Synthesis and labeling of a piperazine‐based library of 11C‐labeled ligands for imaging of the vesicular acetylcholine transporter

The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a–f, six potential VAChT PET tracers, [¹¹C]‐(±)5a–f, were ¹¹C‐labeled by a palladium (0)‐mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [¹¹C]‐(±)5a–f were obtained in radiochemical purities >95% with decay‐corrected radiochemical yields and specific radioactivities between 4–25% and 124–597 GBq/µmol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [¹¹C]‐(±)5d and [¹¹C]‐(±)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine‐based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach     

Synthesis and in vivo evaluation of [O‐methyl‐11C] 2‐(4‐methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methyl‐ piperidin‐4‐yl)acetamide as an imaging probe for 5‐HT2A receptors

2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT_2A antagonist, was labeled by [¹¹C]‐methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C] 4 cannot be used as PET ligand for imaging 5‐HT_2A receptors. Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of a Bruton's tyrosine kinase inhibitor, [11C]Tolebrutinib,via palladium-NiXantphos-mediated carbonylation

Bruton's tyrosine kinase (BTK) is a key component in the B-cell receptor signaling pathway and is consequently a target for in vivo imaging of B-cell malignancies as well as in multiple sclerosis (MS) with positron emission tomography (PET). A recent Phase 2b study with Sanofi's BTK inhibitor, Tolebrutinib (also known as [a.k.a.] SAR442168, PRN2246, or BTK'168) showed significantly reduced disease activity associated with MS. Herein, we report the radiosynthesis of [¹¹C]Tolebrutinib ([¹¹C] 5 ) as a potential PET imaging agent for BTK. The N-[¹¹C]acrylamide moiety of [¹¹C] 5 was labeled by ¹¹C-carbonylation starting from [¹¹C]CO, iodoethylene, and the secondary amine precursor via a novel palladium-NiXantphos - mediated carbonylation protocol, and the synthesis was fully automated using a commercial carbon-11 synthesis platform (TracerMaker™, Scansys Laboratorieteknik). [¹¹C] 5 was obtained in a decay-corrected radiochemical yield of 37 ± 2% (n = 5, relative to starting [¹¹C]CO activity) in >99% radiochemical purity, with an average molar activity of 45 GBq/μmol (1200 mCi/μmol). We envision that this methodology will be generally applicable for the syntheses of labeled N-acrylamides.     

Radiosynthesis of [11C]SL25.1188 via [11C]CO2 fixation for imaging monoamine oxidase B

Carbon‐11‐labelled (S)‐5‐methoxymethyl‐3‐[6‐(4,4,4‐trifluorobutoxy)benzo[d]isoxazol‐3‐yl]oxazolidin‐2‐[¹¹C]‐one ([¹¹C]SL25.1188), a promising reversibly binding radiotracer for imaging central monoamine oxidase B, was rapidly prepared via an intramolecular cyclization reaction in an automated one‐pot procedure directly from [¹¹C]CO₂, thereby precluding the use of [¹¹C]COCl₂. Formulated [¹¹C]SL25.1188 was isolated in 12 ± 1% uncorrected radiochemical yield, based on starting [¹¹C]CO₂, with a specific activity of 37 ± 2 GBq/µmol at the end of synthesis (30 min; n = 3). Radiochemical and enantiomeric purities were both >99%. The methodology described herein offers an efficient production of [¹¹C]SL25.1188 at ambient temperature and is suitable for human imaging studies.     

In vivo metabotropic glutamate receptor 5 availability-associated functional connectivity alterations in drug-naïve young adults with major depression

There has been increasing interest in glutamatergic neurotransmission as a putative underlying mechanism of depressive disorders. We performed [¹¹C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in drug-naïve young adult patients with major depression to examine alterations in metabotropic glutamate receptor-5 (mGluR5) availability, and to investigate their functional significance relating to neural systems-level changes in major depression. Sixteen psychotropic drug-naïve patients with major depression without comorbidity (median age: 22.8 years) and fifteen matched healthy controls underwent [¹¹C]ABP688 PET imaging and 3-T MRI. For mGluR5 availability, we quantified [¹¹C]ABP688 binding potential (BP_ND) using the simplified reference tissue model. Seed-based functional connectivity analysis was performed using rs-fMRI data with regions derived from quantitative [¹¹C]ABP688 PET analysis as seeds. In region-of-interest (ROI)-based and voxel-based analyses, the [¹¹C]ABP688 BP_ND was significantly lower in patients than in controls in the prefrontal cortex ROI and in voxel clusters within the prefrontal, temporal, and parietal cortices, and supramarginal gyrus. The [¹¹C]ABP688 BP_ND seed-based functional connectivity analysis showed significantly less negative connectivity from the inferior parietal cortex seed to the fusiform gyrus and inferior occipital cortex in patients than in controls. The correlation patterns between [¹¹C]ABP688 BP_ND and functional connectivity strength (β) for the superior prefrontal cortex seed were opposite in the depression and control groups. In conclusion, using a novel approach combining [¹¹C]ABP688 PET and rs-fMRI analyses, our study provides a first evidence of lower mGluR5 availability and related functional connectivity alterations in drug-naïve young adults with major depression without comorbidity.     

Development of a reliable remote‐controlled synthesis of β‐[11C]‐5‐hydroxy‐L‐tryptophan on a Zymark robotic system

Precise staging of neuroendocrine tumors (NET) using positron emission tomography (PET) tracers visualizing their specific metabolic activity is of interest. Besides [¹⁸F]FDOPA, staging NET with carbon‐11 labeled 5‐hydroxytryptophan (5‐HTP) is reported in recent literature. We implemented the multi‐enzymatic synthesis of enantiomerically pure [¹¹C]‐L‐5‐HTP on a Zymark robotic system to compare both tracers in patient studies. [¹¹C]‐5‐HTP can be synthesized in up to 24% radiochemical yields (EOB). Average specific activity is 44 000 GBq/mmol in ca. 50 min from [¹¹C]methyl iodide in radiochemical purities >99 %. The synthesis of 5‐HTP is difficult due to its multi‐enzymatic reaction steps but typical yields can be achieved of ca. 400 MBq. [¹¹C]‐5‐HTP is now reliably used in ongoing studies for staging NET. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and characterization of N‐(2‐chloro‐5‐methylthiophenyl)‐N′‐(3‐methylthiophenyl)‐N′‐[11C]methylguanidine [11C]CNS 5161, a candidate PET tracer for functional imaging of NMDA receptors

N‐methyl‐D ‐aspartate (NMDA) receptors play a key role in excitatory neurotransmission and are linked to a variety of acute and chronic neurodegenerative diseases including epilepsy, schizophrenia, Parkinson's disease and drug abuse. N‐(2‐chloro‐5‐methylthiophenyl)‐N′‐(3‐methylthiophenyl)‐N′‐methylguanidine (CNS 5161) is a high affinity ligand (Ki=1.87±0.25 nM) for the NMDA PCP site, which potentially can be used for functional imaging of this receptor. Herein we report the synthesis of the corresponding positron emission tomography (PET) tracer [¹¹C]CNS 5161 by means of [¹¹C]methylation of the desmethyl guanidine precursor. [¹¹C]CNS 5161 was synthesized with a decay corrected radiochemical yield of 10% within 45 min after end of bombardment (EOB). The final product was prepared in a sterile saline solution suitable for clinical studies with a radiochemical purity of >96% and a specific activity of 41 GBq/mmol at time of injection. Copyright © 2005 John Wiley & Sons, Ltd.     

Efficient syntheses of [11C]zidovudine and its analogs by convenient one‐pot palladium(0)–copper(I) co‐mediated rapid C‐[11C]methylation

The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one‐pot method for Pd(0)–Cu(I) co‐mediated rapid C–C coupling of [¹¹C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [¹¹C]zidovudine, [¹¹C]stavudine, and [¹¹C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.4–7.0 GBq) and specific radioactivity (74–147 GBq/µmol) and with high chemical (>99%) and radiochemical (>99.5%) purities. This one‐pot Pd(0)–Cu(I) co‐mediated rapid C‐[¹¹C]methylation also worked well for syntheses of [methyl‐¹¹C]thymidine and [methyl‐¹¹C]4′‐thiothymidine, resulting twice the radioactivity of those prepared by a previous two‐pot method. The mechanism of one‐pot Pd(0)–Cu(I) co‐mediated rapid C‐[¹¹C]methylation was also discussed.     

Synthesis of new carbon‐11‐labeled 7‐aroyl‐aminoindoline‐1‐sulfonamides as potential PET agents for imaging of tubulin polymerization in cancers

The tubulin polymerization is an attractive target for anticancer therapy and in the development of cancer imaging agents for use in biomedical imaging technique positron emission tomography (PET). 7‐Aroyl‐aminoindoline‐1‐sulfonamides are a novel class of potent antitublin agents. Carbon‐11‐labeled 7‐aroyl‐aminoindoline‐1‐sulfonamides have been synthesized as new potential PET agents for imaging of tubulin polymerization in cancers. The target tracers were prepared by O‐[¹¹C]methylation of their corresponding precursors using [¹¹C]CH₃OTf and isolated by a simplified solid‐phase extraction purification procedure in 40–55% radiochemical yields based on [¹¹C]CO₂ and decay corrected to the end of bombardment (EOB), 15–20 min overall synthesis time from EOB, >98% radiochemical purity, and 74–111 GBq/µmol specific activity at the end of synthesis. Copyright © 2008 John Wiley & Sons, Ltd.     

Automated radiosynthesis of [11C]MTP38—a phosphodiesterase 7 imaging tracer—using [11C]hydrogen cyanide for clinical applications

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[¹¹C]carbonitrile ([¹¹C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [¹¹C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [¹¹C]MTP38 using [¹¹C]hydrogen cyanide ([¹¹C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [¹¹C]MTP38 was performed using an automated ¹¹C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [¹¹C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [¹¹C]CO₂ at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/μmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [¹¹C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [¹¹C]MTP38 for clinical applications using an ¹¹C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [¹¹C]MTP38 suitable for clinical applications.     

Synthesis and biological evaluation of S‐[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5‐HT1A receptors by positron emission tomography (PET)

The novel 2‐mercaptoimidazole derivatives, 1‐[4‐((2‐methoxyphenyl)‐1‐piperazinyl)butyl]‐2‐mercaptoimidazole ( 3 ) and methyl[4‐((2‐methoxyphenyl)‐1‐piperazinyl))butyl] (2‐mercapto‐1‐methylimidazol‐5‐yl)methanamide ( 8 ), were efficiently labelled with ¹¹C through methylation of the thioketone function with [¹¹C]methyl iodide. The resulting radioligands 1‐[4‐((2‐methoxyphenyl)‐1‐piperazinyl))butyl]‐2‐thio[¹¹C]methylimidazole ([¹¹C] 9 ) and methyl[4‐((2‐methoxyphenyl)‐1‐piperazinyl))butyl] (2‐thio[¹¹C]methyl‐1‐methylimidazol‐5‐yl)‐methanamide ([¹¹C] 10 ) were synthesized in radiochemical yields of 20–30% (decay‐corrected, related to [¹¹C]CO₂) at a specific radioactivity of 0.2–0.4 Ci/µmol within 40–45 min including HPLC‐purification. The radiochemical purity exceeded 99%. The reference compounds 9 and 10 were tested in a competitive receptor binding assay to determine their affinity toward the 5‐HT_1A receptor. Both compounds exhibit excellent sub‐nanomolar affinities (IC₅₀=0.576±0.008 nM ( 9 ); IC₅₀=0.86±0.02 nM ( 10 )) for the 5‐HT_1A receptor while displaying a high selectivity towards the 5‐HT_2A subtype of receptors (IC₅₀>480 nM). By contrast, compound 9 also shows substantial binding for the alpha1‐adrenergic receptor (IC₅₀=3.00±0.02 nM) when compared with compound 10 (IC₅₀=54.5±0.6 nM). Preliminary biodistribution studies in rats showed an initial brain uptake of 1.14±0.11 and 0.37±0.04% ID/g after 5 min, which decreased to 0.18±0.04 and 0.16±0.01% ID/g after 60 min for compounds [¹¹C] 9 and [¹¹C] 10 , respectively. For both compounds, the cerebellum and rest of the brain uptake are very similar at the different time points. Unlike [¹¹C] 9 , the radioligand [¹¹C] 10 has significant uptake and retention in the adrenal glands. Due to their washout from the brain compounds [¹¹C] 9 and [¹¹C] 10 seem not to be good candidates as radioligands for imaging 5‐HT_1A receptors by PET. Copyright © 2005 John Wiley & Sons, Ltd.     

A simplified radiosynthesis of [18F]MK‐6240 for tau PET imaging

[¹⁸F]MK‐6240 (6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [¹⁸F]MK‐6240 was synthesized in one step from its bis‐Boc protected precursor N‐[(tert‐butoxy)carbonyl]‐N‐(6‐nitro‐3‐[1H‐pyrrolo[2,3‐c]pyridin‐1‐yl]isoquinolin‐5‐yl) carbamate in DMSO using [¹⁸F] fluoride with TEA HCO₃ with step‐wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis‐Boc ¹⁸F‐labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single‐use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [¹⁸F]MK‐6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies.     

Evaluation and improvement of CuI-mediated 11C-cyanation

CuI-mediated ¹¹C-cyanation was evaluated by synthesizing [¹¹C]perampanel ([¹¹C] 5 ) as a model compound and compared with previous reports. To a DMF solution with 5′-(2-bromophenyl)-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one ( 4 ) and CuI, [¹¹C]NH₄CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min. After HPLC purification, [¹¹C] 5 was obtained in 7.2 ± 1.0% (n = 4) non-decay corrected radiochemical yield with >99% radiochemical purity and a molar activity of 98 ± 28 GBq/μmol. In vivo evaluations of [¹¹C] 5 were performed using small animals. PET scans to check the kinetics of [¹¹C] 5 in the whole body of mice suggested that [¹¹C] 5 spreads rapidly into the brain, heart, and lungs and then accumulates in the small intestine. To evaluate the performance of CuI-mediated ¹¹C-cyanation reaction, bromobenzene ( 6a ) was selected as the model compound; however, it failed. Therefore, optimization of the reaction conditions has been performed, and consequently, the addition of K₂CO₃ and prolonging the reaction time improved the radiochemical yield about double. With this improved method, CuI-mediated ¹¹C-cyanation of various (hetero)aromatic bromides was performed to exhibit the tolerance of most functional groups and to provide ¹¹C-cyanated products in good to moderate radiochemical yields.     

An improved synthesis of [11C]MENET via Suzuki coupling with [11C]methyl iodide

[¹¹C]MENET, a promising norepinephrine transporter imaging agent, was prepared by Suzuki cross coupling of 1 mg N‐t‐Boc pinacolborate precursor with [¹¹C]CH₃I in DMF using palladium complex generated in situ from Pd₂(dba)₃ and (o‐CH₃C₆H₄)₃P together with K₂CO₃ as the co‐catalyst, followed by deprotection with trifluoroacetic acid. This improved radiolabeling method provided [¹¹C]MENET in high radiochemical yield at end of synthesis (EOS, 51 ± 3%, decay‐corrected from end of ¹¹CH₃I synthesis, n = 6), moderate specific activity (1.5–1.9 Ci/µmol at EOS), and high radiochemical (>98%) and chemical purity (>98%) in a synthesis time of 60 ± 5 min from the end of bombardment. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis and evaluation of [11C]RU40555, a selective glucocorticoid receptor antagonist

We demonstrated the synthesis of carbon‐11 labeled 17‐α‐hydroxy‐11‐β‐/4‐/[methyl]‐[1‐methylethyl]‐aminophenyl/‐17α‐[prop‐1‐ynyl]esta‐4‐9‐diene‐3‐one (RU40555), a selective glucocorticoid receptor (GR) antagonist, and examined the in vivo profile of [¹¹C]RU40555. [¹¹C]RU40555 was synthesized by direct N‐methylation with [¹¹C]CH₃OTf at 60°C for 5 min and an injectable solution of [¹¹C]RU40555 was obtained in 31 min at the end of bombardment. The decay‐corrected radiochemical yield was 19%, the specific radioactivity was 57.5±14.0 GBq/µmol, and the radiochemical purity was more than 99% as determined by HPLC. In rat experiments, the effects of adrenalectomy (ADX) on brain accumulation of [¹¹C]RU40555 were examined. ADX significantly decreased plasma corticosterone levels, and significantly increased brain accumulation of [¹¹C]RU40555. We succeeded in developing a rapid automated synthesis method for [¹¹C]RU40555, a GR antagonist, and showed [¹¹C]RU40555 had a potential as a PET tracer for mapping GR. Copyright © 2005 John Wiley & Sons, Ltd.     

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.     

Radiosynthesis of C‐11 labeled auxin (3‐indolyl[1‐11C]acetic acid) and its derivatives from gramine

3‐Indolylacetic acid (IAA) is the major auxin in higher plants and plays a key role in plant growth and development. We report the rapid radiolabeling of the important plant hormone using carbon‐11 (half life: 20.4 min) enabling in vivo imaging of its distribution and movement in whole plants. 3‐Indolyl[1‐¹¹C]acetic acid was synthesized in 2‐steps: (1) reaction of gramine with [¹¹C]cyanide to give 3‐indolyl[1‐¹¹C]acetonitrile in >99% radiochemical purity; (2) hydrolysis of the intermediate in aqueous sodium hydroxide solution to give 3‐indolyl[1‐¹¹C]acetic acid in >98% radiochemical purity after HPLC purification. The overall nondecay corrected radiochemical yield was 28%, synthesis time was 68 min and specific activity was (0.7 mCi/nmol). Hydrolysis proceeded through the formation of 3‐indolyl[1‐¹¹C]acetamide and by varying the temperature of this step, either C‐11 labeled acid or amide were obtained. This procedure provides unexpectedly high C‐11 incorporation in a short time and using a simple and selective hydrolysis without the need of an indole‐nitrogen protecting group or a typical leaving group. Since 3‐indolylacetonitrile and 3‐indolylacetamide are also intermediates in the biosynthesis of IAA, and also function as auxins, this versatile reaction makes all three of these labeled compounds available for imaging studies in whole plants in vivo. Copyright © 2011 John Wiley & Sons, Ltd.     

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.     

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.     

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.