Production of [13N]NH3 with ultra-high specific activity

Aqueous solutions of [¹³N]NH₃ were synthesized according to well-known methods using the ¹⁶O(p, α)¹³N reaction under conditions rendering the smallest possible amount of nitrogen-contaminants. The specific activities and radiochemical yields were measured. Factors, affecting the specific activity of [¹³N]NH₃, were investigated using radio-ionchromatography. The achieved specific activities (GBq/μmol) and radiochemical yields (GBq) of [¹³N]NH₃ were 14±2.8 and 0.3±0.1 (TiCl₃ method)1, 590±200 and 5.4±1.1 (DeVarda's Alloy method), 5500±500 and 12.7±0.1 (ethanol method), and 6200±2700 and 2.8±0.3 (hydrogen method, 3 bar), respectively at 15 μA for 20 min irradiation (1; 5 μA, 5 min irradiation). More than 70% of the N-13 generated with the hydrogen method was of the chemical form [¹³N]N₂.     

Assessment of the best N3 − donors in preparation of [M(N)(PNP)]-based (M = 99mTc-; 188Re) target-specific radiopharmaceuticals: Comparison among succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO2C-PEG600-DTCZ)

Succinic dihydrazide (SDH), N-methyl-S-methyl dithiocarbazate (HDTCZ) and PEGylated N-methyl-S-methyl dithiocarbazate (HO₂C-PEG₆₀₀-DTCZ) are nitrido nitrogen atom donors employed for the preparation of nitride [M(N)]‐complexes (M = ^99mTc and ¹⁸⁸Re).This study aims to compare the capability and the efficiency of these three N^3 − group donors, in the preparation of [M(N)PNP]-based target-specific compounds (M = ^99mTc, ¹⁸⁸Re; PNP = aminodiphosphine).For this purpose, three different kit formulations (SDH kit; HO₂C-PEG₆₀₀-DTCZ kit; HDTCZ kit) were assembled and used in the preparation of [M(N)(cys ~)(PNP3)]^0/+ complexes (cys ~ = cysteine derivate ligands).For each formulation, the radiochemical yield (RCY) of the [M(N)(~ cys)(PNP3)] compounds, was determined by HPLC. The deviation of the percentage of RCY, due to changes in concentration of the N^3 − donors and of the exchanging ligand, was determined.For ^99mTc, data clearly show that HDTCZ is the most efficient donor of N^3 −; however, SDH is the most suitable nitrido nitrogen atom donor for the preparation of [^99mTc(N)(PNP)]-based target-specific agents with high specific activity. When HO₂C-PEG₆₀₀-DTCZ or HDTCZ are used in N^3 − donation, high amounts of the exchanging ligand (10^− 4 M) were required for the formation of the final complex in acceptable yield.The possibility to use microgram amounts of HDTCZ also in [¹⁸⁸Re(N)] preparation (0.050 mg) reduces its ability to compete in ligand exchange reactions, minimizing the quantity of chelators required to obtain the final complex in high yield. This finding can be exploit for increasing the radiolabeling efficiency in [¹⁸⁸Re(N)]-radiopharmaceutical preparations compared to the previously reported HDTCZ-based procedure, notwithstanding a purification process could be necessary to improve the specific activity of the complexes.     

An improved synthesis of 4-[18F]-ADAM,a potent serotonin transporter imaging agent

An improved synthesis of N,N-dimethyl-2-(2-amino-4-[¹⁸F]fluorophenylthio)benzylamine (4-[¹⁸F]-ADAM, 2) as a potent serotonin transporter (SERT) imaging agent is described. Molecular orbital (MO) calculation predicts that N,N-dimethyl-2-(2-nitro-4-trimethylammoniumtrifluoromethanesulfonylphenylthio)benzamide (8) is probably a better precursor than N,N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1) for preparing 2. Radioligand 2 was synthesized by the reaction of either precursor 1 or precursor 8 with K[¹⁸F]/K_2.2.2 at 120 °C followed by reduction with BH₃ at 80 °C. The radiochemical yield (EOB) of 2 synthesized from precursor 1 and 8 was 5.7±2.4% (n=6) and 14.8±4.0% (n=5), respectively, in a synthesis time of 120 min from EOB. The specific activity of 2 was 3 Ci/μmol or 111 GBq/μmol (EOB). Thus, this new synthetic method has significantly improved the radiochemical yield of 4-[¹⁸F]-ADAM and makes this radioligand more accessible to PET Centers without a cyclotron.     

Rat Imaging and In Vivo Stability Studies using [11C]-Dimethyl-Diphenyl Ammonium,a Candidate Agent for PET-Myocardial Perfusion Imaging

BackgroundPET myocardial perfusion imaging (MPI) holds several advantages over SPECT for diagnosing coronary artery disease. The short half-lives of prevailing PET-MPI agents hamper wider clinical application of PET in nuclear cardiology; prompting the development of novel PET-MPI agents. We have previously reported on the potential of radiolabeled ammonium salts, and particularly on that of [¹¹C]dimethyl-diphenyl-ammonium ([¹¹C]DMDPA), for cardiac PET imaging. This study was designed to improve the radiosynthesis and increase the yield of [¹¹C]DMDPA, characterize more meticulously the kinetics of radioactivity distribution after its injection via micro-PET/CT studies, and further explore its potential for PET-MPI.MethodsThe radiosynthetic procedure of [¹¹C]DMDPA was improved with respect to the previously reported one. The kinetics of radioactivity distribution following injection of [¹¹C]DMDPA were investigated in juvenile and young adult male SD rats using microPET/CT, and compared to those of [¹³N]NH₃. Furthermore, the metabolic fate of [¹¹C]DMDPA in vivo was examined after its injection into rats.ResultsFollowing a radiosynthesis time of 25–27 min, 11.9 ± 1.1 GBq of [¹¹C]DMDPA was obtained, with a 43.7% ± 4.3% radiochemical yield (n = 7). Time activity curves calculated after administration of [¹¹C]DMDPA indicated rapid, high and sustained radioactivity uptake in hearts of both juvenile and young adult rats, having a two-fold higher cardiac radioactivity uptake compared to [¹³N]NH₃. Accordingly, at all time points after injection to both juvenile and young adult rats, image quality of the left ventricle was higher with [¹¹C]DMDPA compared to [¹³N]NH₃. In vivo stability studies of [¹¹C]DMDPA indicate that no radioactive metabolites could be detected in plasma, liver and urine samples of rats up to 20 min after injection, suggesting that [¹¹C]DMDPA is metabolically stable in vivo.ConclusionsThis study further illustrates that [¹¹C]DMDPA holds, at least in part, essential qualities required from a PET-MPI probe. Owing to the improved radiosynthetic procedure reported herein, [¹¹C]DMDPA can be produced in sufficient amounts for clinical use.     

Synthesis of carbon-11-labeled tricyclic necroptosis inhibitors as new potential PET agents for imaging of tumor necrosis factor α (TNF-α)

Carbon-11-labeled tricyclic necroptosis inhibitors were first designed and synthesized as new potential PET agents for imaging of tumor necrosis factor α (TNF-α). The target tracers were prepared by O-[¹¹C]methylation of their corresponding precursors using [¹¹C]CH₃OTf under basic conditions and isolated by a simplified SPE method in 50–60% radiochemical yields based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 15–20 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 111–185 GBq/μmol.     

A “dose on demand” Biomarker Generator for automated production of [18F]F− and [18F]FDG

The University of Oklahoma—College of Pharmacy has installed the first Biomarker Generator (BG75) comprising a self-shielded 7.5-MeV proton beam positive ion cyclotron and an aseptic automated chemistry production and quality control module for production of [¹⁸F]F⁻ and clinical [¹⁸F]FDG. Performance, reliability, and safety of the system for the production of “dose on demand” were tested over several months. No-carrier-added [¹⁸F]F⁻ was obtained through the ¹⁸O(p,n)¹⁸F nuclear reaction by irradiation (20–40 min) of a >95% enriched [¹⁸O]H₂O target (280 μl) with a 7.5-MeV proton beam (3.5–5.0 μA). Automated quality control tests were performed on each dose. The HPLC-based analytical methods were validated against USP methods of quality control. [¹⁸F]FDG produced by BG75 was tested in a mouse tumor model implanted with H441 human lung adenocarcinoma cells. After initial installment and optimization, the [¹⁸F]F⁻ production has been consistent since March 2011 with a maximum production of 400 to 450 mCi in a day. The average yield is 0.61 mCi/min and 0.92 mCi/min at 3.8 µA and 5 µA, respectively. The current target window has held up for over 25 weeks against >400 bombardment cycles. [¹⁸F]FDG production has been consistent since June 2012 with an average of six doses/day in an automated synthesis mode (RCY≈50%). The release criteria included USP-specified limits for pH, residual solvents (acetonitrile/ethanol), kryptofix, radiochemical purity/identity, and filter integrity test. The entire automated operation generated minimal radiation exposure hazard to the operator and environment. As expected, [¹⁸F]FDG produced by BG75 was found to delineate tumor volume in a mouse model of xenograft tumor. In summary, production and quality control of “[¹⁸F]FDG dose on demand” have been accomplished in an automated and safe manner by the first Biomarker Generator. The implementation of a cGMP quality system is under way towards the ANDA submission and first clinical use of [¹⁸F]FDG produced by BG75.     

Radiosynthesis of 3-indolyl[1-11C]acetic acid for phyto-PET-imaging: An improved production procedure and formulation method

An improved production procedure and formulation method for the carbon-11 radiolabeled phytohormone, 3-indolyl-[l-¹¹C]acetic acid ([¹¹C]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 [¹¹C]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 [¹¹C]IAA production. This integrated system facilitated routine high radiation level production of [¹¹C]IAA while minimizing radiation exposure to the production chemists.     

Radionuclide impurities in proton-irradiated [18O]H2O for the production of 18F−: Activities and distribution in the [18F]FDG synthesis process

Proton- and neutron-induced activation products in the components of a high-pressure [¹⁸O]H₂O target vessel used for the production of ¹⁸F⁻ in a medical cyclotron have been identified using high resolution gamma spectrometry. The activities leached from the target vessel into the [¹⁸O]H₂O during irradiation, and the distribution of the identified radionuclide impurities in the various cartridges and solutions used in the [¹⁸F]FDG synthesis process have been measured and are discussed from the perspective of waste disposal. The results indicate that, at the energies and beam currents employed, only a few, relatively short-lived radionuclides are present in the irradiated [¹⁸O]H₂O, and that the activities involved (<10 kBq in each case) are well below typical exemption limits. Activities of beta-emitting ³H in irradiated [¹⁸O]H₂O, produced via the ¹⁸O(p,³H)¹⁶O reaction, have also been determined using liquid scintillation spectrometry. Measured activity concentrations, in the range 150–180 kBq g⁻¹, are consistent with those reported by other workers. Analyses of the synthesised [¹⁸F]FDG confirm the radiochemical purity of the product, both for ³H and for gamma-emitting radionuclides in the energy range 25–1650 keV.     

Novel fluorine-18 PET radiotracers based on flumazenil for GABAA imaging in the brain

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

An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [18F]FP-TZTP

The radioligand 3-(4-(3-[¹⁸F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine ([¹⁸F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [¹⁸F]FP-TZTP, automated using a GE TRACERlab™ FX_FN radiosynthesis module. A key facet was the use of a new precursor, 3-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-3-ylthio)propyl 4-methylbenzenesulfonate. The precursor was fluorinated via nucleophilic displacement of the tosyloxy group by potassium cryptand [¹⁸F]fluoride (K[¹⁸F]/K₂₂₂) in CH₃CN at 80 °C for 5 min, and purified by HPLC. Formulated [¹⁸F]FP-TZTP was prepared in an uncorrected radiochemical yield of 29±4%, with a specific activity of 138±41 GBq/μmol (3732±1109 mCi/μmol) at the end of synthesis (35 min; n=3). This methodology offers higher yields, faster synthesis times, an optimized precursor, and simpler automation than previously reported.     

44gSc production using a water target on a 13 MeV cyclotron

IntroductionAccess to promising radiometals as isotopes for novel molecular imaging agents requires that they are routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for the metal of interest is necessary, both of which can introduce significant hurdles in development of less common isotopes. Herein, we describe the production of ⁴⁴Sc (t_1/2 = 3.97 h, E_avg,β⁺ = 1.47 MeV, branching ratio = 94.27%) in a solution target and an automated loading system which allows a quick turn-around between different radiometallic isotopes and therefore greatly improves their availability for tracer development. Experimental yields are compared to theoretical calculations.MethodsSolutions containing a high concentration (1.44–1.55 g/mL) of natural-abundance calcium nitrate tetrahydrate (Ca(NO₃)₂ · 4 H₂O) were irradiated on a 13 MeV proton-beam cyclotron using a standard liquid target. ^44gSc was produced via the ⁴⁴Ca(p,n)^44gSc reaction.Results^44gSc was produced for the first time in a solution target with yields sufficient for early radiochemical studies. Saturation yields of up to 4.6 ± 0.3 MBq/μA were achieved using 7.6 ± 0.3 μA proton beams for 60.0 ± 0.2 minutes (number of runs n = 3). Experimental data and calculation results are in fair agreement. Scandium was isolated from the target mixture via solid-phase extraction with 88 ± 6% (n = 5) efficiency and successfully used for radiolabelling experiments. The demonstration of the production of ⁴⁴Sc in a liquid target greatly improves its availability for tracer development.     

Synthesis of carbon-11-labeled tariquidar derivatives as new PET agents for imaging of breast cancer resistance protein (ABCG2)

Carbon-11-labeled tariquidar derivatives were first designed and synthesized as new PET agents for imaging of breast cancer resistance protein. The target tracers were prepared by O-[¹¹C]methylation of their corresponding acid precursors using [¹¹C]CH3OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 50–60% radiochemical yields based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 15–20 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 111–185 GBq/μmol.     

In-target produced [11C]methane: Increased specific radioactivity

The ¹⁴N(ρ, α)¹¹C reaction on N₂–O₂ or N₂–H₂ gaseous systems as targets in proton bombardment allows for the production of [¹¹C]CO₂ and [¹¹C]CH_4. We report the target production of [¹¹C]CH₄ and the gas phase iodination to produce [¹¹C]CH₃I with high specific radioactivity (SA). SA was calculated for four different radiopharmaceuticals produced in-house from both target produced [¹¹C]CO₂ and [¹¹C]CH_4. For [¹¹C]raclopride we obtained an average SA of 3908 GBq/μmol (106 000 Ci/mmol) at the end of bombardment for the last 52 productions, which is a 32-fold increase compared to when using the in-house [¹¹C]CO₂ target.     

Synthesis and evaluation of 2-amino-5-(4-[18F]fluorophenyl)pent-4-ynoic acid ([18F]FPhPA): A novel 18F-labeled amino acid for oncologic PET imaging

Introduction¹⁸ F-labeled amino acids are important PET radiotracers for molecular imaging of cancer. This study describes synthesis and radiopharmacological evaluation of 2-amino-5-(4-[¹⁸ F]fluorophenyl)pent-4-ynoic acid ([¹⁸ F]FPhPA) as a novel amino acid radiotracer for oncologic imaging.Methods¹⁸ F]FPhPA was prepared using Pd-mediated Sonogashira cross-coupling reaction between 4-[¹⁸ F]fluoroiodobenzene ([¹⁸ F]FIB) and propargylglycine. The radiopharmacological profile of [¹⁸ F]FPhPA was evaluated in comparison with O-(2-[¹⁸ F]fluoroethyl)-L-tyrosine ([¹⁸ F]FET) using the murine breast cancer cell line EMT6 involving cellular uptake studies, radiotracer uptake competitive inhibition experiments and small animal PET imaging.Results¹⁸ F]FPhPA was prepared in 42 ± 10% decay-corrected radiochemical yield with high radiochemical purity >95% after semi-preparative HPLC purification. Cellular uptake of L-[¹⁸ F]FPhPA reached a maximum of 58 ± 14 % radioactivity/mg protein at 90 min. Lower uptake was observed for racemic and D-[¹⁸ F]FPhPA.Radiotracer uptake inhibition studies by synthetic and naturally occurring amino acids suggested that Na⁺-dependent system ASC, especially ASCT2, and Na⁺-independent system L are important amino acid transporters for [¹⁸ F]FPhPA uptake into EMT6 cells. Small animal PET studies demonstrated similar high tumor uptake of [¹⁸ F]FPhPA in EMT6 tumor-bearing mice compared to [¹⁸ F]FET reaching a maximum standardized uptake value (SUV) of 1.35 after 60 min p.i.. Muscle uptake of [¹⁸ F]FPhPA was higher (SUV_30min = 0.65) compared to [¹⁸ F]FET (SUV_30min = 0.40), whereas [¹⁸ F]FPhPA showed a more rapid uptake and clearance from the brain compared to [¹⁸ F]FET.ConclusionL-[¹⁸ F]FPhPA is the first ¹⁸ F-labeled amino acid prepared through Pd-mediated cross-coupling reaction.Advances in Knowledge and Implications for patient CareL-[¹⁸ F]FPhPA displayed promising properties as a novel amino acid radiotracer for molecular imaging of system ASC and system L amino acid transporters in cancer.     

(R)-[11C]verapamil is selectively transported by murine and human P-glycoprotein at the blood–brain barrier,and not by MRP1 and BCRP

IntroductionPositron emission tomography (PET) with [¹¹C]verapamil, either in racemic form or in form of the (R)-enantiomer, has been used to measure the functional activity of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) at the blood–brain barrier (BBB). There is some evidence in literature that verapamil inhibits two other ABC transporters expressed at the BBB, i.e. multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). However, previous data were obtained with micromolar concentrations of verapamil and do not necessarily reflect the transporter selectivity of verapamil at nanomolar concentrations, which are relevant for PET experiments. The aim of this study was to assess the selectivity of verapamil, in nanomolar concentrations, for Pgp over MRP1 and BCRP.MethodsConcentration equilibrium transport assays were performed with [³H]verapamil (5 nM) in cell lines expressing murine or human Pgp, human MRP1, and murine Bcrp1 or human BCRP. Paired PET scans were performed with (R)-[¹¹C]verapamil in female FVB/N (wild-type), Mrp1^(?/?), Mdr1a/b^(?/?), Bcrp1^(?/?) and Mdr1a/b^(?/?)Bcrp1^(?/?) mice, before and after Pgp inhibition with 15 mg/kg tariquidar.ResultsIn vitro transport experiments exclusively showed directed transport of [³H]verapamil in Mdr1a- and MDR1-overexpressing cells which could be inhibited by tariquidar (0.5 μM). In PET scans acquired before tariquidar administration, brain-to-blood ratio (K_b,brain) of (R)-[¹¹C]verapamil was low in wild-type (1.3 ± 0.1), Mrp1^(?/?) (1.4 ± 0.1) and Bcrp1^(?/?) mice (1.8 ± 0.1) and high in Mdr1a/b^(?/?) (6.9 ± 0.8) and Mdr1a/b^(?/?)Bcrp1^(?/?) mice (7.9 ± 0.5). In PET scans after tariquidar administration, K_b,brain was significantly increased in Pgp-expressing mice (wild-type: 5.0 ± 0.3-fold, Mrp1^(?/?): 3.2 ± 0.6-fold, Bcrp1^(?/?): 4.3 ± 0.1-fold) but not in Pgp knockout mice (Mdr1a/b^(?/?) and Mdr1a/b^(?/?)Bcrp1^(?/?)).ConclusionOur combined in vitro and in vivo data demonstrate that verapamil, in nanomolar concentrations, is selectively transported by Pgp and not by MRP1 and BCRP at the BBB, which supports the use of (R)-[¹¹C]verapamil or racemic [¹¹C]verapamil as PET tracers of cerebral Pgp function.     

11C-Labeling of a potent hydroxyethylamine BACE-1 inhibitor and evaluation in vitro and in vivo

IntroductionThe enzyme β-secretase 1 (BACE-1) is associated with the catalytic cleavage of amyloid precursor protein (APP) which leads to the production of amyloid-β, an amyloidogenic peptide that forms insoluble fibrils and is linked to neurodegeneration and Alzheimer's disease (AD). A PET-radioligand for the quantification of BACE-1 would be useful for the understanding of AD. In this report, we describe the synthesis and carbon-11 radiolabeling of a potent hydroxyethylamine BACE-1 enzyme inhibitor (BSI-IV) and its evaluation in vitro and in vivo.Methods¹¹[C]-N¹-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethyl-sulfonamido)-N³-((R)-1-phenylethyl)isophthalamide, a β-secretase inhibitor, denoted here as [¹¹C]BSI-IV was synthesized through a palladium-mediated aminocarbonylation with an aryl halide precursor (I or Br) and [¹¹C]CO. The effect of different palladium/ligand-complexes on radiochemical yield in the carbonylative reaction was investigated. The binding of the labeled compound to BACE-1 enzyme was studied in vitro by frozen section autoradiography from brains of healthy rats. Dynamic small animal PET-CT studies and ex vivo biodistribution were performed in male rats.ResultsThe halide precursors were synthesized in six steps starting from methyl-3-nitrobenzoate with an overall yield of 21–26%. [¹¹C]BSI-IV was obtained in 29 ± 12% decay corrected radiochemical yield (n = 12) with a specific activity of 790 ± 155 GBq/μmol at the end of synthesis with a radiochemical purity of > 99%. The preclinical studies showed that [¹¹C]BSI-IV has a rapid metabolism in rat with excretion to the small intestines.Conclusion¹¹[C]BSI-IV was obtained in sufficient amount and purity to enable preclinical investigation. The preclinical studies showed low specific binding in vitro and fast clearance in vivo and a low uptake in the brain. These findings suggests that [¹¹C]BSI-IV has limited use as a PET-ligand for the study of BACE-1 or AD.     

Tattoos do not affect exercise-induced localised sweat rate or sodium concentration

ObjectivesSkin tattoos have been shown to reduce localised sweat rate and increase sweat sodium concentration ([Na⁺]) when sweating is artificially stimulated. This study investigated whether similar responses are observed with exercise-induced sweating.DesignUnblinded, within-participant control, single trial.MethodsTwenty-two healthy individuals (25.1 ± 4.8 y (Mean ± SD), 14 males) with a unilateral tattoo ≥11.4 cm² in size, ≥2 months in age, and shaded ≥50% participated in this investigation. Participants undertook 20 min of intermittent cycling (4 × 5 min intervals) on a stationary ergometer in a controlled environment (24.6 ± 1.1 °C; 64 ± 6% RH). Resultant sweat was collected into absorbent patches applied at two pairs of contralateral skin sites (pair 1: Tattoo vs. Non-Tattoo; pair 2: Control 1 vs. Control 2 (both non-tattooed)), for determination of sweat rate and sweat [Na⁺]. Paired samples t-tests were used to determine differences between contralateral sites.ResultsTattoo vs. Non-Tattoo: Neither sweat rate (Mean ± SD: 0.92 ± 0.37 vs. 0.94 ± 0.43 mg·cm⁻²·min⁻¹, respectively; p = 0.693) nor sweat [Na⁺] (Median(IQR): 37(32–52) vs. 37(31–45) mM·L⁻¹, respectively; p = 0.827) differed. Control 1 vs. Control 2: Neither sweat rate (Mean±SD: 1.19 ± 0.53 vs. 1.19 ± 0.53 mg·cm⁻²·min⁻¹, respectively; p = 0.917) nor sweat [Na⁺] (Median(IQR): 29(26–41) vs. 31(25–43) mM·L⁻¹, respectively; p = 0.147) differed. The non-significant differences for sweat rate and [Na⁺] between Tattoo vs. Non-Tattoo were inside the range of the within participant variability (sweat rate CVi = 5.4%; sweat [Na⁺] CVi = 4.4%).ConclusionsSkin tattoos do not appear to alter the rate or [Na⁺] of exercise-induced sweating. The influence of skin tattoos on localised sweat responses may have previously been over-estimated.     

[18F]-labeled 2-methoxyphenylpiperazine derivative as a potential brain positron emission tomography imaging agent

This study reports the synthesis and characterization of N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl-4-[¹⁸F]fluorobenzamide ([¹⁸F]MPP3F). The total reaction time for [¹⁸F]MPP3F, including final high-performance liquid chromatography purification, was about 3 h. Typical decay-corrected radiochemical yield was 18.4±3.1%. The radiochemical purity was >98%. Biodistribution in mice showed that [¹⁸F]MPP3F is a potential brain imaging agent for positron emission tomography. The brain uptake of [¹⁸F]MPP3F was 6.59±0.77% Injected Dose/g at 2 min post-injection time. A brain-to-blood ratio of 3.67 was reached at 15 min after injection.     

Efficient synthesis of a fluorine-18 labeled biotin derivative

IntroductionThe natural occurring vitamin biotin, also known as vitamin H or vitamin B₇, plays a major role in various metabolic reactions. Caused by its high binding affinity to the protein avidin with a dissociation constant of about 10^- 15 M the biotin-avidin system was extensively examined for multiple applications. We have synthesized a fluorine-18 labeled biotin derivative [¹⁸F]4 for a potential application in positron emission tomography (PET).MethodsMesylate precursor 3 was obtained by an efficient two-step reaction via a copper catalyzed azide-alkyne cycloaddition (CuAAC) from easily accessible starting materials. [¹⁸F]4 was successfully synthesized by a nucleophilic radiofluorination of precursor 3. A biodistribution study by means of small-animal PET imaging in wt-mice was performed and serum stability was examined.ResultsCompound [¹⁸F]4 was obtained from precursor compound 3 with an average specific activity of 16 GBq/μmol within 45 min and a radiochemical yield of 45 ± 5% (decay corrected). [¹⁸F]4 demonstrated only negligible decomposition in human serum. A qualitative binding study revealed the high affinity of the synthesized biotin derivative to avidin. Blocking experiments with native biotin showed that binding was site-specific. Biodistribution studies showed that [¹⁸F]4 was cleared quickly and efficiently from the body by hepatobiliary and renal elimination.ConclusionAn efficient synthesis for [¹⁸F]4 was established. In vivo characteristics were determined and demonstrated the pharmacokinetic behaviour of [¹⁸F]4.     

Time-efficient and convenient synthesis of [18F]altanserin for human PET imaging by a new work-up procedure

[¹⁸F]Altanserin, an important PET radioligand for the in vivo imaging of the 5-HT_2A receptor, was synthesized from its precursor nitro-altanserin in DMF or DMSO at high temperatures of 150 °C in an overall radiochemical yield (EOB) of 23–25% after 75 min. A new solid phase work-up procedure involving the acidification of the crude reaction mixture and a C18-SepPak-solid phase separation preceded the final HPLC purification. This led to a significantly reduced synthesis time as a result of a stable and early elution from the HPLC column using improved HPLC conditions (MeOH/THF/NaOAc 0.05 N pH 5: 27/18/55, flow: 5 mL/min, Symetry Prep 7 μm C18 (Waters)). The synthesis was performed semi-automatically in a modified GE TracerLab synthesis module using an in-house-developed program. The synthesized [¹⁸F]altanserin was used in our ongoing human and animal PET imaging studies.