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This is a position paper of the Radiopharmacy Committee of the EANM (European Association of Nuclear Medicine) addressing toxicology studies for application of new diagnostic and therapeutic radiopharmaceuticals (RP) that are not approved (i.e., not having a marketing authorization or a monograph in the European Pharmacopoeia), excluding endogenous and ubiquitous substances in humans. This paper discusses the requirements for clinical trials with radiopharmaceuticals for clinical research applications, not necessarily intended to aim at a marketing authorization. If marketing authorization is intended, scientific advice of the competent authorities is mandatory and cannot be replaced by this position paper. The position paper reflects the view of the Radiopharmacy Committee of the EANM and can be used as a basis for discussions with the responsible authorities.

The development of novel radiopharmaceuticals is very rapid and highly innovative both for diagnostic and therapeutic applications. The translation into the clinic, however, is hampered by the high regulatory demands in Europe. This article describes the main rules, guidelines and guidance documents in the European Union in relation to the pharmaceutical regulatory framework. Until today a great number of radiopharmaceuticals are introduced clinically using specific national pathways outside the clinical trial regulation and examples are provided. In this context, the European Pharmacopoeia with a legal status plays an important role in defining quality standards. For clinical trials the application system and regulatory framework in Europe is currently considerably changing. Whereas the current clinical trial directive requires a lengthy and complicated national application process, the new regulation 536/2014 will introduce a streamlined and unified European application process. This new regulation also takes into account the specific properties of radioactive investigational medicinal products and has introduced exceptions for good manufacturing practices (GMP) and labelling for radiopharmaceuticals. Besides the main regulatory texts, several guidelines have been published, e.g. related to toxicity testing or first in man studies. In relation to radiopharmaceuticals professional organization, in particular the EANM, have published a number of documents in relation to GMP, documentation and toxicity studies, that support professionals in the application process. All these documents are summarized and discussed.

Oncogenic K-ras is capable to control tumor growth and progression by rewiring cancer metabolism. In vitro NIH-Ras cells convert glucose to lactate and use glutamine to sustain anabolic processes, but their in vivo environmental adaptation and multiple metabolic pathways activation ability is poorly understood. Here, we show that NIHRas cancer cells and tumors are able to coordinate nutrient utilization to support aggressive cell proliferation and survival. Using PET imaging and metabolomics-mass spectrometry, we identified the activation of multiple metabolic pathways such as: Glycolysis, autophagy recycling mechanism, glutamine and serine/glycine metabolism, both under physiological and under stress conditions. Finally, differential responses between in vitro and in vivo systems emphasize the advantageous and uncontrolled nature of the in vivo environment, which has a pivotal role in controlling the responses to therapy.

The doctorate project is focused on the development and standardization of a general method for F-18 radiolabelling of biologically interesting molecules (e.g. peptides and oligomers), to carry out in vivo imaging assays by PET (Positron Emission Tomography). The selected procedure deals with the introduction of a terminal alkynyl group into the biological substrate, and the synthesis of a functionalizable F-18 molecule containing an azide moiety. Once introduced the radioisotope, the following Huisgen dipolar cycloaddition between the alkyne and the azide affords the desired radiolabelled biomolecule. After problematic and non-producing attempts in employing commercial available or described azides, a fully new fluorinated azide was designed. It is composed by a bifunctionalized aryl bringing, not directly linked to the ring, an azide group at one side, and a PEG chain terminated by a fluoride atom at the other. The aim is to obtain a precursor with suitable characteristics of versatility, easy handling, stability, and reactivity, necessary to make efficient conjugation to biomolecules, and to minimize non-specific binding during PET exam. The synthetic work was carried-out in BIOMETRA Department labs of Milan University, in collaboration with the professor Patrizia Ferraboschi research group, while the radiochemistry activities were performed in Tecnomed Foundation (Milano-Bicocca University) labs. Various synthetic pathways were tested in order to obtain an azidic precursor useful for F-18 introduction, and for the subsequent cycloaddition reaction. In particular, a strategy of consecutive orthogonal protection-deprotection steps brought to the synthesis of three different precursor types (tosylate, mesylate, and iodinated), and the fluorinated reference standard. Starting from commercially available methyl 4-(bromomethyl)benzoate, the ester group was reduced to alcohol. The alcohol residue was protected as tetrahydropyranyl ether, while bromine was employed as l

Anti-VEGF therapy perturbs tumor metabolism, severely impairing oxygen, glucose, and ATP levels. In this study, we investigated the effects of anti-VEGF therapy in multiple experimental tumor models that differ in their glycolytic phenotypes to gain insights into optimal modulation of the metabolic features of this therapy. Prolonged treatments induced vascular regression and necrosis in tumor xenograft models, with highly glycolytic tumors becoming treatment resistant more rapidly than poorly glycolytic tumors. By PET imaging, prolonged treatments yielded an increase in both hypoxic and proliferative regions of tumors. A selection for highly glycolytic cells was noted and this metabolic shift was stable and associated with increased tumor aggressiveness and resistance to VEGF blockade in serially transplanted mice. Our results support the hypothesis that the highly glycolytic phenotype of tumor cells studied in xenograft models, either primary or secondary, is a cell-autonomous trait conferring resistance to VEGF blockade. The finding that metabolic traits of tumors can be selected by antiangiogenic therapy suggests insights into the evolutionary dynamics of tumor metabolism.

The preparation of an Investigational Medicinal Product Dossier (IMPD) for a radiopharmaceutical to be used in a clinical trial is a challenging proposition for radiopharmaceutical scientists working in small-scale radiopharmacies. In addition to the vast quantity of information to be assembled, the structure of a standard IMPD is not well suited to the special characteristics of radiopharmaceuticals. This guideline aims to take radiopharmaceutical scientists through the practicalities of preparing an IMPD, in particular giving advice where the standard format is not suitable. Examples of generic IMPDs for three classes of radiopharmaceuticals are given: a small molecule, a kit-based diagnostic test and a therapeutic radiopharmaceutical.

This document is meant to complement Part B of the EANM ‘Guidelines on current good radiopharmacy practice (cGRPP) in the preparation of radiopharmaceuticals’ issued by the Radiopharmacy Committee of the European Association of Nuclear Medicine, covering small-scale in-house preparation of radiopharmaceuticals with automated modules. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals, which are not intended for commercial purposes or distribution.

OBJECTIVES: To evaluate the role of the metabolic characteristics of cervical tumor uptake as predictors of a) lymph node (LN) metastases, b) recurrence, in the preoperative staging of early-stage cervical cancer. METHODS: 89 patients with FIGO stage IB1 and IIA <4cm cervical cancer were imaged with FDG-PET/CT before radical hysterectomy and pelvic lymphadenectomy. PET/CT images were analyzed and correlated to histological findings. Maximum and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG) of cervical lesions were calculated by an iterative adaptive algorithm. These parameters were correlated to the presence of: a) LN metastases, b) relapse after primary treatment. RESULTS: Out of the 89 patients who underwent preoperative PET/CT scan for staging purpose, 16 were negative at cervical level: they were all pN0 and without recurrence during follow-up (mean 34.1±14.5months). In 69 patients MTV and TLG were significantly higher (p=0.0006 and p=0.03) in pN1 patients in comparison to pN0 patients, while SUV values did not show significant differences between the two groups. No significant correlations were found between SUVmax, SUVmean, MTV, TLG and the evidence of relapse (mean follow-up 29.2±15.5months). CONCLUSIONS: In early-stage cervical cancer MTV and TLG correlate with the presence of nodal metastases, but their clinical impact on patients management has to be clarified. The absence of pathological cervical uptake could be a good prognostic factor, while SUVmax, SUVmean, MTV, TLG of the cervical uptake have not been found predictors of recurrence.

The aim of this paper is to assess the activation phenomena and to evaluate the risk of external exposure and intake doses for the maintenance staff of two medical cyclotrons. Two self-shielded cyclotrons are currently operating in the facility for the routine production of (11)C and (18)F. Four radiochemistry laboratories are linked to the cyclotrons by means of shielded radioisotope delivery lines. Radiopharmaceuticals are prepared both for the PET Diagnostic Department, where four CT-PET scanners are operating with a mean patient workload of 40 d(-1) and for [(18)F]FDG external distribution, to provide radiopharmaceuticals for other institutions. In spite of the fact that air contamination inside the radiochemistry laboratories during the synthesis represents the largest 'slice of the pie' in the evaluation of annual intake dose, potential contamination due to the activated particulate, generated during cyclotron irradiation by micro-corrosion of targets and other components potentially struck by the proton beam and generated neutrons, should be considered. In this regard, the most plausible long-lived (T(1/2) > 30 d) radioisotopes formed are: (97)Tc, (56)Co, (57)Co, (58)Co, (60)Co, (49)V, (55)Fe, (109)Cd, (65)Zn and (22)Na. The results for the operating personnel survey has revealed only low-level contamination for (65)Zn in one test, together with minor (18)F intake, probably due to the environmental dispersion of the radioisotope during the [(18)F]FDG synthesis.

This guidance is meant as a guidance to Part B of the EANM "Guidelines on Good Radiopharmacy Practice (GRPP)" issued by the Radiopharmacy Committee of the EANM (see www.eanm.org), covering the small-scale "in house" preparation of radiopharmaceuticals which are not kit procedures. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of, for example, PET, therapeutic or other radiopharmaceuticals which are not intended for commercial purposes or distribution.

60)Cu and (64)Cu are useful radioisotopes for positron emission tomography (PET) radiopharmaceuticals and may be used for the preparation of promising agents for diagnosis and radiotherapy. In this study, the production and purification of (60/64)Cu starting from (60/64)Ni using a new automated system, namely Alceo, is described. A dynamic process for electrodeposition and dissolution of (60/64)Ni/(60/64)Cu was developed. Preliminary production yields of (60)Cu and (64)Cu were 400 and 300mCi, respectively. (64)Cu was used to radiolabel the hypoxia detection tracer ATSM with a specific activity of 2.2+/-1.3Ci/mumol.

The aim of this paper is to evaluate the risks and doses for the internal contamination of the radiochemistry staff in a high workload medical cyclotron facility. The doses from internal contamination derive from the inhalation of radioactive gas leakage from the cells by personnel involved in the synthesis processes and are calculated from urine sample measurements. Various models are considered for the calculation of the effective committed dose from the analysis of these urine samples, and the results are compared with data obtained from local environmental measurement of the radioactivity released inside the lab.

Purpose: The aim of this study was to develop a cellular model for the concurrent imaging of reporter genes expression by using positron emission tomography (PET) and bioluminescence imaging (BLI) for the assessment of estrogen receptor activity in vivo in a breast cancer model. Methods: Two reporters were chosen: a mutated form of the dopaminergic D2 receptor (D2R80A) for PET imaging, and the Firefly Luciferase for BLI. The presence of an IRES sequence between the two reporters ensured the coordinated expression driven by the same regulatory sequence containing an estrogen responsive element (ERE). To prevent chromatin effects on reporter expression, the construct was flanked by insulator sequences (Matrix Attachment Region, MAR). Results: In vitro studies showed that the vector was efficient in coordinating the expression of the two genes. Moreover, stably transfected cells implanted in recipient animals maintained their capacity to express the reporters and react to systemic treatments permitting the in vivo study of ERs activity by PET and BLI imaging. In vitro expression analysis after long-term treatments showed different behaviour of the two reporter proteins in monitoring estrogen-dependent transcription outlining the importance of multi-reporter systems. With this model, PET and BLI can be applied to the concurrent evaluation of gene expression induced by estrogen and its analogues by using a bicistronic construct. Conclusion: The combined features of rapid, sensitive, sequential BLI and tomographic and quantitative PET imaging will allow the use of this strategy for the in vivo evaluation of molecular processes also for pharmacodynamic studies.

Purpose. Huntington¿s disease (HD) is a progressive neurodegenerative disorder, which is characterised by prominent neuronal cell loss in the basal ganglia with motor and cognitive disturbances. One of the most well-studied pharmacological models of HD is produced by local injection in the rat brain striatum of the excitotoxin quinolinic acid (QA), which produces many of the distinctive features of this human neurodegenerative disorder. Here, we report a detailed analysis, obtained both in vivo and in vitro of this pharmacological model of HD. Materials and methods. By combining emission tomography (PET) with autoradiographic and immunocytochemical confocal laser techniques, we quantified in the QA-injected striatum the temporal behavior (from 1 to 60 days from the excitotoxic insult) of neuronal cell density and receptor availability (adenosine A2A and dopamine D2 receptors) together with the degree of microglia activation. Results. Both approaches showed a loss of adenosine A2A and dopamine D2 receptors paralleled by an increase of microglial activation. Conclusion. This combined longitudinal analysis of the disease progression, which suggested an impairment of neurotransmission, neuronal integrity and a reversible activation of brain inflammatory processes, might represent a more quantitative approach to compare the differential effects of treatments in slowing down or reversing HD in rodent models with potential applications to human patients.

Standards and des-methyl precursors of (R)- and (S)-thionisoxetine, potent and selective norepinephrine reuptake inhibitors, were synthesized and radiolabeled with carbon-11. Both enantiomers of the N-methyl-3-(2-thiomethylphenoxy)-3-phenylpropanamine and the 3-(2-thiomethylphenoxy)-3-phenylpropylamine were obtained via multi-step syntheses, while the radiosyntheses were carried out using [(11)C]CH(3)I. The radiochemical yields were 26%, decay corrected and the specific radioactivity ranging from 2 to 3Ci/mumol. The HPLC analyses were performed using a chiral column: during the radiolabeling, no racemization occurred and the isomers were synthesized with high enantiomeric purity

The aim of this paper is to report the data concerning the contamination of the exhausted air from the hot cells dedicated to the large-scale synthesis of positron emission tomography (PET) radiopharmaceuticals. Two cyclotrons are currently operating in Ospedale San Raffaele for the routine production of C and F. They are linked with four radiochemistry laboratories by means of shielded radioisotope delivery lines. The above labs are dedicated both to the large scale preparation and to the research and development of PET radiopharmaceuticals. The department hosts four CT-PET scanners, which operate with a mean patient workload of 40 per day. Radiosyntheses are performed using automated modules located in 10 hot cells. The air outlets are monitored online by a 2-inch NaI(Tl) counter in a Marinelli geometry counting volume. Contamination values up to 10(5) Bq L(-1) have been measured at the hot cell exit point during the synthesis. The corresponding concentrations at the point of release in atmosphere are largely above the threshold of 1.29 Bq L(-1), defined by national regulations as the limit for free environmental release. A shielded gas storage system controlled by a dedicated, customized software program has thus been installed to prevent the potentially hazardous release of gaseous radioactive contaminants. The system has allowed us to maintain the effective dose to neighboring population groups below the limit of 10 muSv y(-1)

The present article describes the decommissioning of a compact, self-shielded, 11 MeV medical cyclotron. A Monte Carlo simulation of the possible nuclear reactions was performed in order to plan the decommissioning activities. In the course of the cyclotron dismantling, cyclotron components, shields, and floor concrete samples were measured. Residual activities were analyzed with a Ge(Li) detector and compared with simulation data. Doses to staff involved in the decommissioning procedure were monitored by individual TL dosimeters. The simulations identified five radioactive nuclides in shields and floor concrete: 55Fe and 45Ca (beta emitters, total specific activity: 2.29 x 10(4) Bq kg) and 152Eu, 154Eu, 60Co (gamma emitters, total specific activity: 1.62 x 10(3) Bq kg-1). Gamma-ray spectrometry confirmed the presence of gamma emitters, corresponding to a total specific activity of 3.40 x 10(2) Bq kg-1. The presence of the radioisotope 124Sb in the lead contained in the shield structure, corresponding to a simulated specific activity of 9.38 x 10(3) Bq kg-1, was experimentally confirmed. The measured dose from external exposure of the involved staff was <20 muSv, in accordance with the expected range of values between 10 and 20 muSv. The measured dose from intake was negligible. Finally, the decommissioning of the 11 MeV cyclotron does not represent a risk for the involved staff, but due to the presence of long-lived radioisotopes, the cyclotron components are to be treated as low level radioactive waste and stored in an authorized storage area

An improved synthesis of the precursor acetic acid-piperidine-4-yl ester by acetylation of 4-hydroxypiperidine hydrochloride in anhydrous chloroform was developed. A procedure for fast evaluation and characterization of products originated by acetylation of the 4-piperidinol using LC-APCI/MS with an acetonitrile-water gradient method on a Merck Purosphere RP-18 column was also developed. The highly purified precursor allowed the production of [C-11]MP4A for PET studies of acethylcholine neurotransmission system. The tracer was produced with > 98% radiochemical purity, with yields ranging 20-60% (decay-corrected) from EOB. (c) 2005 Elsevier Ltd. All rights reserved.

Purpose: The aim of this study was to evaluate the suitability of [ 11C]SCH442416 for the in vivo imaging of adenosine A2A receptors. Methods: In rats and Macaca nemestrina, we evaluated the time course of the cerebral distribution of [11C]SCH442416. Furthermore, in rats we investigated the rate of metabolic degradation, the inhibitory effects of different drugs acting on adenosine or dopamine receptors and the modification induced by the intrastriatal administration of quinolinic acid (QA). Results: The rate of metabolic degradation of [11C]SCH442416 in rats was slow; 60 min after tracer injection, more than 40% of total plasma activity was due to unmetabolised [11C]SCH442416. At the time of maximum uptake, radioactive metabolites represented only 6% of total extractable activity in the cerebellum and less than 1% in the striatum. In the striatum, the region with the highest expression of A2A receptors, the in vivo uptake of [ 11C]SCH442416 was significantly reduced only by drugs acting on A2A receptors or by QA, a neurotoxin that selectively reduces the number of intrastriatal GABAergic neurons. Position emission tomography (PET) studies in monkeys indicated that the tracer rapidly accumulates in brain, reaching maximum uptake between 5 and 10 min. Twenty minutes after the injection, radioactivity concentration in the striatum was two times that in the cerebellum. Conclusion: The specificity of binding, the rank order of regional distribution in the brain of rats and M. nemestrina, the good signal to noise ratios and the low amount of radioactive metabolites in brain and periphery indicate that [11C]SCH442416 is a promising tracer for the in vivo imaging of A2A adenosine receptors using PET. © Springer-Verlag 2004.

The selective dopamine D(3) receptor ligands N-4-[4-[(2,3-dichlorophenyl)piperazin-1-yl]butyl]1-methoxy-2-naphthalencarboxamide (1) and N-4-[4-[(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (2) were labeled with (11)C (t(1/2) = 20.4 min) as potential radioligands for the noninvasive assessment of the dopamine D(3) neurotransmission system in vivo with positron emission tomography (PET). The radiosynthesis consisted in an O-methylation of the des-methyl precursors N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-1-hydroxy-2-naphthalenecarboxamide (3) and N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-hydroxy-2-benzofurancarboxamide (4) with [(11)C]methyl iodide using tBuOK/HMPA and KOH/DMSO, respectively. The radiotracers [(11)C]1 and [(11)C]2 were obtained in 35 min with over 99% radiochemical purity, 74 +/- 37 GBq/mumol of specific radioactivity, 13% and 26% radiochemical yield (EOB, decay-corrected). Distribution studies in rats demonstrated that the new tracers [(11)C]1 and [(11)C]2 cross the blood-brain barrier and localize in the brain. However, the kinetics of cerebral uptake did not reflect the regional expression of the D(3) receptors. Despite their in vitro pharmacological profile, [(11)C]1 and [(11)C]2 do not display an in vivo behavior suitable to image D(3) receptor expression using PET.

(4S)-1-[(S)-3-Mercapto-2-methylpropanoyl]-4-phenylthio-L-proline (Zofenoprilat, 2), the active metabolite of the potent ACE inhibitor Zofenopril Calcium (1), was labelled with carbon-11 (t1/2=20.4 min) to evaluate its pharmacokinetics behaviour in human body using Positron Emission Tomography (PET). [11C]2 labelling procedures were based on the use of immobilized Grignard reagent and the acylation of (S)-4-phenylthio-L-proline methyl ester (5) with 11C-labelled methacryloyl chloride, followed by a Michael addition with thiobenzoic acid. The radiochemical yield was 5-10% (EOB, decay corrected) and specific radioactivity ranged from 0.5 to 1.5 Ci/micromol (18.5-55.5 GBq/micromol). Preliminary in vivo human evaluation of [11C]2 showed that the drug accumulates in organs which express high levels of ACE, like lungs and kidneys, and in organs involved in drug metabolism such as the liver and gall bladder. Results of the distribution of [11C]2 showed a measurable concentration of the drug in the target tissues such as the kidney and to a minor extent, the heart, where it can afford organ protection.

High specific radioactivity is required for receptor studies with PET. Hereby we wish to report our experience using Nuclear Interface PET Tracer Synthesizer for preparation of Carbon-11 radioligands and module's modifications, which allowed to achieve high specific radioactivity

The radiolabelling with the positron-emitter Carbon-11 and the biological evaluation in rats of 3-[2-[4-(2-[C-11]methoxyphenyl)piperazin-1 -yl]ethyl] pyrimido [5,4-b] indole-2,4-dione ([C-11]RN5), alpha(1)-adrenoceptor antagonist (K-i = 0.21 nM), as a putative radioligand for the noninvasive assessment of alpha(1)-adrenoceptors with positron emission tomography (PET) is reported. The radiosynthesis procedure consisted of O-methylation of des-methyl precursor with [C-11]methyl iodide in the presence of potassium hydroxide in dimethylformamide (DMF) at 80 degreesC. [C-11]RN5 was obtained in >99% radiochemical purity in 25 min with a radiochemical yield in the 20-30% range, end of synthesis (EOS) (non-decay corrected) and a specific radioactivity of 92.5 18.5 GBq/mumol. Pre-clinical studies in rats showed a high uptake of [C-11]RN5 in heart, spleen, adrenal gland. lung and kidney but not in the brain. Inhibition studies with high doses of different adrenergic antagonists indicate that more than 70% of myocardial uptake of [C-11]RN5 is due to specific binding to alpha(1)-adrenoceptors. Our results indicate that [C-11]RN5 is suitable to be further developed as a potential radioligand for the in vivo PET imaging of myocardial alpha(1)-adrenoceptors in humans. (C) 2002 Published by Elsevier Science B.V

In implementing published procedures for the incorporation of [C-11]carbon dioxide on the immobilized Grignard reagents for the radiosynthesis of [C-11]acyl chlorides, several modifications on a commercial PET tracer synthesizer module for C-11-methylations were made to obtain reliable and reproducible production processes for routine clinical applications. High yields of [carbonyl-C-11]WAY-100635 and [C-11]zofenoprilat were obtained via C-11-carboxylation using [carbonyl-C-11]cyclohexanecarbonyl chloride and 2-methyl-[1-C-11]acryloyl chloride prepared with the modified module. (C) 2002 Elsevier Science Ltd. All rights reserved.

The procedure previously reported for the radiosynthesis of [123I]betaCIT was modified in order to improve both radiochemical yield and purity of betaCIT (2beta-carbomethoxy-3beta(4-iodophenyl) tropane) to be injected for SPECT (Single Photon Emission Computed Tomography) analysis imaging. The overall procedure, involving a HPLC purification step, results in quite good and reproducible yields of a highly purified tracer.

(+/-)-1-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2-propanol (bisoprolol) is a potent, clinically used beta(1)-adrenergic agent. (R)-(+) and (S)-(-) enantiomers of bisoprolol were labelled with carbon-11 (t(1/2)=20.4 min) as putative tracers for the non-invasive assessment of the beta(1)-adrenoceptor subtype in the human heart and brain with positron emission tomography (PET). The radiosynthesis consisted of reductive alkylation of des-iso-propyl precursor with [2-11C]acetone in the presence of sodium cyanoborohydride and acetic acid. The stereo-conservative synthesis of (R)-(+) and (S)-(-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-amino-2-propanol to be used as the precursors for the radiosynthesis of [11C]bisoprolol enantiomers was readily accomplished by the use of the corresponding chiral epoxide in three steps starting from the commercially available hydroxybenzyl alcohol. The final labelled product (either (+) or (-)-1-[4-(-isopropoxyethoxymethyl)-phenoxy]-3- [11C]isopropylamino-2-propanol) was obtained in 99% radiochemical purity in 30 min with 15+/-5% (EOS, non-decay corrected) radiochemical yield and 3.5+/-1 Ci/micromol specific radioactivity. Preliminary biological evaluation of the tracer in rats showed that about 30% of heart uptake of [11C](S)-bisoprolol is due to specific binding. The high non-specific uptake in lung might mask the heart uptake, thus precluding the use of [11C](S)-bisoprolol for heart and lung studies by PET. The remarkably high uptake of the tracer in rat brain areas rich of beta-adrenergic receptors such as pituitary (1.8+/-0.3% I.D. at 30 min) was blocked by pre-treatment with the beta-adrenergic antagonists propranolol (45%) and bisoprolol (51%, p<0.05). [11C](S)-bisoprolol deserves further evaluation in other animal models as a putative beta(1) selective radioligand for in vivo investigation of central adrenoceptors.

Emission tomography techniques and, in particular, positron emission tomography (PET) enable the in vivo study of several physiological and neurochemical variables in human subjects using methods originally developed for quantitative autoradiography. In particular, PET allows one to evaluate in human subjects: (a) the effect of specific neurochemical challenges on regional brain function at rest or under activation; (b) the activity of neurotransmitters and the regional expression of specific molecular targets during pathology including their modulation by drug treatment; (c) the kinetics of drug disposition and activity directly in the target organ. This is of primary interest in the field of biological psychiatry and in psychoactive drugs development, where it is particularly difficult to reproduce human diseases using animal models in view of the peculiarity of this field and the large heterogeneity of each psychiatric illness also inside the same clinical definition. The aim of this paper is to review the principal strategies and the main results of the use of PET in psychopharmacology.

The novel quinoline-2-carboxamide derivatives N-[methyl-C-11]-3-methyl-4-phenyl-N-(phenyl-methyl)quinoline-2-carboxamide ([C-11]4), (+/-)-N-[methyl-C-11]-3-methyl-N-(1-methylpropyl)-4- phenylquinoline-2-carboxamide ([C-11]5), and (+/-)-N-[methyl-C-11]-3-methyl-4-(2-fluorophenyl)-N-(1-methylpropyl)quinoline-2-carboxamide ([C-11]6) were labeled with carbon-11 (t(1/2) = 20.4 min, beta (+) = 99.8%) as potential radioligands for the noninvasive assessment of peripheral benzodiazepine type receptors (PBR) in vivo with positron emission tomography (PET). The radiosynthesis consisted of N-methylation of the desmethyl precursors 3-methyl-4-phenyl-N-(phenylmethyl)quinoline-2-carboxamide (4a), (+/-)-3-methyl-N-(1-methylpropyl)-4-phenylquinoline-2-carboxamide (5a), and (+/-)-4-(2-fluorophenyl)-3-methyl-N-(1-methylpropyl)quinoline-2-carboxamide (6a) with either [C-11]methyl iodide or [C-11]methyl triflate in the presence of tetrabutylammonium hydroxide or potassium hydroxide in dimethylformamide. The radioligands [C-11]4, [C-11]5, and [C-11]6 were synthesized with over 99% radiochemical purity in 30 min, 30 +/- 5% radiochemical yield, calculated at the end of synthesis (EOS) non-decay-corrected, and 2.5 +/- 1.2 Ci/mu mol of specific radioactivity. Inhibition studies in rats following intravenous pre-administration of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195, 1) showed high specific binding to PER of [C-11]4, [C-11]5, and [C-11]6 in heart, lung, kidney, adrenal gland, spleen, and brain. The biological data suggest that [C-11]5, [C-11]6, and particularly [C-11]4 are promising radioligands for PER imaging in vivo with PET.

Erytro-(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[ iso-propylamino]-2-butanol (ICI 118551) a potent clinically used beta2 adrenergic antagonist, was labelled with carbon-11 (t1/2 = 20.4 min) as a potential radioligand for the non-invasive assessment of beta2 adrenergic receptors in the lung with positron emission tomography (PET). The radiolabelled compound was prepared by reductive N-alkylation of its des-isopropyl precursor with [2-11C]acetone. (+/-)-[11C]ICI 118551 was obtained in greater than 98% radiochemical purity in 30 min with a radiochemical yield of 15 + 5% (non-decay corrected) and a specific radioactivity 2.5 +/- 0.5 Ci/micromol. The biological evaluation of racemic erythro (+/-)-[11C]ICI 118551 in rats and Macaca Nemestrina shows a high radioactivity uptake in lung and heart. However, in both animal models no detectable displacement of lung radioactivity concentration was observed after pre-treatment with propranolol or ICI 118551, which indicates that in this organ, radioligand uptake is mostly due to non-specific binding. The biological data suggest that erythro (+/-)-[11C]ICI 118551 is not adequate to be further developed as a tracer for beta2 adrenergic receptor imaging in vivo

This paper describes the radiosynthesis of [C-11]CGP62349, a potential ligand to assess GABA, receptors in vivo. C-11 was introduced by O-methylation of the corresponding des-methyl precursor, namely CGP67780. The final product was obtained with a reliable method in good yield. The radioligand was tested in monkey, revealing negligible blood brain barrier penetration and brain uptake, thus prompting us to search for a new target structure with a better lipophilicity. NUCL MED BIOL 27;6:565-569, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.

Carbon-11 labeled acetone is a useful radiosynthetic precursor. Previously, strict control of no-carrier-added stoichiometry was required to prepare it from reaction of CO2 and methyl lithium. However, excess methyl lithium may be selectively quenched to avoid reaction with nascent acetone to give tert-butanol. We report a simple pKa-based strategy to sequentially and selectively quench MeLi and acetone to give yields of up to 100% acetone even in the presence of a large excess of MeLi. The method gives good yields of acetone under conditions that previously precluded its synthesis

The title carnitine derivative was labelled both with [11C]methyl iodide and [3H]methyl iodide. The former was synthesized in order to improve the knowledge of the acyl carnitines fate in humans. The latter was synthesized, at approximately the same concentration level as that of the former, in order to optimize its radiosynthesis, taking advantage from the long half-life of the tritium. # 1999 Elsevier Science Ltd. All rights reserved.

The neural correlates of recovery from aphasia are largely unknown. Several different sources of evidence, from clinical studies to neurophysiological investigations, have suggested a contribution of the contralateral, undamaged hemisphere in recovery from aphasia. Eight patients with unilateral left hemispheric stroke were submitted to a standard language examination and to a [18F]FDG PET study in the recent phase after stroke (within 2 weeks) and 6 months later. All patients had a substantial recovery of specific aspects of language functions at the follow-up. Analysis of regional glucose metabolism showed hypometabolism in structurally unaffected regions both in the left and in the right hemisphere (diaschisis), in the acute stage. Glucose metabolism increased significantly on both sides in all patients at the second PET study. Regional analysis showed significant positive correlations between changes in metabolic values in several cortical and subcortical regions in the right hemisphere and changes in language performance at follow-up. The present findings show that an extensive, bihemispheric depression of metabolism is found in the acute stage after stroke in aphasic patients. Language recovery in the first months after aphasia onset is associated with regression of functional depression (diaschisis) in structurally unaffected regions, in particular in the right hemisphere.

Estrogen receptors are expressed in several brain areas of various animal species, and steroid hormones exert physiologic and biochemical effects on the central nervous system. The aim of the present study was to evaluate in female adult rats, the suitability of 16 alpha [18F]fluoro-17 beta-estradiol ([18F]FES), a selective estrogen receptor ligand, for the in vivo assessment of brain estrogen receptors. This was considered to be a preliminary step in evaluating the potential usefulness of [18F]FES for studies of cerebral estrogen receptors with positron emission tomography (PET) in nonhuman primates and human subjects. We evaluated (a) the time course of the metabolic degradation of [18F]FES in blood; (b) the time course of distribution of the tracer in discrete cerebral areas; (c) the inhibitory effect of increasing doses of cold estradiol on cerebral [18F]FES uptake; and (d) the possibility of in vivo quantification of estrogen receptor binding parameters using both equilibrium and dynamic kinetic analyses. We quantified [18F]FES binding to estrogen receptors using both equilibrium and dynamic kinetic analyses. The results of this study indicate that [18F]FES is a suitable tracer for the measurement of estrogen receptors in the pituitary and hypothalamus, using either the equilibrium or the kinetic analysis. However, [18F]FES is inadequate for the in vivo investigation of estrogen binding sites in brain areas with low receptor density, such as the hippocampus.