Prospects of medium specific activity 177Lu in targeted therapy of prostate cancer using 177Lu‐labeled PSMA inhibitor

Targeted radionuclide therapy using ¹⁷⁷Lu‐labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA‐617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of ¹⁷⁷Lu‐PSMA‐617 at hospital radiopharmacy using moderate specific activity ¹⁷⁷Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA‐617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of ¹⁷⁷Lu‐PSMA‐617. Based on these, 7.4 GBq therapeutic dose of ¹⁷⁷Lu‐PSMA‐617 was formulated by incubating 160 µg of PSMA‐617 with indigenously produced ¹⁷⁷LuCl₃ (555 GBq/µg specific activity of ¹⁷⁷Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% (n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic ⁶⁸Ga‐PSMA‐11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of ¹⁷⁷Lu‐PSMA‐617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity ¹⁷⁷Lu at an affordable cost.     

Synthesis of a 11C‐labelled taxane derivative by [1‐11C]acetylation

The ¹¹C‐labelling of the taxane derivative BAY 59‐8862 ( 1 ), a potent anticancer drug, was carried out as a module‐assisted automated multi‐step synthesis procedure. The radiotracer [¹¹C]1 was synthesized by reacting [1‐¹¹C]acetyl chloride ( 6 ) with the lithium salt of the secondary hydroxy group of precursor 3 followed by deprotection. After HPLC purification of the final product [¹¹C]1 , its solid‐phase extraction, formulation and sterile filtration, the decay‐corrected radiochemical yield of [¹¹C]1 was in the range between 12 and 23% (related to [¹¹C]CO₂; n=10). The total synthesis time was about 54 min after EOB. The radiochemical purity of [¹¹C]1 was greater than 96% and the chemical purity exceeded 80%. The specific radioactivity was 16.8±4.7 GBq/µmol (n=10) at EOS starting from 80 GBq of [¹¹C]CO₂. Copyright © 2006 John Wiley & Sons, Ltd.     

Fine‐tuning of the automated [18F]PSMA‐1007 radiosynthesis

Radiolabeled prostate‐specific membrane antigen (PSMA) targeting PET‐tracers have become desirable radiopharmaceuticals for the imaging of prostate cancer (PC). Recently, the PET radiotracer [¹⁸F]PSMA‐1007 was introduced as an alternative to [⁶⁸Ga]Ga‐PSMA‐11, for staging and diagnosing biochemically recurrent PC. We incorporated a one‐step procedure for [¹⁸F]PSMA‐1007 radiosynthesis, using both Synthra RNplus and GE TRACERlab FxFN automated modules, in accordance with the recently described radiolabeling procedure. Although the adapted [¹⁸F]PSMA‐1007 synthesis resulted in repeatable radiochemical yields (55 ± 5%, NDC), suboptimal radiochemical purities of 87 ± 8% were obtained using both modules. As described here, modifications made to the radiolabeling and the solid‐phase extraction purification steps reduced synthesis time to 32 minutes and improved radiochemical purity to 96.10%, using both modules, without shearing the radiochemical yield.     

Automated production of [68Ga]Ga‐DOTANOC and [68Ga]Ga‐PSMA‐11 using a TRACERlab FXFN synthesis module

The interest in gallium‐68 labelled positron‐emission tomography probes continues to increase around the world. However, one of the barriers for routine clinical use is the cost of the automated synthesis units for relatively simple labelling procedures. Herein, we describe the adaptation of a TRACERlab FX_FN synthesis module for the automated production of gallium‐68 radiopharmaceuticals using a cation‐exchange cartridge for postprocessing of the ⁶⁸Ge/⁶⁸Ga generator eluate. The recovery of activity from the cartridge was 95.6% to 98.9% using solutions of acidified sodium chloride (5 M with pH = 1‐3). The radiosyntheses of [⁶⁸Ga]Ga‐DOTANOC and [⁶⁸Ga]Ga‐PSMA‐11 were performed using acetate sodium buffer or 4‐(2‐hydroxyethyl)piperazine‐1‐ethanesulfonic acid, with a total duration of 21 and 23 minutes, respectively, including generator elution and radiopharmaceutical dispensing. Activity yields were 77% ± 2% for [⁶⁸Ga]Ga‐PSMA‐11 and 68% ± 3% for [⁶⁸Ga]Ga‐DOTANOC (n > 100). The labelled peptides had a radiochemical purity exceeding 97%, and all quality control parameters were in conformity with the limits prescribed by the European Pharmacopoeia.     

Synthesis of [1‐11C]propyl and [1‐11C]butyl iodide from [11C]carbon monoxide and their use in alkylation reactions

A method to prepare [1‐¹¹C]propyl iodide and [1‐¹¹C]butyl iodide from [¹¹C]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [¹¹C]carbon monoxide and hydrogen gave [1‐¹¹C]propionaldehyde and [1‐¹¹C]propionic acid. The carbonylation products were reduced and subsequently converted to [1‐¹¹C]propyl iodide. Labelled propyl iodide was obtained in 58±4% decay corrected radiochemical yield and with a specific radioactivity of 270±33 GBq/µmol within 15 min from approximately 12 GBq of [¹¹C]carbon monoxide. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Butyl iodide was obtained correspondingly from propene and approximately 8 GBq of [¹¹C]carbon monoxide, in 34±2% decay corrected radiochemical yield and with a specific radioactivity of 146±20 GBq/µmol. The alkyl iodides were used in model reactions to synthesize [O‐propyl‐1‐¹¹C]propyl and [O‐butyl‐1‐¹¹C]butyl benzoate. Propyl and butyl analogues of etomidate, a β‐11‐hydroxylase inhibitor, were also synthesized. Copyright © 2006 John Wiley & Sons, Ltd.     

Production of [68Ga]Ga-PSMA: Comparing a manual kit-based method with a module-based automated synthesis approach

The labeling of peptides with gallium-68 is often initially performed by manual labeling, but with high clinical demand, other alternatives are needed. Cold-kits or automated synthesis are viable options for standardized methods and deemed pharmaceutically more acceptable. This study compares these [⁶⁸Ga]Ga-PSMA-11 production methods. Data from 40 kit-based and 40 automated syntheses of [⁶⁸Ga]Ga-PSMA-11 were analyzed. Pre-set criteria were evaluated including radiochemical purity, radionuclidic purity, chemical purity, physiological acceptability and sterility. The operator time and radiation dose received were measured. The robustness and repeatability of each method were assessed and a comparison of the running costs of each method is also provided. For both the methods all the analyzed products met the release criteria. No differences were found in radiochemical purity, radiochemical identity, radionuclidic purity, and sterility. However, radiochemical yield and apparent molar activity showed significant differences. For both methods, whole body radiation exposure to operators was lower than with manual labeling (25 – 40 μSv). The exposure during kit-based labeling (14.5 ± μSv) was seven times higher than that of automated synthesis (2.05 ± 0.99 μSv). The automated synthesis was the more expensive method. Both methods are sound alternatives to manual synthesis and offer higher quality, better radiation protection and a more reliable manufacturing of radiopharmaceuticals.     

Automated radiosynthesis of [18F]SPA‐RQ for imaging human brain NK1 receptors with PET

[¹⁸F]SPA‐RQ is an effective radioligand for imaging brain neurokinin type‐1 (NK₁) receptors in clinical research and drug discovery with positron emission tomography. For the automated regular production of [¹⁸F]SPA‐RQ for clinical use in the USA under an IND we chose to use a modified commercial synthesis module (TRACERlab FX_F‐N; GE Medical Systems) with an auxiliary custom‐made robotic cooling–heating reactor, after evaluating several alternative radiosynthesis conditions. The automated radiosynthesis and its quality control are described here. [¹⁸F]SPA‐RQ was regularly obtained within 150 min from the start of radiosynthesis in high radiochemical purity (>99%) and chemical purity and with an overall decay‐corrected radiochemical yield of 15±2% (mean±S.D.; n=10) from cyclotron‐produced [¹⁸F]fluoride ion. The specific radioactivity of [¹⁸F]SPA‐RQ at the end of synthesis ranged from 644 to 2140 mCi/µmol (23.8–79.2 GBq/µmol). Copyright © 2005 John Wiley & Sons, Ltd.     

Facile and improved synthesis of [11C]Me‐QNB

[¹¹C]Me‐QNB is a muscarinic acetylcholinergic receptor antagonist that has been used for the assessment of myocardial muscarinic receptors density in different cardiovascular pathologies. In the current technical note, we report a facile, highly efficient and fully automated method for the preparation of this radiotracer. The radiosynthesis was performed by reaction of [¹¹C]CH₃I with the desmethylated precursor (QNB) at room temperature using the captive solvent method. Excellent radiochemical yield (91.1 ± 2.4%, decay‐corrected) and radiochemical purity (>99.5%), and good specific activity (137 ± 5 GBq/µmol) were obtained when the purification was performed by reverse phase HPLC in overall synthesis time <31 min. Purification using solid‐phase extraction offered lower radiochemical yield (27.6 ± 3.1%, decay‐corrected) and radiochemical purity (>95%) but higher specific activity (244 ± 18 GBq/µmol) in shorter reaction times (<21 min). These results, especially concerning radiochemical yield, significantly improve those previously reported in which the reaction was performed in a vial and the purification step was based on ionic chromatography.     

Synthesis of [1‐11C]ethyl iodide from [11C]carbon monoxide and its application in alkylation reactions

A method is presented for preparing [1‐¹¹C]ethyl iodide from [¹¹C]carbon monoxide. The method utilizes methyl iodide and [¹¹C]carbon monoxide in a palladium‐mediated carbonylation reaction to form a mixture of [1‐¹¹C]acetic acid and [1‐¹¹C]methyl acetate. The acetates are reduced to [1‐¹¹C]ethanol and subsequently converted to [1‐¹¹C]ethyl iodide. The synthesis time was 20 min and the decay‐corrected radiochemical yield of [1‐¹¹C]ethyl iodide was 55 ± 5%. The position of the label was confirmed by ¹³C‐labelling and ¹³C‐NMR analysis. [1‐¹¹C]Ethyl iodide was used in two model reactions, an O‐alkylation and an N‐alkylation. Starting with approximately 2.5 GBq of [¹¹C]carbon monoxide, the isolated decay‐corrected radiochemical yields for the ester and the amine derivatives were 45 ± 0.5% and 25 ± 2%, respectively, based on [¹¹C]carbon monoxide. Starting with 10 GBq of [¹¹C]carbon monoxide, 0.55 GBq of the labelled ester was isolated within 40 min with a specific radioactivity of 36 GBq/µmol. Copyright © 2004 John Wiley & Sons, Ltd.     

Design and synthesis of enantiopure 18F‐labelled [18F]trifluoromethyltryptophan from 2‐halotryptophan derivatives via copper(I)‐mediated [18F]trifluoromethylation and evaluation of its in vitro characterization for the serotonergic system imaging

We synthesized [¹⁸F]trifluoromethyl‐l ‐tryptophan ([¹⁸F]CF₃‐l ‐Trp) using Cu(I)‐mediated [¹⁸F]trifluoromethylation to image serotonergic system. Radiochemical yield was 6 ± 1.5% (n = 9), and radiochemical purity was over 99%. The molar activity was 0.44 to 0.76 GBq/μmol. [¹⁸F]CF₃‐l ‐Trp was stable for up to 6 hours in mouse and human sera at 37°C. Protein‐binding was 0.26 ± 0.03% and 0.34 ± 0.02% in human and mouse serum at 60 minutes, respectively. In conclusion, enantiopure [¹⁸F]CF₃‐l ‐Trp was synthesized as a feasible imaging agent for the serotonergic system.     

Automated radiosynthesis of the adenosine A2A receptor-targeting radiotracer [18F]FLUDA

[¹⁸F] FLUDA is a selective radiotracer for in vivo imaging of the adenosine A_2A receptor (A_2AR) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [¹⁸F] FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [¹⁸F] FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one-pot two-step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69–333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [¹⁸F] FLUDA.     

Automated synthesis of (R)-[18F]MH.MZ on the iPhase Flexlab reaction platform

(R)-[¹⁸F]MH.MZ ([¹⁸F]MH.MZ) is a promising positron emission tomography (PET) radiotracer for in vivo study of the 5-HT_2A receptor. To facilitate clinical trials, a fully automated radiosynthesis procedure for [¹⁸F]MH.MZ was developed using commercially available materials on the iPhase Flexlab module. The overall synthesis time was 100 min with a radiochemical yield of 7 ± 0.9% (n = 3). The radiochemical purity was greater than 99% for [¹⁸F]MH.MZ with a molar activity of 361 ± 57 GBq/μmol (n = 3). The protocol described herein reliably provides [¹⁸F]MH.MZ that meets all relevant release criteria for a GMP radiopharmaceutical.     

Improved protocol for the radiosynthesis of [18F]FTC-146: A potent and selective sigma-1 receptor radioligand

[¹⁸F]FTC-146 was introduced as a very potent and selective sigma-1 receptor radioligand, which has shown promising application as an imaging agent for neuropathic pain with positron emission tomography. In line with a multi-laboratory project on animal welfare, we chose this radioligand to investigate its potential for detecting neuropathic pain and tissue damage in tumor-bearing animals. However, the radiochemical yield (RCY) of around 4–7% was not satisfactory to us, and efforts were made to improve it. Herein, we describe an improved approach for the radiosynthesis of [¹⁸F]FTC-146 resulting in a RCY, which is sevenfold higher than that previously reported. A tosylate precursor was synthesized and radio-fluorination experiments were performed via aliphatic nucleophilic substitution reactions using either K[¹⁸F]F-Kryptofix®222 (K_2.2.2)-carbonate system or tetra-n-butylammonium [¹⁸F]fluoride ([¹⁸F]TBAF). Several parameters affecting the radiolabeling reaction such as solvent, ¹⁸F-fluorination agent with the corresponding amount of base, labeling time, and temperature were investigated. Best labeling reaction conditions were found to be [¹⁸F]TBAF and acetonitrile as solvent at 100°C. The new protocol was then translated to an automated procedure using a FX2 N synthesis module. Finally, the radiotracer reproducibly obtained with RCYs of 41.7 ± 4.4% in high radiochemical purity (>98%) and molar activities up to 171 GBq/μmol.     

Radiosynthesis of the diastereomerically pure (E)‐[11C]ABP688

We report an efficient protocol for the radiosynthesis of diastereomerically pure (E)‐[¹¹C]ABP688, a positron emission tomography (PET) tracer for metabotropic glutamate type 5 (mGlu5) receptor imaging. The protocol reliably provides sterile and pyrogen‐free formulation of (E)‐[¹¹C]ABP688 suitable for preclinical and clinical PET imaging with >99% diastereomeric excess (d.e.), >99% overall radiochemical purity (RCP), 14.9 ± 4.3% decay‐corrected radiochemical yield (RCY), and 148.86 ± 79.8 GBq/μmol molar activity in 40 minutes from the end of bombardment.     

FASTlab Radiosynthesis of the 18F‐labelled HER2‐binding Affibody molecule [18F]GE‐226

An ¹⁸F‐labelled human epidermal growth factor receptor (HER2) receptor binding radiotracer is a potential tool to non‐invasively identify HER2 positive tumour lesions in subjects with recurrent metastatic breast cancer. Having explored the manual radiochemistry to conjugate the Affibody molecule Z_HER2:2891 with [¹⁸F]4‐fluorobenzaldehyde, we have developed and optimised a full protocol for the automated GE FASTlab synthesiser. Our chemometric model predicted the best radiochemical purity for a short conjugation time (2.8 minutes), a low temperature (65°C), and a medium Affibody molecule precursor amount (5.5 mg). Under these optimised conditions, [¹⁸F]GE‐226 was produced after solid‐phase extraction purification with activity yield of 30% ± 7 (n = 18) and a radiochemical purity of 94% ± 2 (n = 18). The synthesis and purification was complete after 43 minutes and provided apparent molar activities of 12 to 30 GBq/μmol (n = 12) at the end of synthesis.     

Radiosynthesis of 1‐iodo‐2‐[11C]methylpropane and 2‐methyl‐1‐[11C]propanol and its application for alkylation reactions and C―C bond formation

The multitude of biologically active compounds requires the availability of a broad spectrum of radiolabeled synthons for the development of positron emission tomography (PET) tracers. The aim of this study was to synthesize 1‐iodo‐2‐[¹¹C]methylpropane and 2‐methyl‐1‐[¹¹C]propanol and investigate the use of these reagents in further radiosynthesis reactions. 2‐Methyl‐1‐[¹¹C]propanol was obtained with an average radiochemical yield of 46 ± 6% d.c. and used with fluorobenzene as starting material. High conversion rates of 85 ± 4% d.c. could be observed with HPLC, but large precursor amounts (32 mg, 333 μmol) were needed. 1‐Iodo‐2‐[¹¹C]methylpropane was synthesized with a radiochemical yield of 25 ± 7% d.c. and with a radiochemical purity of 78 ± 7% d.c. The labelling agent 1‐iodo‐2‐[¹¹C]methylpropane was coupled to thiophenol, phenol and phenylmagnesium bromide. Average radiochemical conversions of 83% d.c. for thiophenol, 40% d.c. for phenol, and 60% d.c. for phenylmagnesium bromide were obtained. In addition, [¹¹C]2‐methyl‐1‐propyl phenyl sulphide was isolated with a radiochemical yield of 5 ± 1% d.c. and a molar activity of 346 ± 113 GBq/μmol at the end of synthesis. Altogether, the syntheses of 1‐iodo‐2‐[¹¹C]methylpropane and 2‐methyl‐1‐[¹¹C]propanol were achieved and applied as proof of their applicability.     

Optimization of the radiosynthesis of [18F]MEFWAY for imaging brain serotonin 1A receptors by using the GE TracerLab FXFN‐Pro module

The aim of this study was to develop a highly reliable radiofluorination method for the preparation of N‐{2‐[4‐(2‐methoxyphenyl)piperazinyl]ethyl}‐N‐(2‐pyridyl)‐N‐(4‐¹⁸F‐fluoromethylcyclohexane)carboxamide ([¹⁸F]Mefway) by using a fully automated system. The optimal condition is composed of two parts. The extraction system of the trapped F‐18 in the anion exchange resin (i.e., quaternary methylamine cartridge) is a complex of Kryptofix 2.2.2. (K222, 4 mg/0.9 mL methanol) and K₂CO₃ (1 mg/0.1 mL H₂O). After removing the solvents, the trans‐tosylated Mefway precursor (1 mg/0.5 mL acetonitrile) was reacted with dried K222‐K[¹⁸F] at 100°C for 5 min. After purification and formulation, [¹⁸F]Mefway was obtained with 38 ± 2.4% (decay corrected, n = 34) radiochemical yield, a total synthesis time of 52 ± 3.4 min, specific activity was 120.6 ± 8.7 GBq/µmol at the end of synthesis and a radiochemical purity of 99%. According to the quality control tests, formulated [¹⁸F]Mefway is suitable to apply parenteral clinical application.     

Synthesis of [11C‐carbonyl]hydroxyureas by a rhodium‐mediated carbonylation reaction using [11C]carbon monoxide

[¹¹C]Hydroxyurea has been successfully labelled using [¹¹C]carbon monoxide at low concentration. The decay‐corrected radiochemical yield was 38±3%, and the trapping efficiency of [¹¹C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium‐mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5‐cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]₂) and 1,2‐bis(diphenylphosphino)ethane (dppe). (¹³C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by ¹³C‐NMR. In order to perform accurate LC–MS identification, the derivative 1‐hydroxy‐3‐phenyl[¹¹C]urea was synthesized in a 35±4% decay‐corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1‐hydroxy‐3‐phenyl[¹¹C]urea was collected starting from 6.75 GBq of [¹¹C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [¹¹C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients. Copyright © 2006 John Wiley & Sons, Ltd.     

Preparation and stability of ethanol‐free solution of [18F]florbetapir ([18F]AV‐45) for positron emission tomography amyloid imaging

We have developed an ethanol‐free formulation method of [¹⁸F]florbetapir ([¹⁸F]AV‐45) using a commercially available automated JFE multi‐purpose synthesizer. We have also evaluated the radiochemical stability in an ethanol‐free solution of [¹⁸F]AV‐45 under visible light irradiation and dark conditions by comparison with a conventional 10% ethanol solution of [¹⁸F]AV‐45. [¹⁸F]AV‐45 was obtained with a radiochemical yield of 55.1 ± 2.2% (decay‐corrected to end of bombardment), specific activity of 591.6 ± 90.3 GBq/µmol and radiochemical purity of >99% within a total synthesis time of about 73 min. The radiochemical purity of [¹⁸F]AV‐45 formulated by dissolving the ethanol‐free solution was found to decrease as a function of the period of exposure to visible light. In contrast, the visible light photolysis could be suppressed by adding 10% ethanol to the formulation or by avoiding exposure to visible light. In the radiosynthesis of [¹⁸F]AV‐45 formulated by dissolving the ethanol‐free solution, [¹⁸F]AV‐45 could be obtained with high radiochemical purity and high stability by avoiding exposure to visible light. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of (±) 3‐(6‐nitro‐2‐quinolinyl)‐[9‐methyl‐11C]‐3,9‐diazabicyclo‐[4.2.1]‐nonane ([11C‐methyl]NS 4194)

(±) 3‐(6‐Nitro‐2‐quinolinyl)‐[9‐methyl‐¹¹C]‐3,9‐diazabicyclo‐[4.2.1]‐nonane ([¹¹C‐methyl]NS 4194), a selective serotonin reuptake inhibitor (SSRI), was synthesised within 35 min after end of bombardment with a radiochemical purity >98%. It had a decay‐corrected radiochemical yield of 7% after preparative HPLC, and a specific radioactivity around 37 GBq/μmol (EOS). A typical production starting with 40 GBq [¹¹C]CO₂ yielded 800 MBq of radiolabelled [¹¹C‐methyl]NS 4194 in a formulated solution. The synthesis of the precursor to [¹¹C‐methyl]NS 4194, (±) 9‐H‐3‐[6‐nitro‐(2‐quinolinyl)]‐3,9‐diazabicyclo‐[4.2.1]‐nonane, as well as the unlabelled analogue (±) 9‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,9‐diazabicyclo‐[4.2.1]‐nonane (NS 4194), are also described. Copyright © 2002 John Wiley & Sons, Ltd.