Background: [ 18 F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer's disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [ 18 F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [ 18 F]AV1451 to use only 0.5 mg precursor, optimized the Boc-deprotection step and developed a simplified method for HPLC purification of the radiotracer., Results: An optimized [ 18 F]AV1451 synthesis using a TRACERLab FX FN module led to high radiochemical yield (202 ± 57 mCi per synthesis) and doses with excellent radiochemical purity (98 ± 1%) and good specific activity (2521 ± 623 Ci/mmol)., Conclusion: An updated and operationally simple synthesis of [ 18 F]AV1451 has been developed that is fully automated and prepares radiotracer doses suitable for use in clinical tau PET studies.

A new variant of the Strecker synthesis using no-carrier-added [ 11 C]cyanide for the synthesis of radiolabeled amino acids is described. The protocol is fully automated using a radiochemistry synthesis module and applied to the production of a number of new PET radiotracers. [ 11 C- Carbonyl ]sarcosine, [ 11 C- carbonyl ]methionine, [ 11 C- carbonyl ]- N -phenylglycine, and [ 11 C- carbonyl ]glycine are all synthesized in moderate to good radiochemical yields. The synthesis of [ 11 C- carbonyl ]sarcosine has been validated for production of doses for clinical use, and preliminary evaluation of the new radiotracer in PC3 tumor-bearing mice is also reported.

There is wide variability in the reported prevalence rates of abnormal smell in Parkinson disease (PD). This study assessed the prevalence of abnormal smell, using the University of Pennsylvania Smell Identification Test (UPSIT), in 183 patients with PD with confirmed PET imaging evidence of nigrostriatal denervation. Impaired olfaction in this sample was nearly universal (97.8 %). Wide-ranging prior olfactory impairment estimates may reflect not only uncertainty regarding diagnostic classification, but also the use of inaccurate normative data and differences in olfactory tests used.

Introduction: Although most previous cognitive studies of β-amyloidopathy in PD focused on cortical plaque deposition, recent postmortem studies point to an important role of striatal β-amyloid plaque deposition. The aim of this study was to investigate the relative contributions of striatal and cortical β-amyloidopathy to cognitive impairment in PD., Methods: Patients with PD (n = 62; age, 68.9 ± 6.4 years; H & Y stage: 2.7 ± 0.5; MoCA score: 25.2 ± 3.0) underwent [(11) C]Pittsburgh compound B β-amyloid, [(11) C]dihydrotetrabenazine monoaminergic, and [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase brain PET imaging and neuropsychological assessment. [(11) C]Pittsburgh compound B β-amyloid data from young to middle-aged healthy subjects were used to define elevated [(11) C]Pittsburgh compound B binding in patients., Results: Elevated cortical and striatal β-amyloid deposition were present in 37% and 16%, respectively, of this predominantly nondemented cohort of patients with PD. Increased striatal β-amyloid deposition occurred in half of all subjects with increased cortical β-amyloid deposition. In contrast, increased striatal β-amyloid deposition did not occur in the absence of increased cortical β-amyloid deposition. Analysis of covariance using global composite cognitive z scores as the outcome parameter showed significant regressor effects for combined striatal and cortical β-amyloidopathy (F = 4.18; P = 0.02) after adjusting for covariate effects of cortical cholinergic activity (F = 5.67; P = 0.02), caudate nucleus monoaminergic binding, duration of disease, and age (total model: F = 3.55; P = 0.0048). Post-hoc analysis showed significantly lower cognitive z score for combined striatal and cortical β-amyloidopathy, compared to cortical-only β-amyloidopathy and non-β-amyloidopathy subgroups., Conclusions: The combined presence of striatal and cortical β-amyloidopathy is associated with greater cognitive impairment than cortical β-amyloidopathy alone in PD., (© 2015 International Parkinson and Movement Disorder Society.)

The most commonly utilized PET radionuclide is fluorine-18 ((18)F) because of its convenient half-life and excellent imaging properties. In this review, we present the first analysis of patents issued for radiotracers labeled with fluorine-18 (between 2009 and 2015), and provide perspective on current trends and future directions in PET radiotracer development.

Objective: To investigate the relationship between time spent in non-exercise and exercise physical activity and severity of motor functions in Parkinson disease (PD)., Background: Increasing motor impairments of PD incline many patients to a sedentary lifestyle. We investigated the relationship between duration of both non-exercise and exercise physical activity over a 4-week period using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire and severity of clinical motor symptoms in PD. We accounted for the magnitude of nigrostriatal degeneration., Methods: Cross-sectional study. PD subjects, n = 48 (40 M); 69.4 ± 7.4 (56-84) years old; 8.4 ± 4.2 (2.5-20) years motor disease duration, mean UPDRS motor score 27.5 ± 10.3 (7-53) and mean MMSE score 28.4 ± 1.9 (22-30) underwent [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation and completed the CHAMPS questionnaire and clinical assessment., Results: Bivariate correlations showed an inverse relationship between motor UPDRS severity scores and duration of non-exercise physical activity (R = -0.37, P = 0.0099) but not with duration of exercise physical activity (R = -0.05, P = 0.76) over 4 weeks. Multiple regression analysis using UPDRS motor score as outcome variable demonstrated a significant regressor effect for duration of non-exercise physical activity (F = 6.15, P = 0.017) while accounting for effects of nigrostriatal degeneration (F = 4.93, P = 0.032), levodopa-equivalent dose (LED; F = 1.07, P = 0.31), age (F = 4.37, P = 0.043) and duration of disease (F = 1.46, P = 0.23; total model (F = 5.76, P = 0.0004)., Conclusions: Non-exercise physical activity is a correlate of motor symptom severity in PD independent of the magnitude of nigrostriatal degeneration. Non-exercise physical activity may have positive effects on functional performance in PD., (Published by Elsevier Ltd.)

The phenol of 1-(3-(1H-imidazol-1-yl)propyl)-3-(4-hydroxy-3-methoxyphenyl)thiourea was selectively carbon-11 labelled to generate [ 11 C]PBD150 in 7.3% yield from [ 11 C]methyl triflate (non-decay corrected; radiochemical purity ≥95%, specific activity = 5.7 Ci/µmol, n=5). Evaluation of [ 11 C]PBD150 by small animal PET imaging (mouse and rat) determined it does not permeate the blood brain barrier, indicating previously described therapeutic effect in transgenic mice was likely not the result of inhibiting central nervous system glutaminyl cyclase.

Background: Cholinergic projection systems degeneration is associated with dopamine nonresponsive features of Parkinson's disease (PD). Cholinergic deficits are variable in nondemented PD. Identification of cholinergic deficits in PD may help with selection of suitable patients for targeted cholinergic drug treatment in PD. The objective of this retrospective multivariate predictor analysis study was to identify clinical markers indicative of cholinergic deficits in PD patients, as assessed by acetylcholinesterase ([(11) C]PMP) positron emission tomography., Methods: One hundred thirty-seven PD patients (34 female) participated; median modified Hoehn and Yahr score was 2.5 (range, 1-4), average age 65.6 ± 7.4 years, and average duration of motor disease symptoms of 6.0 ± 4.2 years. Subjects were dichotomized as "normocholinergic" or "hypocholinergic" based on a 5(th) percentile cutoff from normal for the basal forebrain-cortical and pedunculopontine nucleus-thalamic cholinergic projection systems. Previously identified clinical indices of cholinergic denervation were used for statistical prediction of cholinergic deficits. Logistic regression determined which risk factors predicted cholinergic deficits. Sensitivity, specificity, and accuracy were determined for the (combinations of) significant predictor variables., Results: Forty-nine (35.8%) hypocholinergic PD subjects were identified. The combination of rapid eye movement (REM) sleep behavior disorder (RBD) symptoms and fall history showed highest diagnostic accuracy (81.1%) for predicting combined thalamic and cortical cholinergic deficits. A combined assessment of 8.5 m walk time and lower score on the Montreal cognitive assessment scale provided diagnostic accuracy of 80.7% for predicting isolated cortical cholinergic denervation., Conclusion: Assessment of clinical indices of cholinergic denervation may be useful for identifying suitable subjects for trials of targeted cholinergic drug treatments in PD., (© 2014 International Parkinson and Movement Disorder Society.)

Background: There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied., Objective: To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations., Methods: Cross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates., Results: There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (-0.98 ± 1.01) compared to the non-diabetics (-0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001)., Conclusion: Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.

Interest in quantifying metal-Aβ species in vivo led to the synthesis and evaluation of [ 11 C]L2-b and [ 18 F]FL2-b as radiopharmaceuticals for studying the metallobiology of Alzheimer's disease (AD) using positron emission tomography (PET) imaging. [ 11 C]L2-b was synthesized in 3.6% radiochemical yield (nondecay corrected, n = 3), >95% radiochemical purity, from the corresponding desmethyl precursor. [ 18 F]FL2-b was synthesized in 1.0% radiochemical yield (nondecay corrected, n = 3), >99% radiochemical purity, from a 6-chloro pyridine precursor. Autoradiography experiments with AD positive and healthy control brain samples were used to determine the specificity of binding for the radioligands compared to [ 11 C]PiB, a known imaging agent for β-amyloid (Aβ) aggregates. The K d for [ 11 C]L2-b and [ 18 F]FL2-b were found to be 3.5 and 9.4 nM, respectively, from those tissue studies. Displacement studies of [ 11 C]L2-b and [ 18 F]FL2-b with PiB and AV-45 determined that L2-b binds to Aβ aggregates differently from known radiopharmaceuticals. Finally, brain uptake of [ 11 C]L2-b was examined through microPET imaging in healthy rhesus macaque, which revealed a maximum uptake at 2.5 min (peak SUV = 2.0) followed by rapid egress ( n = 2).

Cholinergic denervation has been associated with falls and slower gait speed and β-amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra-nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [(11) C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11) C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic "off" state. A subset of subjects (n = 61) underwent [(11) C]Pittsburgh compound-B β-amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal β-amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non-freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ(2)  = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ(2)  = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β-amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra-nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran-Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra-nigral pathological conditions studied. Extra-nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society., (© 2014 International Parkinson and Movement Disorder Society.)

Introduction: The dysfunction of glycogen synthase kinase-3β (GSK-3β) has been implicated in a number of diseases, including Alzheimer's disease. The ability to non-invasively quantify GSK-3β activity in vivo is therefore of critical importance, and this work is focused upon development of inhibitors of GSK-3β radiolabeled with carbon-11 to examine quantification of the enzyme using positron emission tomography (PET) imaging., Methods: (11)C PyrATP-1 was prepared from the corresponding desmethyl-piperazine precursor in an automated synthesis module. In vivo rodent and primate imaging studies were conducted on a Concorde MicroPET P4 scanner to evaluate imaging properties and in vitro autoradiography studies with rat brain samples were carried out to examine specific binding., Results: 2035±518MBq (55±14mCi) of [(11)C]PyrATP-1 was obtained (1%-2% non-corrected radiochemical yield at end-of-synthesis based upon [(11)C]CO2) with high chemical (>95%) and radiochemical (>99%) purities, and good specific activities (143±52GBq/μmol (3874±1424Ci/mmol)), n=5. In vivo microPET imaging studies revealed poor brain uptake in rodents and non-human primates. Pretreatment of rodents with cyclosporin A resulted in moderately increased brain uptake suggesting Pgp transporter involvement. Autoradiography demonstrated high levels of specific binding in areas of the rodent brain known to be rich in GSK-3β., Conclusion: (11)C PyrATP-1 is readily synthesized using standard carbon-11 radiochemistry. However the poor brain uptake in rodents and non-human primates indicates that the radiotracer is not suitable for the purposes of quantifying GSK-3β in neurological and psychiatric disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The principles of green chemistry have been applied to a radiochemistry setting. Eleven carbon-11 labeled radiopharmaceuticals have been prepared using ethanol as the only organic solvent throughout the entire manufacturing process. The removal of all other organic solvents from the process simplifies production and quality control (QC) testing, moving our PET Center towards the first example of a green radiochemistry laboratory. All radiopharmaceutical doses prepared are suitable for clinical use., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cathepsin K is a cysteine peptidase primarily located in osteoclasts, cells involved in normal growth and remodeling of bone but that are also responsible for bone loss in osteolytic diseases such as osteoporosis. In vivo imaging of cathepsin K may provide a method to assess changes in osteoclast numbers in such disease states. To that end, two high-affinity and selective cathepsin K inhibitors were radiolabeled with carbon-11. In vivo microPET imaging studies demonstrated uptake and prolonged retention of radioactivity in actively growing or remodeling bone regions (e.g., distal ulnar, carpal, distal and proximal humeral, distal femur, proximal tibia, tail vertebrae). Uptake into bone could be blocked by pre- or co-injection of unlabeled ligand, supporting a specific and saturable binding mechanism for radiotracer localization. These proof-of-concept studies indicate that radiolabeled cathepsin K inhibitors may have potential as in vivo imaging radiotracers for assessing changes of osteoclast numbers in osteolytic diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: (-)-5-(18)F-fluoroethoxybenzovesamicol ((18)F-FEOBV) is a vesamicol derivative that binds selectively to the vesicular acetylcholine transporter (VAChT) and has been used in preclinical studies to quantify presynaptic cholinergic nerve terminals. This study presents, to our knowledge, the first-in-human experience with (18)F-FEOBV, including radiation dosimetry, biodistribution, tolerability and safety in human subjects, and brain kinetics and methods for quantitative analysis of (18)F-FEOBV., Methods: Whole-body (18)F-FEOBV scans were obtained in 3 healthy human volunteers. Seven additional subjects underwent dynamic brain imaging 0-120, 150-180, and 210-240 min after bolus injection of (18)F-FEOBV. Arterial blood sampling was performed with chromatographic identification of authentic (18)F-FEOBV to determine the arterial plasma input function. Analysis methods included nonlinear least-squares fitting of a 2-tissue-compartmental model, reference tissue modeling, and late single-scan imaging., Results: No pharmacologic or physiologic changes were observed after intravenous administration of up to 1.3 μg of (18)F-FEOBV. Radiation dosimetry estimates indicate that more than 400 MBq may be administered without exceeding regulatory radiation dose limits. Kinetic analysis showed brain uptake to be relatively high with single-pass extraction of 25%-35%. VAChT binding estimates varied by a factor of greater than 30 between the striatum and cortex. Coefficients of variation in k3 estimates varied from 15% to 30%. Volume of distribution measures yielded a dynamic range of approximately 15 but with little reduction in variability. Reference tissue approaches yielded more stable estimates of the distribution volume ratio (1 + BPND), with coefficients of variation ranging from 20% in the striatum to 6%-12% in cortical regions. The late static distribution of (18)F-FEOBV correlated highly with the distribution volume ratio estimates from reference tissue models (r = 0.993)., Conclusion: (18)F-FEOBV PET confirms that the tracer binds to VAChT with the expected in vivo human brain distribution. Both reference tissue modeling and late static scanning approaches provide a robust index of VAChT binding.

Positron (β(+)) emission tomography (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiological structures and biochemical pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biologically active molecules labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochemistry and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochemistry. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings.

The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson's disease. We studied 124 subjects with Parkinson's disease (32 female/92 male; 65.5 ± 7.4 years old; 6.0 ± 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 ± 0.5) and 25 control subjects (10 female/15 male, 66.8 ± 10.1 years old). All subjects underwent (11)C-dihydrotetrabenazine vesicular monoaminergic transporter type 2 and (11)C-methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1-3 and 5, respectively. Regression analysis of the Conditions 1-3 postural sway-related factor [R(2)adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (β = -0.389, t = -3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson's disease. We conclude that postural sensory integration function of subjects with Parkinson's disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson's disease, possibly by participating in integration of multimodal sensory input information.

(-)-[(18) F]Flubatine was selected for clinical imaging of α4 β2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (-)-[(18) F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (-)-[(18) F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [(18) F]fluoride in an automated synthesis module. Subsequent deprotection of the Boc group with 1-M HCl yielded (-)-[(18) F]flubatine, which was purified by semi-preparative HPLC. (-)-[(18) F]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 (-)-[(18) F]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 [(18) F]flubatine, with about 25% clearance from the thalamus by the end of imaging at 90 min., (Copyright © 2013 John Wiley & Sons, Ltd.)

Introduction: Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging of the GABAA/benzodiazepine receptor by comparing them to [(11)C]flumazenil in rhesus monkey., Methods: Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of [(18)F]AH114726 and [(18)F]GEH120348 was confirmed by displacement studies using unlabeled flumazenil., Results: [(18)F]GEH120348 and [(18)F]AH114726 were obtained in 13-24% yields (end of synthesis) with high chemical (>95%) and radiochemical (>99%) purities, and high specific activities (2061 ± 985 Ci/mmol). The in vivo pharmacokinetics of [(18)F]AH114726 and [(18)F]GEH120348 were determined in a non-human primate and directly compared with [(11)C]flumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of [(11)C]flumazenil and the known concentrations of GABAA/benzodiazepine receptors in the monkey brain. [(18)F]AH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to [(11)C]flumazenil. In contrast, [(18)F]GEH120348 showed higher initial brain uptake but very different pharmacokinetics with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil., Conclusion: The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to [(11)C]flumazenil, support that [(18)F]AH114726 is a suitable option for imaging the GABAA receptor., (© 2013.)

Introduction: A novel one-pot method for preparing [(18)F]fluoromethylcholine ([(18)F]FCH) via in situ generation of [(18)F]fluoromethyl tosylate ([(18)F]FCH2OTs), and subsequent [(18)F]fluoromethylation of dimethylaminoethanol (DMAE), has been developed., Methods: [(18)F]FCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-(18) synthesis module. Initially ditosylmethane was fluorinated to generate [(18)F]FCH2OTs. DMAE was then added and the reaction was heated at 120 °C for 10 min to generate [(18)F]FCH. After this time, reaction solvent was evaporated, and the crude reaction mixture was purified by solid-phase extraction using C(18)-Plus and CM-Light Sep-Pak cartridges to provide [(18)F]FCH formulated in USP saline. The formulated product was passed through a 0.22 µm filter into a sterile dose vial, and submitted for quality control testing. Total synthesis time was 1.25 h from end-of-bombardment., Results: Typical non-decay-corrected yields of [(18)F]FCH prepared using this method were 91 mCi (7% non-decay corrected based upon ~1.3 Ci [(18)F]fluoride), and doses passed all other quality control (QC) tests., Conclusion: A one-pot liquid-phase synthesis of [(18)F]FCH has been developed. Doses contain extremely low levels of residual DMAE (31.6 µg/10 mL dose or ~3 ppm) and passed all other requisite QC testing, confirming their suitability for use in clinical imaging studies., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Introduction: To improve the synthesis and quality control of carbon-11 labeled radiopharmaceuticals, we report the fully automated loop syntheses of [¹¹C]raclopride and [¹¹C]DASB using ethanol as the only organic solvent for synthesis module cleaning, carbon-11 methylation, HPLC purification, and reformulation., Methods: Ethanolic loop chemistry is fully automated using a GE TRACERLab FX(C-Pro) synthesis module, and is readily adaptable to any other carbon-11 synthesis apparatus. Precursors (1 mg) were dissolved in ethanol (100 μL) and loaded into the HPLC loop. [¹¹C]MeOTf was passed through the HPLC loop and then the labeled products were purified by semi-preparative HPLC and reformulated into ethanolic saline., Results: Both [¹¹C]raclopride (3.7% RCY; >95% RCP; SA=20831 Ci/mmol; n=64) and [¹¹C]DASB, both with (3.0% RCY; >95% RCP; SA=15152Ci/mmol; n=9) and without (3.0% RCY; >95% RCP; SA=10931 Ci/mmol; n=3) sodium ascorbate, have been successfully prepared using the described methodology. Doses are suitable for human use and the described methods are now employed for routine clinical production of both radiopharmaceuticals at the University of Michigan., Conclusions: Ethanolic loop chemistry is a powerful technique for preparing [¹¹C]raclopride and [¹¹C]DASB, and we are in the process of adapting it for other carbon-11 radiopharmaceuticals prepared in our laboratories ([¹¹C]PMP, [¹¹C]PBR28 etc.)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In order to image the translocator protein (TSPO) 18kDa in the clinic using positron emission tomography (PET) imaging, we had a cause to prepare [(11)C]PBR28. In this communication we highlight our novel, recently developed, one-pot synthesis of the desmethyl-PBR28 precursor, as well as present an optimized fully automated preparation of [(11)C]PBR28 using a GE TRACERlab FX(C-Pro). Following radiolabelling, purification is achieved by HPLC and, to the best of our knowledge, the first reported example of reconstituting [(11)C]PBR28 into ethanolic saline using solid-phase extraction (SPE). This procedure is operationally simple, and provides high quality doses of [(11)C]PBR28 suitable for use in clinical PET imaging studies. Typical radiochemical yield using the optimized method is 3.6% yield (EOS, n=3), radiochemical and chemical purity are consistently >99%, and specific activities are 14,523Ci/mmol., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [(11)C]acetate and [(11)C]palmitate, can be automated on the GE Tracerlab FX(C-Pro) by utilizing Grignard reactions. Radiochemical purities of the [(11)C]acetate and the [(11)C]palmitate products were high (>98% and >99.9%, respectively) with average non-corrected yields of 18% (n = 3) and 10% (n = 5), respectively. These data comprise the validation trials for site qualification of clinical production of both radiopharmaceuticals., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Modifications of a GE TracerLab FX(C-Pro), which can be implemented for solid-phase [(11)C]methylation are described. The simplified procedure for synthesis of [(11)C]choline uses a single Sep-Pak CM-Light cation-exchange cartridge for both solid-supported reaction and purification. Compared with the commonly used two Sep-Pak method, the low back-pressure of this Sep-Pak enables efficient and reliable production of [(11)C]choline using a TracerLab FX(C-Pro) without requirement for any gas pressure adjustment. Typical radiochemical yields (RCY) are >60%, radiochemical purity (RCP) is 99.9% and levels of residual precursor in the final product, which may inhibit the uptake of [(11)C]choline, are reduced to 1 μg/mL. Similarly, modification of a GE TracerLab FX(FN) is reported which enables gas-phase production of [(18)F]fluoromethylcholine, suitable for pre-clinical use, (in 4-6% RCY and >99.7% RCP) using a related Sep-Pak method. These modifications can be utilized for solid-phase [(11)C]methylation and [(18)F]fluoromethylation of other radiotracers, and allow straightforward switching to other module configurations for solution-phase radiochemistry or loop chemistry. In addition, we report a convenient HPLC ion chromatography method, which can monitor residual precursor and the radiochemical purity of product at the same time, providing highly efficient quality control for routine clinical application. The reported HPLC method is appropriate for analysis of doses of both [(11)C]choline and [(18)F]fluoromethylcholine, and eliminates the need for a GC method to determine residual precursor levels., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The worldwide shortage of technetium-99m has created an immediate and urgent need for access to [(18)F]sodium fluoride for PET imaging of bone metastasis. In order to facilitate global availability of [(18)F]sodium fluoride for diagnostic nuclear medicine imaging procedures, a straightforward method for rapid production of [(18)F]sodium fluoride for injection, USP, using a modified GE Tracerlab FX-FN is presented.

Radiolytic decomposition of high specific concentration radiopharmaceuticals is an undesired side-effect that can hamper development of novel PET tracers. This was particularly evident in a series of carbon-11 and fluorine-18 labeled mono- and dimethyl-substituted aryl amines, where rapid decomposition was observed in isolation and formulation steps. We tested a number of additives that inhibit radiolysis and can be safely added to the synthesis procedures (purification and isolation) and reformulation steps to provide suitable clinical formulations. Ethanol and sodium ascorbate are established anti-oxidant stabilizers that completely inhibit radiolytic decomposition and are amenable to human use. Herein, we also demonstrate for the first time that nitrones are non-toxic radical scavengers that are capable of inhibiting radiolysis.

4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix 2.2.2) is used in the routine preparation of [18F]-labeled tracers employed in positron emission tomography (PET) imaging. Confirming the absence of Kryptofix in radiopharmaceuticals is a quality control criterion required before they can be released for human use. Analysis of Kryptofix levels using the iodoplatinate spot-test can be complicated by false-positive results due to nitrogen containing tracers and/or false-negative results caused by added stabilizers. To overcome this issue, we have developed a universal TLC method for the rapid and reliable determination of Kryptofix levels in the wide range of fluorine-18 radiopharmaceuticals we prepare, including complex multi-component formulations.