Search

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported

Prostate-specific membrane antigen (PSMA)-targeted radioligands have played an increasing role in the diagnosis of prostate cancer. [68Ga]Ga-P16-093 is a PSMA-targeting agent for positron emission tomography imaging, currently under a Phase 2 clinical trial. In the present study, P16-093 was labeled with 18F via [18F]AlF2+ complex formation, and the biological properties of [18F]AlF-P16-093 were evaluated. Optimization of radiolabeling efficiency was performed by testing a series of parameters, including the amount of free ligand; the amount of Al3+; and the influence of solvent, pH, temperature, reaction time, and reaction volume. Optimal labeling results were achieved at pH 5 by reacting at 60 °C for 15 min in a vial containing 74-370 MBq of [18F]fluoride, 46 nmol of P16-093, 40 nmol of AlCl3·6 H2O, and 50% EtOH. [18F]AlF-P16-093 was prepared with a non-decay-corrected radiochemical yield of 54.4 ± 4.4% (n = 9) within 30 min (final radiochemical purity ≥95%). In vitro, [18F]AlF-P16-093 showed PSMA-specific high uptakes in PIP-PC3 cells. The binding affinity of [18F]AlF-P16-093 to PSMA was determined as Kd of 12.4 ± 2.0 nM. The tumor uptake in mice with a xenografted PSMA-expressing PIP-PC3 tumor was high (18.8 ± 5.14% ID/g at 1 h postinjection) and retained without washout for 2 h. In addition, tumor uptake was almost completely blocked by coinjecting a PSMA inhibitor, 2-PMPA. The bone activity at 1 h post injection was higher with [18F]AlF-P16-093 (2.83 ± 0.49% ID/g) in comparison to that of [68Ga]Ga-P16-093 (0.26 ± 0.07% ID/g). In summary, an efficient and simple radiosynthesis of [18F]AlF-P16-093 was achieved. [18F]AlF-P16-093 showed desirable in vivo pharmacokinetics and excellent PSMA-targeting properties for imaging PSMA expression in prostate cancer.

Introduction Since the approval of three 18F labeled β-amyloid-targeting PET imaging agents, Amyvid (florbetapir f18, AV-45), Neuraceq (florbetaben f18, AV-1) and Vizamyl (flutemetamol f18, F-PIB), they have increasingly been employed to assist differential diagnosis of Alzheimer's disease in patients with dementia. Also, they are frequently used in selecting patients participating drug trials aiming to reduce β-amyloid (Aβ) plaques in the brain. The first approved tracer in this class was [18F]AV-45, which is metabolized rapidly in blood and some of its N-demethylated metabolites cross the blood brain barrier and resulted in lowering the image contrast. To improve metabolic stability of [18F]AV-45, we hypothesized that substituting N-CH3 with N-CD3 at the metabolically labile position, creating [18F]D3FSP, may reduce in vivo N-demethylation. We report the preclinical evaluation of [18F]D3FSP as an Aβ imaging agent. Methods Preclinical pharmacology of [18F]D3FSP was evaluated using in vitro autoradiography and competitive binding assay. Biodistribution of [18F]D3FSP was evaluated in wild-type CD-1 mice. In vivo metabolism in mice and in vitro microsomal metabolism were analyzed by HPLC. Single dose acute toxicity of D3FSP was also performed in rats. Results [18F]D3FSP showed high binding affinity to β-amyloid plaques (Ki = 3.44 ± 1.22 nM, a value similar as AV-45 (Ki = 4.02 ± 0.22 nM)), and displayed excellent β-amyloid binding in AD brain sections consistent with known Aβ regional distribution. After an iv injection it exhibited good initial brain uptake and fast washout in wild-type CD-1 mice. In vitro microsomal metabolism and in vivo metabolism in mice did not result in any significant differences between [18F]D3FSP and [18F]AV-45. No treatment-related mortality or any adverse effects were observed in single dose acute toxicity studies administered at hundred-folds of maximum human dose. Conclusion A new small molecule, [18F]D3FSP, was prepared and tested as an alternative to [18F]AV-45 to reduce N-demethylation in vivo. This strategy did not lead to better in vivo stability. However, [18F]D3FSP displayed very similar Aβ targeting property comparable to [18F]AV-45. Preclinical studies suggest that [18F]D3FSP is useful as a β-amyloid-targeting PET imaging agent.

Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [68Ga]Ga-PSMA-093 ([68Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating 68Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[68Ga/177Lu]-DOTAGA derivatives, (R)-[68Ga/177Lu]-13 and (S)-[68Ga/177Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[177Lu]Lu-13 and (S)-[177Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[177Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding 68Ga agents were comparable between structural isomers. The natGa and natLu equivalents showed high binding PSMA affinity (IC50 = 24-111 nM), comparable to that of the parent agent, [natGa]Ga-PSMA-093 (IC50 = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [68Ga/177Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new 177Lu-DOTAGA-based radionuclide therapy agents in the future.

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron emission tomography (PET) with the aromatase inhibitor [(11)C]vorozole in a sample of 43 adult, normal-weight, overweight, or obese men and women. A subsample of 27 also completed personality measures to examine the relationship between aromatase and personality traits related to self-regulation and inhibitory control. Results indicated that aromatase availability in the amygdala was negatively associated with body mass index (BMI) (in kilograms per square meter) and positively correlated with scores of the personality trait constraint independent of sex or age. Individual variations in the brain’s capacity to synthesize estrogen may influence the risk of obesity and self-control in men and women.

INTRODUCTION: [(68)Ga]Ga-P15-041 ([(68)Ga]Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer that can be generator-produced. We undertook a Phase 0/I clinical trial to assess its potential for imaging bone metastases in prostate cancer including assessment of radiotracer biodistribution and dosimetry. METHODS: Subjects with prostate cancer and known or suspected osseous metastatic disease were enrolled into one of two arms: dosimetry or dynamic. Dosimetry was performed with 6 whole body PET acquisitions and urine collection spanning 3 hours; normal organ dosimetry was calculated using OLINDA/EXM. Dynamic imaging included a 60-minute acquisition over a site of known or suspected disease followed by two whole body scans. Bootstrapping and subsampling of the acquired list-mode data were conducted to recommend image acquisition parameters for future clinical trials. RESULTS: Up to 233 MBq (6.3 mCi) of [(68)Ga]Ga-P15-041 was injected into 12 enrolled volunteers, 8 in dosimetry and 4 in dynamic cohorts. Radiotracer accumulated in known bone lesions and cleared rapidly from blood and soft tissue. The highest individual organ dose was 0.135 mSv/MBq in the urinary bladder wall. The average effective dose was 0.0173 ± 0.0036 mSv/MBq. An average injected activity of 166.5 MBq (4.5 mCi) resulted in absorbed dose estimates of 22.5 mSv to the urinary bladder wall, 8.2 mSv to the kidneys, and an effective dose of 2.9 mSv. Lesion signal to noise ratios on images generated from subsampled data were significantly higher for injected activities above 74 MBq (2 mCi) and were also significantly higher for imaging at 90 minutes than at 180 minutes post-injection. CONCLUSIONS: Dosimetry estimates are acceptable and [(68)Ga]Ga-P15-041 uptake characteristics in patients with confirmed bone metastases support its continued development. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Use of [(68)Ga]Ga-P15-041 would not require cyclotron infrastructure for manufacturing and distribution, allowing for improved patient access to a promising PET bone imaging agent.

Positron emission tomography (PET) imaging using 68Ga-labeled bisphosphonates to target bone metastasis could be a valuable tool in cancer diagnosis and monitoring therapeutic treatment. A 68Ga labeled ligand, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) containing one bisphosphonate group (HBED-CC-BP, 1) was prepared and evaluated. The new ligand, 1, reacted rapidly to form [68Ga]Ga-1, via complexing with [68Ga]GaCl3 eluted from a commercially available 68Ge/68Ga generator (in a sodium acetate buffer at pH 4, reaching >95% labeling yield at room temperature in 5 min). The resulting [68Ga]Ga-1 showed excellent stability in vitro and in vivo. [68Ga]Ga-1 displayed high binding affinity to hydroxyapatite and good uptake in the tibia and femur bone of normal mice. Biodistribution and MicroPET imaging studies of [68Ga]Ga-1 in normal mice and rats showed excellent bone uptake and retention comparable to that of Na[18F]F. The results suggested that [68Ga]Ga-1 might be suitable as a bone imaging agent in humans and it could be useful as a convenient alternative to the current bone imaging PET agent, Na[18F]F, without the need of a near-by cyclotron. Also, an automated synthesis module was developed to produce clinical doses of [68Ga]Ga-1 in a consistent and reproducible manner. Currently, the investigation new drug application (IND) for [68Ga]Ga-HBED-CC-BP, [68Ga]Ga-1, has received FDA approval, and it is currently under clinical trial (IND #129870).

Incontinence and impotence occur following radical prostatectomy due to injury to nerves and sphincter muscle. Preserving nerves and muscle adjacent to prostate cancer risks positive surgical margins. Advanced imaging with MRI has improved cancer localization but limitations exist.To measure the accuracy for assessing extra-prostatic extension at nerve bundles for 2 PSMA-PET tracers and to compare the PET accuracy to standard-of-care predictors including MRI and biopsy results.We studied men with PSMA-targeted PET imaging, performed prior to prostatectomy in men largely with intermediate to high-risk prostate cancer, and retrospectively evaluated for assessment of extra-prostatic extension with whole-mount analysis as reference standard. Two different PSMA-PET tracers were included:Pre-operative PSMA-PET imaging was available for 71 patients with eitherPresurgical PSMA-PET appeared useful as a tool for surgical planning, changing treatment plans in men with ≥4+3 or multi-core 3+4 prostate cancer resulting in preservation of nerve-bundles.

Prostate-specific membrane antigen (PSMA) is a promising molecular target for imaging of prostate adenocarcinoma.Patients were enrolled into two cohorts. The biodistribution cohort included 8 treated prostate cancer patients without recurrence, who underwent 6 whole body PET/CT scans with urine sampling for dosimetry using OLINDA/EXM. The dynamic cohort included 15 patients with BCR and 2 patients with primary prostate cancer. Two patients with renal cell carcinoma were also enrolled for exploratory use. A dynamic PET/CT was followed by 2 whole body scans for imaging protocol optimization based on bootstrapped replicates.Based on its favorable imaging characteristics and diagnostic performance in prostate cancer

This study was undertaken to evaluate radiation dosimetry for the prostate-specific membrane antigen targeted [68Ga]Ga-P16-093 radiopharmaceutical, and to initially assess agent performance in positron emission tomography (PET) detection of the site of disease in prostate cancer patients presenting with biochemical recurrence. Under IND 133,222 and an IRB-approved research protocol, we evaluated the biodistribution and pharmacokinetics of [68Ga]Ga-P16-093 with serial PET imaging following intravenous administration to ten prostate cancer patients with biochemical recurrence. The recruited subjects were all patients in whom a recent [68Ga]Ga-PSMA-11 PET/X-ray computed tomography (CT) exam had been independently performed under IND 131,806 to assist in decision-making with regard to their clinical care. Voided urine was collected from each subject at ~ 60 min and ~ 140 min post-[68Ga]Ga-P16-093 injection and assayed for Ga-68 content. Following image segmentation to extract tissue time-activity curves and corresponding cumulated activity values, radiation dosimetry estimates were calculated using IDAC Dose 2.1. The prior [68Ga]Ga-PSMA-11 PET/CT exam (whole-body PET imaging at 60 min post-injection, performed with contrast-enhanced diagnostic CT) served as a reference scan for comparison to the [68Ga]Ga-P16-093 findings. [68Ga]Ga-P16-093 PET images at 60 min post-injection provided diagnostic information that appeared equivalent to the subject’s prior [68Ga]Ga-PSMA-11 scan. With both radiopharmaceuticals, sites of tumor recurrence were found in eight of the ten patients, identifying 16 lesions. The site of recurrence was not detected with either agent for the other two subjects. Bladder activity was consistently lower with [68Ga]Ga-P16-093 than [68Ga]Ga-PSMA-11. The kidneys, spleen, salivary glands, and liver receive the highest radiation exposure from [68Ga]Ga-P16-093, with estimated doses of 1.7 × 10−1, 6.7 × 10−2, 6.5 × 10−2, and 5.6 × 10−2 mGy/MBq, respectively. The corresponding effective dose from [68Ga]Ga-P16-093 is 2.3 × 10−2 mSv/MBq. [68Ga]Ga-P16-093 provided diagnostic information that appeared equivalent to [68Ga]Ga-PSMA-11 in this limited series of ten prostate cancer patients presenting with biochemical recurrence, with the kidneys found to be the critical organ. Diminished tracer appearance in the urine represents a potential advantage of [68Ga]Ga-P16-093 over [68Ga]Ga-PSMA-11 for detection of lesions in the pelvis.

[Image: see text] [(18)F]AV-45 (florbetapir f18, Amyvid) is an FDA-approved PET imaging agent targeting Aβ plaques in the brain for diagnosis of Alzheimer’s disease (AD). Its metabolites led to a high background in the brain and large bone uptake of [(18)F]F(–), produced from dealkylation of the PEG chain. To slow down the in vivo metabolism, we report the design, synthesis, and evaluation of a highly deuterated derivative, [(18)F]D15FSP, and compared it with N-methyl-deuterated [(18)F]D3FSP and nondeuterated [(18)F]AV-45. D15FSP displayed excellent binding affinity (K(i) = 7.52 nM) to Aβ aggregates. In vitro autoradiography of [(18)F]D15FSP, [(18)F]D3FSP, and [(18)F]AV-45 showed excellent binding to Aβ plaques in human AD brain sections. Biodistribution studies displayed lower bone uptake at 120 min for [(18)F]D15FSP compared to that for [(18)F]D3FSP and [(18)F]AV-45 (1.44 vs 4.23 and 4.03%ID/g, respectively). As the highly deuterated [(18)F]D15FSP displayed excellent Aβ binding affinity, high initial brain penetration, and lower bone retention, it might be suitable for PET imaging in detecting Aβ plaques.

Prostate-specific membrane antigen (PSMA)-targeted radioligands have played an increasing role in the diagnosis of prostate cancer. [

The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon-11-labeled AAs given the short half-life of carbon-11 (11 C, t1/2 =20.4 min). A facile synthetic pathway to prepare enantiomerically pure 11 C-labeled l-asparagine was developed using a partially protected serine as a starting material with a four-step transformation providing a chiral five-membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were confirmed by X-ray crystallography. Utilizing a [11 C]cyanide nucleophilic ring opening reaction followed by selective acidic hydrolysis and deprotection, enantiomerically pure l-[4-11 C]asparagine was synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid component, reaction temperature and reaction time, a reliable two-step method for synthesizing l-[4-11 C]asparagine was presented: within a 45±3 min (n=5, from end-of-bombardment), the desired enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69±4 % (n=5) and overall two-step radiochemical yield of 53±2 % (n=5) based on starting [11 C]HCN, and with radiochemical purity of 96±2 % (n=5).

Since the approval of threePreclinical pharmacology of [[A new small molecule, [

Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l -tyrosine and l -glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with 125I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC50 = 1–13 nM). In vitro cell uptake studies demonstrated that compounds containing an l -tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l -tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [125I]8 and [125I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [125I]19a/19b and [125I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [125I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2–3-fold lower uptake in the liver and blood than that observed for [125I]MIP-1095. [125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.

A rapid, mild radiosynthesis of freebase [11C]nicotine was developed by the methylation of freebase nornicotine with [11C]methyl triflate in acetone (5 min, 45 °C). A basic (pH 10.5–11.0) HPLC system reproducibly yielded freebase [11C]nicotine as a well-defined single peak. The freebase [11C]nicotine was concentrated by solid phase extraction and formulated in 50 µL ethanol (370 MBq/50 µL) without evaporative loss suitable for a cigarette spiking study. A radiochemical yield of 60.4±4.7% (n=3), radiochemical purity ≥99.9% and specific activity of 648 GBq/µmol at EOB for 5 min beams were achieved.

The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon-11-labeled AAs given the short half-life of carbon-11 (

A rapid method for the synthesis of carbon-11 radiolabeled indole was developed using a sub-nanomolar quantity of no-carrier-added [(11)C]cyanide as radio-precursor. Based upon a reported synthesis of 2-(2-nitrophenyl)acetonitrile (), a highly reactive substrate 2-nitrobenzyl bromide () was evaluated for nucleophilic [(11)C]cyanation. Additionally, related reaction conditions were explored with the goal of obtaining of highly reactive 2-(2-nitrophenyl)-[1-(11)C]acetonitrile () while inhibiting its rapid conversion to 2,3-bis(2-nitrophenyl)-[1-(11)C]propanenitrile (). Next, a RANEY® Nickel catalyzed reductive cyclization method was utilized for synthesizing the desired [2-(11)C]indole with hydrazinium monoformate as the active reducing agent. Extensive and iterative screening of basicity, temperature and stoichiometry was required to overcome the large stoichiometry bias that favored 2-nitrobenzylbromide () over [(11)C]cyanide, which both caused further alkylation of the desired nitrile and poisoned the RANEY® Nickel catalyst. The result is an efficient two-step, streamlined method to reliably synthesize [2-(11)C]indole with an entire radiochemical yield of 21 ± 2.2% (n = 5, ranging from 18-24%). The radiochemical purity of the final product was >98% and specific activity was 176 ± 24.8 GBq μmol(-1) (n = 5, ranging from 141-204 GBq μmol(-1)). The total radiosynthesis time including product purification by semi-preparative HPLC was 50-55 min from end of cyclotron bombardment.

An operationally friendly, two-step, one-pot process has been developed for the rapid synthesis of carbon-11 labeled indole-3-acetic acid ([11C]IAA or [11C]auxin). By replacing an aprotic polar solvent with tetraethylene glycol, nucleophilic [11C]cyanation and alkaline hydrolysis reactions were performed consecutively in a single pot without a time-consuming intermediate purification step. The entire production time for this updated procedure is 55 min, which dramatically simplifies the entire synthesis and reduces the starting radioactivity required for a whole plant imaging study.

Carbon-11 (β+ emitter, t 1/2 = 20.4 min) radiolabeled l-glutamine is a potentially useful molecular imaging agent that can be utilized with positron emission tomography for both human oncological diagnosis and plant imaging research. Based upon a previously reported [11C]cyanide end-capping labeling method, a systematic investigation of nucleophilic cyanation reactions and acidic hydrolysis reaction parameters, including base, metal ion source, phase transfer catalyst, solvent, reaction temperature and reaction time, was conducted. The result was a milder, more reliable, two-step method which provides l-[5-11C]-glutamine with a radiochemical yield of 63.8 ± 8.7 % (range from 51 to 74 %, n = 10) with >90 % radiochemical purity and >90 % enantiomeric purity. The total synthesis time was 40–50 min from the end of bombardment. In addition, an Fmoc derivatization method was developed to measure the specific activity of this radiotracer.

We constructed a hand-held device to efficiently trap [(11)C]CO2 from the cyclotron target, safely transport up to 3.7GBq (100mCi) doses to remote sites and release it without the need for a liquid cryogen. The system consists of a 180W furnace and a miniature molecular sieve trap (80-100mg; 80-100mesh 13×) placed inside a lead pig weighing 11.1kg. The overall [(11)C]CO2 delivery efficiency of the device is ~82% (> 99% trapping efficiency). Radiation dose rates measured at 30cm from the surface of the pig are

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [(11)C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11-70%, p0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.

An improved production procedure and formulation method for the carbon-11 radiolabeled phytohormone, 3-indolyl-[l- 11 C]acetic acid ([ 11 C]IAA), was developed by modifying selected original reaction parameters. This updated procedure both doubled the yield (from 25.9±6.7% ( n =12) to 61.0±0.3% ( n =10)) and increased the concentration (0.2–0.4 GBq/0.15–0.3 mL), enabling us to provide the radiotracer [ 11 C]IAA suitable for in vivo phyto-PET-imaging studies. The specific activity was improved by more than a factor of three (26.7±5.6 GBq/µmol to 82.5±36.1 GBq/µmol). The total synthesis time for both production and formulation was 81.8±3.0 min ( n =10). In addition, a streamlined semi-remote controlled production system, containing five processing modules, was designed and built for routine [ 11 C]IAA production. This integrated system facilitated routine high radiation level production of [ 11 C]IAA while minimizing radiation exposure to the production chemists.

A rapid, mild radiosynthesis of freebase [

Graphical analysis (GA) is an efficient method for estimating total tissue distribution volume ( VT) from positron emission tomography (PET) uptake data. The original GA produces a negative bias in VT in the presence of noise. Estimates of VT using other GA forms have less bias but less precision. Here, we show how the bias terms are related between the GA methods and how using an instrumental variable (IV) can also reduce bias. Results are based on simulations of a two-compartment model with VT's ranging from 10.5 to 64 mL/cm3 and from PET image data with the tracer [11C]DASB ([11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl) benzonitrile). Four estimates of VT (or distribution volume ratio (DVR) using a reference tissue) can be easily computed from different formulations of GA including the IV. As noise affects the estimates from all four differently, they generally do not provide the same estimates. By taking the median value of the four estimates, we can decrease the bias and reduce the effect of large values contributing to noisy images. The variance of the four estimates can serve as a guide to the reliability of the median estimate. This may provide a general method for the generation of parametric images with little bias and good precision.

Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferiormore » olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.« less

Salvinorin A (SA) is a potent kappa opioid agonist with a brief duration of action. Consistent with this, our previous positron emission tomography (PET) studies of carbon-11 labeled SA showed that brain levels decrease rapidly after intravenous administration. SA is rapidly metabolized, giving the much less potent salvinorin B (SB), which is presumed to be responsible in part for SA's brief duration of action. To test this, we labeled the metabolically stable methyl ester of SA and SB with carbon-11 and compared their pharmacokinetics by PET imaging after intravenous administration to baboons. Labeling of salvinorin B ethoxymethyl ether (EOM-SB), a derivative with greater potency and resistance to metabolism, provided an additional test of the role of metabolism in brain efflux. Plasma analysis confirmed that SB and EOM-SB exhibited greater metabolic stability than SA. However, the three compounds exhibited very similar pharmacokinetics in brain, entering and exiting rapidly. This suggests that metabolism is not solely responsible for the brief brain residence time of SA. We determined that whole-brain concentrations of EOM-SB declined more slowly than SA after intraperitoneal administration in rodents. This is likely due to a combination in EOM-SB's increased metabolic stability and its decreased plasma protein affinity. Our results suggest that protecting salvinorin A derivatives from metabolism will prolong duration of action, but only when administered by routes giving slow absorption.

Introduction We reinvestigated the synthesis of [ N -methyl- 11 C]vorozole, a radiotracer for aromatase, and discovered the presence of an N -methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [ N -methyl- 11 C]vorozole. Methods Norvorozole was alkylated with [ 11 C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ( 13 C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N -methylated products. Pure [ N -methyl- 11 C]vorozole and the contaminating isomer were compared by PET imaging in the baboon. Results Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [ N -methyl- 11 C]vorozole with and without the contaminating N-3 isomer revealed that only [ N -methyl- 11 C]vorozole binds to aromatase. [ N -methyl- 11 C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions. Conclusions The discovery of a contaminating labeled isomer and the development of a method for isolating pure [ N -methyl- 11 C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

Methamphetamine is one of the most addictive and neurotoxic drugs of abuse. It produces large elevations in extracellular dopamine in the striatum through vesicular release and inhibition of the dopamine transporter. In the U.S. abuse prevalence varies by ethnicity with very low abuse among African Americans relative to Caucasians, differentiating it from cocaine where abuse rates are similar for the two groups. Here we report the first comparison of methamphetamine and cocaine pharmacokinetics in brain between Caucasians and African Americans along with the measurement of dopamine transporter availability in striatum. Methamphetamine’s uptake in brain was fast (peak uptake at 9 minutes) with accumulation in cortical and subcortical brain regions and in white matter. Its clearance from brain was slow (except for white matter which did not clear over the 90 minutes) and there was no difference in pharmacokinetics between Caucasians and African Americans. In contrast cocaine’s brain uptake and clearance were both fast, distribution was predominantly in striatum and uptake was higher in African Americans. Among individuals, those with the highest striatal (but not cerebellar) methamphetamine accumulation also had the highest dopamine transporter availability suggesting a relationship between METH exposure and DAT availability. Methamphetamine’s fast brain uptake is consistent with its highly reinforcing effects, its slow clearance with its long lasting behavioral effects and its widespread distribution with its neurotoxic effects that affect not only striatal but also cortical and white matter regions. The absence of significant differences between Caucasians and African Americans suggests that variables other than methamphetamine pharmacokinetics and bioavailability account for the lower abuse prevalence in African Americans.

Dopamine's role in inhibitory control is well recognized and its disruption may contribute to behavioral disorders of discontrol such as obesity. However, the mechanism by which impaired dopamine neurotransmission interferes with inhibitory control is poorly understood. We had previously documented a reduction in dopamine D2 receptors in morbidly obese subjects. To assess if the reductions in dopamine D2 receptors were associated with activity in prefrontal brain regions implicated in inhibitory control we assessed the relationship between dopamine D2 receptor availability in striatum with brain glucose metabolism (marker of brain function) in ten morbidly obese subjects (BMI>40 kg/m(2)) and compared it to that in twelve non-obese controls. PET was used with [(11)C]raclopride to assess D2 receptors and with [(18)F]FDG to assess regional brain glucose metabolism. In obese subjects striatal D2 receptor availability was lower than controls and was positively correlated with metabolism in dorsolateral prefrontal, medial orbitofrontal, anterior cingulate gyrus and somatosensory cortices. In controls correlations with prefrontal metabolism were not significant but comparisons with those in obese subjects were not significant, which does not permit to ascribe the associations as unique to obesity. The associations between striatal D2 receptors and prefrontal metabolism in obese subjects suggest that decreases in striatal D2 receptors could contribute to overeating via their modulation of striatal prefrontal pathways, which participate in inhibitory control and salience attribution. The association between striatal D2 receptors and metabolism in somatosensory cortices (regions that process palatability) could underlie one of the mechanisms through which dopamine regulates the reinforcing properties of food.

We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11C-raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11C-raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled raclopride, pretreatment with methamphetamine (METH) or pretreatment with gamma-vinyl-GABA [S+-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11C-raclopride binding was compared to data from animals that were anesthetized for the uptake period ("Anesthetized Uptake") and full time activity curves were used to calculate 11C-raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11C-raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold raclopride, both groups demonstrated approximately 30% reduction in 11C-raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11C-raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.

Initial validation studies of new radiotracers generally involve kinetic models that require a measured arterial input function. This allows for the separation of tissue binding from delivery and blood flow effects. However, when using a tracer in a clinical setting, it is necessary to eliminate arterial blood sampling due to its invasiveness and the extra burden of counting and analyzing the blood samples for metabolites. In some cases, it may also be necessary to replace dynamic scanning with a shortened scanning period some time after tracer injection, as is done with FDG (F-18 fluorodeoxyglucose). These approximations represent loss of information. In this work, we considered several questions related to this: (1) Do differences in experimental conditions (drug treatments) or populations affect the input function, and what effect, if any, does this have on the final outcome measure? (2) How do errors in metabolite measurements enter into results? (3) What errors are incurred if the uptake ratio is used in place of the distribution volume ratio? (4) Is one- or two-point blood sampling any better for FDG data than the standardized uptake value? and (5) If blood sampling is necessary, what alternatives are there to arterial blood sampling? The first three questions were considered in terms of data from human dynamic positron emission tomography (PET) studies under conditions of baseline and drug pretreatment. Data from [11C]raclopride studies and those from the norepinephrine transporter tracer (S,S)-[11C]O-methyl reboxetine were used. Calculation of a metabolic rate for FDG using the operational equation requires a measured input function. We tested a procedure based on two blood samples to estimate the plasma integral and convolution that occur in the operational equation. There are some tracers for which blood sampling is necessary. Strategies for brain studies involve using the internal carotids in estimating the radioactivity after correcting for partial volume and spillover in order to eliminate arterial sampling. Some venous blood samples are still required for metabolite measurements. The ultimate solution to the problem of arterial sampling may be a wrist scanner, which acts as a small PET camera for imaging the arteries in the wrist. This is currently under development.

Cyclotron targets for the production of [ 18 F]-fluoride usually use a thin metal window to contain the 18 O-enriched water during irradiation. This window is activated by the proton beam, and undesired radioisotopes can enter the target water. A pre-packaged strong anion exchange resin is commonly used for [ 18 O]-water recovery. A two-column method has been developed which delivers >95% of the [ 18 F]-fluoride for radiosynthesis while rejecting >99.9% of the contaminants.

Despite the widespread use of chronic brain implants in experimental and clinical settings, the effects of these long-term procedures on brain metabolism and receptor expression remain largely unknown. Under the hypothesis that intracerebral microdialysis transiently alters tissue metabolism, we performed a series of 18FDG microPET scans prior to and following surgical implantation of microdialysis cannulae. Parallel microPET measures using the competitive dopamine (DA) D2 receptor antagonist, 11C-raclopride, provided an assay of DA stability in these same animals. 18FDG scans were performed prior to microdialysis cannulation and again at 2, 12, 24, 48, 120, 168, 360 and 500 h (0.2, 0.5, 1, 2, 5, 7, 15 and 25 days). Separate animals received a sham surgery and the control group had no surgical intervention. For the first 24 h (scans at 2, 12 and 24 h post-surgery) uptake was reduced in both hemispheres. However, by 48 h, contralateral uptake had returned to pre-surgical levels. The striking finding was that from 48 to 500 h, the microdialysis cannulation produced widespread ipsilateral reductions in 18FDG uptake that encompassed the entire hemisphere. Despite the extent and persistence of these reductions, 11C-raclopride binding and ECF DA concentrations remained stable.

Methylphenidate (MP) and amphetamine (AMP) are first-line treatments for attention-deficit hyperactivity disorder. Although both drugs have similar therapeutic potencies, the stimulatory effect of AMP on extracellular dopamine (ECF DA) is greater than that of MP. We compared extracellular effects directly against synaptic changes. ECF DA was assessed by microdialysis in freely moving rodents and synaptic dopamine (DA) was measured using PET and [11C]-raclopride displacement in rodents and baboons. Microdialysis data demonstrated that MP (5.0 mg/kg, i.p.) increased ECF DA 360% +/- 31% in striatum, which was significantly less than that by AMP (2.5 mg/kg, i.p.; 1398% +/- 272%). This fourfold difference was not reflected by changes in synaptic DA. In fact, rodent PET studies showed no difference in striatal [11C]-raclopride binding induced by AMP (2.5 mg/kg, i.p.; 25% +/- 4% reduction) compared with that by MP (5.0 mg/kg, i.p.; 21% +/- 4% reduction). Primate PET experiments also showed no differences between AMP (0.5 mg/kg, i.v.; 24% +/- 4% reduction) and MP (1.0 mg/kg, i.v.; 25% +/- 7% reduction) induced changes in [11C]-raclopride binding potential. The similar potencies of MP and AMP to alter synaptic DA, despite their different potencies in raising ECF DA, could reflect their different molecular mechanisms.

The monoamine oxidase A and B (MAO A and B) radiotracers [(11)C]clorgyline (CLG) and [(11)C]L-deprenyl (DEP) and their deuterium labeled counterparts (CLG-D and DEP-D) were compared to determine whether their distribution and kinetics in humans are consistent with their physical, chemical and pharmacological properties and the reported ratios of MAO A:MAO B in post-mortem human tissues. Irreversible binding was consistently higher for DEP in brain, heart, kidneys and spleen but not lung where CLG >DEP and not in thyroid where there is no DEP binding. The generally higher DEP binding is consistent with its higher enzyme affinity and larger free fraction in plasma while differences in regional distribution for CLG and DEP in brain, heart, thyroid and lungs are consistent with different relative ratios of MAO A and B in humans.

Reboxetine is a specific norepinephrine transporter (NET) inhibitor and has been marketed in several countries as a racemic mixture of the (R,R) and (S,S) enantiomers for the treatment of depression. Its methyl analog (methylreboxetine, MRB) has been shown to be more potent than reboxetine itself. We developed a nine-step synthetic procedure to prepare the normethyl precursor, which was used to synthesize [11C]O-methylreboxetine ([11C]MRB). We also developed a convenient resolution method using a chiral HPLC column to resolve the racemic precursor to obtain enantiomerically pure individual precursors that lead to the individual enantiomers (R,R)-[11C]MRB and (S,S)-[11C]MRB. Here we report an evaluation of the racemate and individual enantiomers of [11C]MRB as radioligands for PET imaging studies of NET systems in baboons both in brain and in peripheral organs. The relative regional distribution of the radioactivity after injection of [11C]MRB in baboon brain is consistent with the known distribution of NET. For a NET-poor region such as striatum, there were no significant changes in the striatal uptakes with and without the nisoxetine pretreatment. In contrast, a significant blocking effect was observed in NET-rich regions such as thalamus and cerebellum after injection of racemic [11C]MRB, with an even more dramatic effect after injection of (S,S)-[11C]MRB. These results, along with the fact that there was no regional specificity and no blocking effect by nisoxetine for (R,R)-[11C]MRB, suggest the enantioselectivity of MRB in vivo, consistent with previous in vitro and in vivo studies in rodents. PET studies of baboon torso revealed a blocking effect by desipramine only in the heart, a NET-rich organ, after injection of (S,S)-[11C]MRB, but not the (R,R)-isomer. These studies demonstrate that the use of (S,S)-[11C]MRB would allow a better understanding of the role that NET plays in living systems.

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers, l -[ 11 C]deprenyl and deuterium-substituted l -[ 11 C]deprenyl ( l -[ 11 C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke.

Toluene is a widely abused solvent with demonstrated addictive potential in humans. Here we explore if conditioned place preference can be used to study the abuse-related effects of inhaled toluene in rats. Animals were confined to a distinctive compartment of a three-compartment chamber while exposed to toluene vapor and later tested for preference for that compartment compared to appropriate control subjects. In this study, a flame ionization detector was used for on-line monitoring of toluene vapor concentrations inside the conditioning apparatus coupled with computerized recording of the time spent by the animals on the test day in each of the chambers. Sprague-Dawley rats were exposed to 810, 1895 or 4950 ppm of toluene vapors in either the black or white compartment during 30-min pairing sessions given every other day alternating with air exposure for the total of six pairings for each treatment. Rats that received air in both sides (control group) did not show any preference for either side with approximately equal time spent in each compartment on the test day (241 +/- 33 and 234 +/- 34 s, for white and black box, respectively). However, the 1895- and 4950-ppm test groups, but not the 810-ppm group, demonstrated a significant preference for the side paired with toluene exposure. When a subsequent test session was performed during toluene exposures, no conditioned place preference was observed. Thus, toluene produced a clear conditioned place preference that appears to be most evident when animals are not intoxicated. This procedure should be useful for further studies of the abuse-related effects of abused inhalants.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of many biogenic and dietary amines. Though studies of MAO have focused mainly on its regulatory role in the brain, MAO in peripheral organs also represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines, which can cross the blood brain barrier. Indeed, robust central and peripheral MAO activity is a major requirement in the safe use of many CNS drugs, particularly antidepressants, and thus an awareness of the MAO inhibitory potential of drugs is essential in therapeutics. In this study, we examined the feasibility of quantifying MAO A in peripheral organs in healthy human subjects using comparative positron emission tomography (PET) imaging with carbon-11 (t1/2: 20.4 min) labeled clorgyline ([11C]clorgyline) a suicide inactivator of MAO A and its deuterium labeled counterpart ([11C]clorgyline-D2). Heart, lungs, kidneys, thyroid, and spleen showed a robust deuterium isotope effect characteristic of MAO and the magnitude of the effect was similar to that of trancylcypromine, an irreversible MAO inhibitor used in the treatment of depression. Liver time-activity curves were not affected by deuterium substitution precluding the estimation of liver MAO in vivo. In organs showing an isotope effect, MAO A is greatest in the lungs and kidneys followed by the thyroid and heart. This method, which has been previously applied in the human brain, opens the possibility to also directly assess the effects of different variables including smoking, dietary substances, drugs, disease, and genetics on peripheral MAO A in humans. Synapse 49:178–187, 2003. Published 2003 Wiley-Liss, Inc.

In this research, we aim to directly measure the specific activity (SA) of the carbon-11 cyanide ([(11)C]CN¯) produced by our in-house built automated [(11)C]HCN production system and to identify the major sources of (12)C-cyanide ((12)CN¯). The [(11)C]CN¯ is produced from [(11)C]CO2, which is generated by the (14)N(p,α)(11)C nuclear reaction using a cyclotron. Direct measurement of cyanide concentrations was accomplished using a relatively inexpensive, and easy to use ion selective electrode (ISE) which offered an appropriate range of sensitivity for detecting mass. Multiple components of the [(11)C]HCN production system were isolated in order to determine their relative contributions to (12)CN¯ mass. It was determined that the system gases were responsible for approximately 30% of the mass, and that the molecular sieve/nickel furnace unit contributed approximately 70% of the mass. Beam on target (33µA for 1 and 10min) did not contribute significantly to the mass. Additionally, we compared the SA of our [(11)C]HCN precursor determined using the ISE to the SA of our current [(11)C]CN¯ derived radiotracers determined by HPLC to assure there was no significant difference between the two methods. These results are the first reported use of an ion selective electrode to determine the SA of no-carrier-added cyanide ion, and clearly show that it is a valuable, inexpensive and readily available tool suitable for this purpose.

With the goal of investigating the pharmacokinetics of the abused solvent, toluene we have adapted the rapid coupling of methyl iodide with tributylphenylstannane mediated by palladium(0) complex to the synthesis of no-carrier-added [ 11 C]toluene starting with 11 CH 3 I. Two methods for purification and formulation of the tracer were developed. The first one yielded [ 11 C]toluene dissolved in dimethylacetamide/saline solution, for the second one we adapted supercritical fluid technology where the tracer was purified using and conventional C 18 HPLC column and pure supercritical CO 2 fluid as a mobile phase operating at 2000 psi. Formulation of the tracer in cyclodextrin resulted in a significantly higher integrated uptake and distribution volume values. Additionally, we observed higher uptake and slower clearance of 11 C-toluene in white matter, consistent with higher lipid content and neurotoxicological evidence indicating restricted and diffuse white matter changes in toluene abusers. This trend was observed when either DMA or cyclodextrin was used as a vehicle. It appears then, that the choice of a vehicle affected only the degree of bioavailability, but not the regional brain pharmacokinetics. Finally, we demonstrated the effect of a decreased percent difference between DV values for the studies performed on the same day, that is, test/retest variability was lower for all brain regions in β-cyclodextrin experiments. Present results clearly demonstrate that the choice of a vehicle has a significant effect on tracer uptake and should be considered as a potential factor contributing to the pharmacokinetic measurements.

Inhalant abuse is a rapidly growing health problem particularly among adolescents. Yet we know little about the neural mechanisms underlying the abuse liability of inhalants, particularly when compared to other addictive drugs. Specifically, our understanding of the relationship between the regional brain pharmacokinetics and features classically associated with drug reinforcement is lacking. Under the hypothesis that the abuse liability of toluene can be related to its pharmacokinetic properties and the pattern of regional brain uptake, we developed the methodology for radiolabeling and purifying [ 11 C]toluene for use in PET studies. Here we report the regional brain distribution and kinetics of the widely abused solvent toluene in non-human primates and the whole body biodistribution in mice. To our knowledge, this is the first reported study of the in vivo brain pharmacokinetics of labeled toluene in non-human primates. Rapid uptake of radioactivity into striatal and frontal regions was followed by rapid clearance from the brain. Concurrent findings in rodents indicate similar radiotracer kinetics, with excretion through kidneys and liver. Taken together, our data provides insight into pharmacokinetic features possibly associated with the abuse liability of toluene.