Average Specific Radioactivity Research Articles

Indoor Air Radon Concentration in Premises of Public Companies and Workplaces in Latvia.

Considering the multitudes of people who spend their time working indoors in public premises and workplaces, it is worth knowing what their level of exposure is to natural radioactive radon gas, the second most widespread and dangerous carcinogen for lung cancer development after cigarette smoking. This state-level study covered most of the territory of Latvia and conducted 941 radon measurements with Radtrack2, placed for 4–6 months in the premises of public companies, educational institutions, medical care institutions, etc. The study found that 94.7% of samples did not exceed the national permissible limit (200 Bq/m3), the level at which preventive measures should be initiated. The median value of average specific radioactivity of radon in these premises was 48 Bq/m3 (Q1 and Q3 being 27 and 85 Bq/m3), which is below the average of the European region. Slightly higher concentrations were observed in well-insulated premises with plastic windows and poorer air exchange, mostly in schools (59 (36, 109) Bq/m3) and kindergartens (48 (32, 79) Bq/m3). Industrial workplaces had surprisingly low radon levels (28 (16, 55) Bq/m3) due to strict requirements for air quality and proper ventilation. Public premises and workplaces in Latvia mostly have low radon concentrations in the air, but more attention should be paid to adequate ventilation and air exchange.

Radiosynthesis of no-carrier-added meta-[124I]iodobenzylguanidine for PET imaging of metastatic neuroblastoma

Meta-iodobenzylguanidine (mIBG) has been radiolabelled at the no-carrier-added level with [124I] for a proof of concept study to assess the diagnostic accuracy of [124I]mIBG PET/CT in detecting metastatic deposits in patients diagnosed with metastatic neuroblastoma. Radiolabelling of mIBG was achieved via the iododesilylation reaction between [124I]sodium iodide and meta-trimethylsilylbenzylguanidine. [124I]mIBG was produced in 62–70 % radioiodide incorporation yield from [124I]sodium iodide. The average amount of formulated [124I]mIBG was 359 MBq (range 344–389 MBq) with an average specific radioactivity of 4.1 TBq μmol−1 (range 1.8–5.9 TBq μmol−1) at end of synthesis.

Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2.

The cannabinoid receptor type 2 (CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [(18) F]RS-126 was obtained in ≥99% radiochemical purity with an average specific radioactivity of 98 GBq/μmol at the end of the radiosynthesis. [(18) F]RS-126 showed a logD7.4 value of 1.99 and is stable invitro in rat and human plasma over 120min, whereas 55% intact parent compound was found invivo in rat blood plasma at 10min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in invivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [(18) F]RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [(18) F]RS-126 using PET imaging. In summary, [(18) F]RS-126 demonstrated high specificity toward CB2 receptor invitro and invivo and is a promising radioligand for imaging CB2 receptor expression. Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [(18) F]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in invivo displacement experiments with rats. Time activity curve of [(18) F]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).

Microwave-assisted radiosynthesis of [(18) F]ASEM, a radiolabeled α7-nicotinic acetylcholine receptor antagonist.

An improvement of the original radiochemical synthesis of [(18) F]ASEM, an α7-nicotinic acetylcholinergic receptor radioligand, is reported. The new procedure utilizes microwave-assisted radiofluorination. In addition, a new preparative HPLC method was developed to eliminate a chemical impurity in the final product. Quality control procedures were also enhanced to improve detection of product with enhanced resolution of potential impurities. [(18) F]ASEM was produced in 20.1 ± 8.9% non-decay corrected (NDC) yield with an average synthesis time of 57 min and an average specific radioactivity of 856 ± 332 GBq/µmol (23 ± 9 Ci/µmol).

Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326: An agonist probe for the α7 nicotinic acetylcholine receptor

The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). We prepared the high-affinity (K(d) = 0.2 nM) α7 nAChR agonist, 5'-(2-[(18)F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [(18)F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [(18)F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. [(18)F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90 min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/μmol (3,781 mCi/μmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.

Synthesis of [(11)C]Am80 via Novel Pd(0)-Mediated Rapid [(11)C]Carbonylation Using Arylboronate and [(11)C]Carbon Monoxide.

(11)C-labeled methylbenzoates [(11)C]4a-d were synthesized using Pd(0)-mediated rapid cross-coupling reactions employing [(11)C]carbon monoxide and arylboronic acid neopentyl glycol esters 3a-d under atmospheric pressure in methanol-dimethylformamide (MeOH-DMF), in radiochemical yields of 12 ± 5-26 ± 13% (decay-corrected based on [(11)C]O). The reaction conditions were highly favorable for the synthesis of [(11)C]Am80 ([(11)C]2) and [(11)C]methyl 4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl)benzoate ([(11)C]2-Me) using 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide (5), both of which produced a decay-corrected radiochemical yield (RCY) of 26 ± 13%, with >99% radiochemical purity and an average specific radioactivity of 44 GBq/μmol. The yields of [(11)C]4a, [(11)C]2-Me, and [(11)C]2 were improved by the use of a 2-fold excess of the solvents and reagents under the same conditions to give respective yields of 66 ± 8, 65 ± 7, and 48 ± 2%.

5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice

The radiosynthesis and in vivo evaluation of 5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole [11C]rac-(1), a potential PET tracer for α7 nicotinic acetylcholine receptors (α7-nAChR), are described. Syntheses of the nonradioactive standard rac-1 and corresponding desmethyl precursor 7 were achieved in several reaction steps. Radiomethylation of 7 with [11C]CH3I afforded [11C]rac-1 in an average radiochemical yield of 30±5% (n=5) with high radiochemical purity and an average specific radioactivity of 444±74GBq/μmol (n=5). The total synthesis time was 30min from end-of-bombardment. Biodistribution studies in mice showed that [11C]rac-1 penetrates the blood–brain barrier and specifically labels neuronal α7-nAChRs.

Evaluation of 4-[18F]fluorobenzoyl-FALGEA-NH2 as a positron emission tomography tracer for epidermal growth factor receptor mutation variant III imaging in cancer

This study describes the radiosynthesis, in vitro and in vivo evaluation of the novel small peptide radioligand, 4-[(18)F]fluorobenzoyl-Phe-Ala-Leu-Gly-Glu-Ala-NH(2,) ([(18)F]FBA-FALGEA-NH(2)) as a positron emission tomography (PET) tracer for imaging of the cancer specific epidermal growth factor receptor (EGFR) variant III mutation, EGFRvIII. For affinity, stability and PET measurements, H-FALGEA-NH(2) was radiolabelled using 4-[(18)F]fluorobenzoic acid ([(18)F]FBA). The binding affinity of ([(18)F]FBA)-FALGEA-NH(2) was measured on EGFRvIII expressing cells, NR6M. Stability studies in vitro and in vivo were carried out in blood plasma from nude mice. PET investigations of [(18)F]FBA-FALGEA-NH(2) were performed on a MicroPET scanner, using seven nude mice xenografted subcutaneously with human glioblastoma multiforme (GBM) tumours, expressing the EGFRvIII in its native form, and five nude mice xenografted subcutaneously with GBM tumours lacking EGFRvIII expression. Images of [(18)F]FDG were also obtained for comparison. The mice were injected with 5-10 MBq of the radiolabelled peptide or [(18)F]FDG. Furthermore, the gene expression of EGFRvIII in the tumours was determined using quantitative real-time PCR. Radiolabelling and purification was achieved within 180 min, with overall radiochemical yields of 2.6-9.8% (decay-corrected) and an average specific radioactivity of 6.4 GBq/μmol. The binding affinity (K(d)) of [(18)F]FBA-FALGEA-NH(2) to EGFRvIII expressing cells was determined to be 23 nM. The radiolabelled peptide was moderately stable in the plasma from nude mice where 53% of the peptide was intact after 60 min of incubation in plasma but rapidly degraded in vivo, where no intact peptide was observed in plasma 5 min post-injection. The PET imaging showed that [(18)F]FBA-FALGEA-NH(2) accumulated preferentially in the human GBM xenografts which expressed high amounts of the mutated receptor. The average tumour-to-muscle ratio (T/M) in the EGFRvIII tumours was 7.8 at 60 min post-injection, compared with 4.6 in the wild-type EGFR tumours. Furthermore, there was a strong correlation (R=0.86, P=.007) between the expression of EGFRvIII in the tumours and the tracer uptake expressed as T/M. Our results indicate that, despite its rapid metabolism, [(18)F]FBA-FALGEA-NH(2) binds preferentially to EGFRvIII in the tumours in vivo and is a promising lead for further development of EGFRvIII specific peptide radiopharmaceuticals.

Carbonyl‐11C]Benzyl acetate: Automated radiosynthesis via Pd‐mediated [11C]carbon monoxide chemistry and PET measurement of brain uptake in monkey

[carbonyl-(11)C]Benzyl acetate ([(11)C]1) has been proposed as a potential agent for imaging glial metabolism of acetate to glutamate and glutamine with positron emission tomography (PET). [(11)C]1 was synthesized from [(11)C]carbon monoxide, iodomethane and benzyl alcohol via palladium-mediated chemistry. The radiosynthesis was automated with a modified Synthia platform controlled with in-house developed Labview software. Under production conditions, [(11)C]1 was obtained in 10% (n = 6) decay-corrected radiochemical yield from [(11)C]carbon monoxide in > 96% radiochemical purity and with an average specific radioactivity of 2,415 mCi/micromol. The total radiosynthesis time was about 45 min. Peak uptake of radioactivity in brain (SUV = 3.1) was relatively high and may be amenable to measuring uptake and metabolism of acetate in glial cells of the brain.

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

The 14N(ρ, α) 11C reaction on N 2–O 2 or N 2–H 2 gaseous systems as targets in proton bombardment allows for the production of [ 11C]CO 2 and [ 11C]CH 4. We report the target production of [ 11C]CH 4 and the gas phase iodination to produce [ 11C]CH 3I with high specific radioactivity (SA). SA was calculated for four different radiopharmaceuticals produced in-house from both target produced [ 11C]CO 2 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]CO 2 target.

6-Chloro-3-(((1-[ 11C]methyl)-2-( S)-pyrrolidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine ([ 11C]JHU85270), a potent ligand for nicotinic acetylcholine receptor imaging by positron emission tomography

6-Chloro-3-((1-methyl)-2-( S)-pyrrolidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine (JHU85270), a novel high-affinity ligand for the α4 β2 nicotine acetylcholine receptor (nAChR) ( K i=86, 115 pM; K i JHU 85270 / K i epibatidine = 1.7 ) with a log D 7.4=1.6 was synthesized in 56% overall yield. [ 11C]JHU85270 was synthesized from [ 11C]-methyl iodide and the corresponding normethyl precursor. The average time of radiosynthesis, purification, and formulation was 37 min from the end of bombardment. The average radiochemical yield of [ 11C]JHU85270 was 37%±3% (non-decay corrected). The average specific radioactivity was 398±165 GBq/μmol (10750±4468 mCi/μmol) and the radiochemical purity was greater than 99%.

Synthesis of 1‐(2,4‐dichlorophenyl)‐4‐cyano‐5‐(4‐[11C]methoxyphenyl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide ([11C]JHU75528) and 1‐(2‐bromophenyl)‐4‐cyano‐5‐(4‐[11C]methoxyphenyl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide ([11C]JHU75575) as potential radioligands for PET imaging of cerebral cannabinoid receptor

AbstractTwo novel ligands for cerebral cannabinoid receptor (CB1), 1‐(2,4‐dichlorophenyl)‐4‐cyano‐5‐(4‐methoxyphenyl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide (JHU75528) and 1‐(2‐bromophenyl)‐4‐cyano‐5‐(4‐methoxyphenyl)‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide (JHU75575) have been synthesized. Both JHU75528 and JHU75575 display a combination of higher binding affinity and lower lipophilicity than those of Rimonabant (SR141716), a high affinity CB1 selective antagonist, and AM281, the only available ligand for emission tomography imaging of CB1 in human subjects. Radiolabeled [11C]JHU75528 and [11C]JHU75575 were prepared by reaction of [11C]methyl iodide with nor‐methyl precursors. The average radiochemical yield, specific radioactivity, and radiochemical purity of [11C]JHU75528 were 16%, 235 GBq/µmol (6360 mCi/µmol), and 99%, respectively; those of [11C]JHU75575 were 8%, 196 GBq/µmol (5308 mCi/µmol), and 99%, respectively. Both ligands hold promise as PET radioligands for imaging CB1 receptor. Copyright © 2006 John Wiley & Sons, Ltd.

Radiosynthesis of the α4β2 nicotinic acetylcholine receptor ligand: 5-((1-[11C]-methyl-2-(S)-pyrrolidinyl)methoxy)-2-chloro-3-((E)-2-(2-fluoropyridin-4-yl)vinyl)pyridine

5-((1-[11C]-methyl-2-(S)-pyrrolidinyl)methoxy)-2-chloro-3-((E)-2-(2-fluoropyridin-4-yl)-vinyl)pyridine ([11C]-FPVC) was synthesized from [11C]-methyl iodide and the corresponding normethyl precursor. The average time of synthesis, purification, and formulation was 42 min with an average non-decay-corrected radiochemical yield of 19%. The average specific radioactivity was 359 GBq/µmol (9691 mCi/µmole) at end of synthesis (EOS). Copyright © 2006 John Wiley & Sons, Ltd.

Synthesis of [11C]gefitinib for imaging epidermal growth factor receptor tyrosine kinase with positron emission tomography

We have synthesized N-(3-chloro-4-fluorophenyl)-7-[11C]methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine, [11C]gefitinib ([11C]Iressa), a high affinity (IC50 = 2 nM) inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK), in solution and in a semi-automated stainless loop methylation system using [11C]methyl triflate. The trapping efficiency for [11C]methyl triflate in solution was higher than in the solvent film generated in the loop system, thus the overall radiochemical yield was considerably higher for the synthesis in solution. The average radiochemical yield for the solution chemistry was 15% with an average specific radioactivity of approximately 9000 mCi/µmole at EOS in one step from its corresponding desmethyl phenol precursor. Copyright © 2006 John Wiley & Sons, Ltd.

Synthesis, 11C labeling and biological properties of derivatives of the tyrphostin AG957

Four analogues of AG957, a known inhibitor of the tyrosine kinase p210 bcr-abl , have been synthesized and tested for their growth inhibitory effect against the BCR/ABL-positive FDrv210C cells as well as the epidermal growth factor (EGF) receptor-positive Baf/ERX cells. All compounds that can undergo oxidation to the corresponding quinone demonstrated inhibition of FDrv210C cells and Baf/ERX cells. Compounds that cannot become oxidized showed significantly less inhibition of BCR/ABL- or EGF receptor-mediated cell proliferation. The 11C-labeled compounds were prepared by labeling 4-aminobenzoic acid using [ 11C]CH 3I, which afforded the corresponding 11C-labeled methyl ester in excellent yields. Subsequent condensation of the amino group with an appropriately substituted hydroxy benzaldehyde formed the respective Schiff base. Reduction of this compound with NaBH 3CN gave the 11C-labeled inhibitors in an overall radiochemical yield of 17.3±2.1% ( n=3; not decay corrected) and an average specific radioactivity of 40 GBq/µmol (1.1 Ci/µmol) at the end of synthesis. The total synthesis time from EOB including HPLC purification and formulation was 45 min.

Radiosynthesis of 3‐[18F]fluoropropyl and 4‐[18F]fluorobenzyl triarylphosphonium ions

Abstract3‐[18F]Fluoropropyl‐, 4‐[18F]fluorobenzyl‐triphenylphosphonium and 4‐[18F]fluorobenzyltris‐4‐dimethylaminophenylphosphonium cations were synthesized in multi‐step reactions from no carrier added (nca) [18F]fluoride. The time for synthesis, purification, and formulation was 56, 82, and 79 min with an average radiochemical yield of 12, 6 and 15%, respectively (not corrected for decay). The average specific radioactivity for the three radiolabeled compounds was 14.9 GB q/µmole (403 mCi/µmole) at end of synthesis (EOS). Copyright © 2004 John Wiley & Sons, Ltd.

Radiosynthesis of [11C]paclitaxel

Abstract[11C]paclitaxel, a potential solid tumor imaging agent, was synthesized by reacting [α‐11C]benzoyl chloride with the primary amine precursor of paclitaxel. The time for synthesis, purification, and formulation was 38 min from end of bombardment with an average specific radioactivity of 49.9 GBq/μmol (1349 mCi/μmol) at end of synthesis. The average decay corrected radiochemical yield was 7% with greater than 99% radiochemical purity. Copyright © 2002 John Wiley & Sons, Ltd.

11C labelling of AG957—a potential tyrphostin radiotracer for PET

AbstractCarbon‐11 labelled 4‐(N‐2,5‐dihydroxybenzyl)amino methyl benzoate (AG957), a potential radiotracer for imaging bcr–abl receptors was synthesized. [11C]AG957 was prepared by labelling 4‐aminobenzoic acid using [11C]CH3I, which affords the corresponding [11C] methyl ester in excellent yields. Subsequent condensation of the amino group with 2,5‐dihydroxy‐benzaldehyde formed the respective Schiff base. Reduction of this compound with NaBH3CN gave [11C]AG957 in overall decay corrected radiochemical yield of 65–75% (based on 11CH3I) with an average specific radioactivity of 40 GBq/μmol (1.1 Ci/μmol). The total synthesis time from EOB including formulation was 45 min. At physiological pH, the compound was found to be sufficiently stable for in vitro and in vivo investigations. Copyright © 2002 John Wiley & Sons, Ltd.

Radiosynthesis of a ligand for studying the glycine transporter: [11C]ALX‐5407

Abstract[11C]ALX‐5407, R‐N[3‐(4′‐fluorophenyl)‐3‐(4′‐phenylphenoxy)propyl] sarcosine, a chiral glycine transporter 1 antagonist, was labeled with [11C]iodomethane by N‐alkylation of methyl ester protected N‐normethyl precursor, ALX‐5536, and subsequent saponification of the methyl ester protecting group. The time for synthesis, purification, and formulation was 33 minutes with an average specific radioactivity of 3909 mCi/µmol (EOS) and average decay corrected radiochemical yield of 8%. Copyright © 2001 John Wiley & Sons, Ltd.

Radiosynthesis of a potent endothelin receptor antagonist: [11C] L-753,037

[11C]-L-753,037, [(+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-[11C]-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)-cyclopenteno-[1,2-b]pyridine-6-carboxylate], a potent mixed antagonist of endothelin receptor subtypes ETA and ETB, was synthesized by [11C]-methylation of a phenolic precursor. The time for synthesis, purification, and formulation was 17 minutes with an average specific radioactivity of 2535 mCi/µmol (EOS) and average decay corrected radiochemical yield of 3% based on [11C]-methyl iodide. Copyright © 2000 John Wiley & Sons, Ltd.