177Lu‐DOTMP induces G2/M cell cycle arrest and apoptosis in MG63 cell line

Bone pain is the major manifestation of skeletal metastases. Although various treatment modalities are available for bone pain palliation, use of radiolabeled phosphonates is documented to be more effective. Among radionuclides available for this purpose, lutetium‐177 is gaining popularity due to its moderate beta energy, theranostic capability, favorable half‐life and convenient production logistics. ¹⁷⁷Lu‐DOTMP has shown considerable promise as a metastatic bone pain palliating agent in preliminary evaluations and recent clinical studies. Therefore, an attempt was made to elucidate the possible mechanism of in vitro cell death induced by ¹⁷⁷Lu‐DOTMP in MG63 cells. ¹⁷⁷Lu‐DOTMP binding studies were carried out in mineralized bone of MG63 cells and around 50% binding was observed. Skeletons of Wistar rats showed 1.78 ± 0.5% IA/g at a 3 h time period which was almost constant up to 7 days. MG63 cells were incubated with 3.7 and 37 MBq of ¹⁷⁷Lu‐DOTMP for 48 h prior to perform assays. An increase in the magnitude of cell toxicity and apoptotic DNA fragmentation was observed. Enhancement of G2/M phase cell cycle arrest and apoptosis were documented which were dose‐dependent. Thus, ¹⁷⁷Lu‐DOTMP induced apoptotic cell death in MG63 cells, which might be one of the primary causes of pain relief in osseous metastases.     

Ce‐141‐labeled DOTMP: A theranostic option in management of pain due to skeletal metastases

Owing to its favorable radioactive decay characteristics (T_1/2 = 32.51 d, E_β [max] = 434.6 keV [70.5%] and 580.0 keV [29.5%], E_γ = 145.4 keV [48.5%]), ¹⁴¹Ce could be envisaged as a theranostic radionuclide for use in nuclear medicine. The present article reports synthesis and evaluation of ¹⁴¹Ce complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetramethylenephosphonic acid (DOTMP) as a potent theranostic agent targeting metastatic skeletal lesions. Ce‐141 was produced with 314 ± 29 MBq/mg (n = 6) specific activity and >99.9% radionuclidic purity (n = 6). Around 185 MBq dose of [¹⁴¹Ce]Ce‐DOTMP was synthesized with 98.6 ± 0.5% (n = 4) radiochemical yield under optimized conditions of reaction, and the preparation showed adequately high in vitro stability. Biodistribution studies in normal Wistar rats demonstrated significant skeletal localization and retention of injected activity (2.73 ± 0.28% and 2.63 ± 0.22% of injected activity per gram in femur at 3 hours and 14 days post‐injection, respectively) with rapid clearance from non‐target organs. The results of biodistribution studies were corroborated by serial scintigraphic imaging studies. These results demonstrate the potential utility of ¹⁴¹Ce‐DOTMP as a theranostic molecule for personalized patient care of cancer patients suffering from painful metastatic skeletal lesions.     

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.     

90Y/177Lu‐labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation

Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human–mouse chimeric IgG₁ mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of ⁹⁰Y‐labelled Cetuximab and ¹⁷⁷Lu‐labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N‐[(R)‐2‐amino‐3‐(paraisothiocyanato‐phenyl)propyl]‐trans‐(S,S)‐cyclohexane‐1,2‐diamine‐N,N,N′,N″,N″‐pentaacetic acid (CHX‐A″‐DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for ⁹⁰Y‐CHX‐A″‐DTPA‐Cetuximab and 1.14 ± 0.15 GBq/mg for ¹⁷⁷Lu‐CHX‐A″‐DTPA‐Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both ⁹⁰Y‐CHX‐A″‐DTPA‐Cetuximab and ¹⁷⁷Lu‐CHX‐A″‐DTPA‐Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24‐h post‐injection (p.i.) (~16%ID/g) with good tumour‐to‐background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of ⁹⁰Y‐CHX‐A″‐DTPA‐Cetuximab in tumour‐bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation.     

Preparation of 177Lu‐labeled Nimotuzumab for radioimmunotherapy of EGFR‐positive cancers: Comparison of DOTA and CHX‐A″‐DTPA as bifunctional chelators

This study was aimed at evaluating the role of bifunctional chelators DOTA‐NCS and CHX‐A″‐DTPA‐NCS used for conjugating ¹⁷⁷Lu with Nimotuzumab on the radiochemical yields, purity, in vitro stability, and specificity of the radioimmunoconjugates to EGFR. Two immunoconjugates were prepared wherein Nimotuzumab was conjugated with the acyclic ligand p‐NCS‐Bn‐CHX‐A″‐DTPA and macrocyclic ligand p‐NCS‐Bn‐DOTA. These were radiolabeled with ¹⁷⁷Lu, purified on PD‐10 column, and characterized by SE‐HPLC. In vitro stability was determined up to 4 days post preparation. Specificity of the radioimmunoconjugates was ascertained by in vitro studies in A431 cells while the biodistribution patterns were studied in normal Swiss mice up to 96 hours post injection. Four to five molecules of CHX‐A″‐DTPA/DOTA were attached to one molecule of Nimotuzumab. Radiochemical purity of both ¹⁷⁷Lu‐CHX‐A″‐DTPA‐Nimotuzumab and ¹⁷⁷Lu‐DOTA‐Nimotuzumab was determined to be greater than 98%. Both the radioimmunoconjugates exhibited good in vitro stability at 37°C up to 4 days post preparation in saline, and their clearance was largely by the hepatobiliary route. The DOTA‐ and CHX‐A″‐DTPA‐based radioimmunoconjugates could be prepared with good radiochemical purity, in vitro stability, and specificity to EGFR. Further studies in EGFR‐positive cancers would pave way for them for use in the clinics.     

Preparation,evaluation, and first clinical use of 177Lu‐labeled hydroxyapatite (HA) particles in the treatment of rheumatoid arthritis: utility of cold kits for convenient dose formulation at hospital radiopharmacy

While radiation synovectomy (RSV) constitutes a successful paradigm for the treatment of arthritis, a major cornerstone of its success resides in the selection of appropriate radiolabeled agent. Among the radionuclide used for RSV, the scope of using ¹⁷⁷Lu [T_1/2 = 6.65 d, E_β(max) = 497 keV, E_γ = 113 KeV (6.4%), 208 KeV (11%)] seemed to be attractive owing to its suitable decay characteristics, easy availability, and cost‐effective production route. The present article describes a formulation of ¹⁷⁷Lu‐labeled hydroxyapatite (HA) using ready‐to‐use kits of HA particles of 1–10 µm size range. The developed kits enable convenient one‐step preparation of ¹⁷⁷Lu‐HA (400 ± 30 MBq doses) in high radiochemical purity (>99%) and stability at hospital radiopharmacy. The preparation showed promising results in pre‐clinical studies carried out in Wistar rats bearing arthritis in knee joints. In preliminary clinical investigation, significant improvement in the disease conditions was reported in 10 patients with rheumatoid arthritis of knee joints treated with 333 ± 46 MBq doses of ¹⁷⁷Lu‐HA. The studies reveal that while ¹⁷⁷Lu labeled HA particles holds considerable promise as a cost‐effective agent for RSV, the adopted strategy of using HA kits could be a potential step toward wider clinical utilization of radiolanthanide‐labeled HA particles. Copyright © 2014 John Wiley & Sons, Ltd.     

Preparation of clinical‐scale 177Lu‐Rituximab: Optimization of protocols for conjugation,radiolabeling, and freeze‐dried kit formulation

Rituximab is a monoclonal chimeric antibody, which has been approved by the US Food and Drug Administration for immunotherapy of non–Hodgkin lymphoma. Bexxar and Zevalin are the two other approved radiolabeled antibodies for radioimmunotherapy of non–Hodgkin lymphoma; however, they are of murine origin that reduces their treatment efficacy. So as to circumvent this, efforts have been made to radiolabel Rituximab with various therapeutic radioisotopes. In the present study, an effort has been made to optimize the conjugation (bifunctional chelating agent and antibody) and radiolabeling procedures for the preparation of clinical‐scale ¹⁷⁷Lu‐labeled Rituximab. An attempt was also made to prepare the freeze‐dried Rituximab kit for the easy and convenient clinical translation of the agent. Clinical‐scale ¹⁷⁷Lu‐Rituximab (40 mCi, 1.48 GBq) was prepared with >95% radiochemical purity using the kit. Biological evaluation of ¹⁷⁷Lu‐Rituximab was performed by in vitro cell binding studies in Raji cell lines, which showed satisfactory binding at 4°C and 37°C. Pharmacokinetic behavior of the agent, evaluated by biodistribution studies in normal Swiss mice, revealed high blood and liver uptake at the initial time points, although it exhibited slow and gradual clearance with time. The study indicates that clinical‐scale ¹⁷⁷Lu‐Rituximab could be conveniently formulated using the methodology described in the present article.     

Radiolabeling,quality control,biodistribution, and imaging studies of 177Lu‐ibandronate

The purposes of this study were as follows: (1) to radiolabel ibandronic acid (IBA, a third‐generation bisphosphonate) with ¹⁷⁷Lu, investigating optimal labeling conditions, and (2) to analyze biodistribution and imaging properties of intravenous ¹⁷⁷Lu‐ibandronate (¹⁷⁷Lu‐IBA) administered in animals. ¹⁷⁷Lu‐labeled methylene diphosphonate (¹⁷⁷Lu‐MDP) served as a comparator agent. Differing proportions of IBA solution and ¹⁷⁷LuCl₃ solution were combined to determine an optimal ratio for radiolabeling purposes, varying pH, temperature, and time to establish ideal reactivity conditions. Radiochemical purity of the labeled compounds was then assessed by paper chromatography. In vitro and in vivo stabilities were also measured at specific time intervals. In Kunming mice, biodistributions of ¹⁷⁷Lu‐IBA and ¹⁷⁷Lu‐MDP and respective agent activities in various organs were monitored by gamma counter, and we performed single photon computed tomography/computed tomography (SPECT/CT) imaging of ¹⁷⁷Lu‐IBA in normal New Zealand White rabbits. Radiolabeling yields for ¹⁷⁷Lu‐IBA proved to be >97% within 30 minutes at 90°C, and its radiochemical purity ensured stability in vitro and in vivo. Furthermore, we found that ¹⁷⁷Lu‐IBA is readily soluble in water, showing higher skeletal uptake than ¹⁷⁷Lu‐MDP but lower uptake by liver and spleen. The image quality of ¹⁷⁷Lu‐IBA was so clear that even after 6 days, analysis was still feasible.     

Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

Following our recently published fluorine‐18 labeling method, “Radio‐fluorination on the Sep‐Pak”, we have successfully synthesized 6‐[¹⁸F]fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t‐butanol) of its quaternary ammonium salt precursor, 6‐(N,N,N‐trimethylamino)nicotinaldehyde trifluoromethanesulfonate ( 2 ), through a fluorine‐18 containing anion exchange cartridge (PS‐HCO₃). Over 80% radiochemical conversion was observed using 10 mg of precursor within 1 minute. The [¹⁸F]fluoronicotinaldehyde ([¹⁸F] 5 ) was then conjugated with 1‐(6‐(aminooxy)hexyl)‐1H‐pyrrole‐2,5‐dione to prepare the fluorine‐18 labeled maleimide functionalized prosthetic group, 6‐[¹⁸F]fluoronicotinaldehyde O‐(6‐(2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime, 6‐[¹⁸F]FPyMHO ([¹⁸F] 6 ). The current Sep‐Pak method not only improves the overall radiochemical yield (50 ± 9%, decay‐corrected, n = 9) but also significantly reduces the synthesis time (from 60‐90 minutes to 30 minutes) when compared with literature methods for the synthesis of similar prosthetic groups.     

Radiolabeling,quality control,and biological characterization of 177Lu‐labeled kanamycin

Kanamycin is an antibiotic, isolated from Streptomyces kanamyceticus, which is used to treat serious bacterial infections. The fact that the present radioligand ^99mTc‐kanamycin used for diagnosis is short‐lived, raised a need to label and study kanamycin with one of the most important beta (β) radiation emitting isotope ¹⁷⁷Lu. Labeling yield of ¹⁷⁷Lu‐kanamycin was confirmed by different chromatography techniques such as paper chromatography, TLC, HPLC. Several experiments were performed to optimize labeling with changing reaction conditions such as pH, temperature, amount of ligand, and reaction time. In vitro stability analysis was performed incubation with human serum. Electrophoresis analysis was also conducted to determine the charge on ¹⁷⁷Lu‐kanamycin. The biodistribution and scintigraphy were performed in normal mice and rabbit, respectively, at different time intervals of postinjection. ¹⁷⁷Lu‐kanamycin was prepared with very high yield (~100%), with excellent stability in vivo and in vitro (>99% 6 hr postprep.), at pH 7. Maximum labeling was achieved at less reaction time (15 min), with maximum conjugation of the ligand (12.5 mg) with ¹⁷⁷Lu. Electrophoresis analysis showed net neutral charge. The radioligand showed rapid clearance from body in biodistribution and scintigraphy studies. The preparation ¹⁷⁷Lu‐kanamycin could be used as a radio‐pharmaceutical for infection imaging purpose, especially when transporting the radioligand to long‐range distances.     

An improved radiosynthesis of O‐(2‐[18F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate: A first‐in‐class cholinesterase PET tracer

O‐(2‐Fluoroethyl)‐O‐(p‐nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl‐serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo . The corresponding radiolabeled O‐(2‐[¹⁸F]fluoroethyl)‐O‐(p‐nitrophenyl) methylphosphonate, [ ¹⁸ F]1 , has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [ ¹⁸ F]1 tracer synthesis was slow even with microwave acceleration, required high‐performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis‐(O,O‐p‐nitrophenyl) methylphosphonate, 2 , with 2‐fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [ ¹⁸ F]1 , was obtained in a non‐decay–corrected radiochemical yield of 8 ± 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 ± 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [ ¹⁸ F]1 , which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo .     

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.     

177Lu‐5‐Fluorouracil a potential theranostic radiopharmaceutical: radiosynthesis,quality control,biodistribution, and scintigraphy

The aim of this study is to develop ¹⁷⁷Lu‐5‐Flourouracil as a potential cancer therapeutic radiopharmaceutical. 5‐Flourouracil (5‐FU) is widely accepted as an anticancer drug of broad spectrum fame. The labeling of 5‐FU was carried out at different set of experimental conditions using high specific activity of ¹⁷⁷LuCl₃. The optimum conditions for maximum radiochemical yield was set: 5‐FU (5 mg), ¹⁷⁷LuCl₃ (185 MBq), diethylenetriaminepentaacetic acid (10 µg), reaction volume (2 mL), pH (5.5), temperature (80°C), and reaction time (20 min). The radiochemical labeling was assessed with Whatman No. 2 paper, instant thin layer chromatographic, and radio‐HPLC, which revealed >94% labeling results with sufficient stability up to 6 h. Serum stability study also showed ¹⁷⁷Lu‐5‐FU promising stability. Biodistribution study in normal rats and rabbits showed liver, stomach, kidney, and heart as area of increased tracer accumulation just after injection, which decreased to 1.4%, 0.4%, 0.2%, and 0.39% ID/g, respectively, after 72 h. Glomerular filtration rate and cytotoxicity study results of ¹⁷⁷Lu‐5‐FU showed it had no adverse effect on renal function and nontoxic to blood cells. The promising characteristics of ¹⁷⁷Lu‐5‐FU, that is, clever elimination from kidney and nontoxic nature toward blood cells make it the radiopharmaceutical for further testing in patients for therapeutic purposes.     

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.     

Preparation of 68Ga‐Mg‐Ca‐phytate colloid and its evaluation as a liver imaging agent

The objective of this study was to investigate the radiosynthesis of ⁶⁸Ga‐Mg‐Ca‐phytate colloid and then characterise the formulation for radiochemical purity (RCP), radioactive particle size distribution, and biodistribution in normal rats. This radiocolloid was prepared by mixing an aqueous solution of phytic acid, ⁶⁸Ga³⁺ ions, a dispersant, Mg²⁺ and Ca²⁺ ions, and then heating the contents at 100°C for 5 minutes. After cooling the vial to 5°C, the solution was basified to pH 5 and stored in the cold. The resulting product contained 92±3% RCP ⁶⁸Ga‐colloidal particles and a low level (8±3%) of soluble ⁶⁸Ga‐Mg‐Ca‐phytate. Particle size experiments defined the radioactive particle population was 6±4% <20 nm, 90±6% 20 to 200 nm, and 4% were >200 nm in diameter. Intravenous injection of the ⁶⁸Ga‐colloid dispersion to rats resulted in 93% uptake by the liver plus spleen, 1% lungs, 1% total blood, and 6% in the carcass after 20 minutes. This optimal formulation remained stable at 5°C for 1½ hours in vitro, and it resulted in the same biodistribution as the formulation prepared at t  = 0 hours. The preclinical data so far indicate that ⁶⁸Ga‐Mg‐Ca‐colloid has excellent potential as a liver imaging agent.     

Production,quality control,and determination of human absorbed dose of no carrier added 177Lu‐risedronate for bone pain palliation therapy

In this study, the radiocomplexation of risedronic acid, a potent bisphosphonate with a no carrier added (NCA) ¹⁷⁷Lu, was investigated and followed by quality control studies, biodistribution evaluation, and dosimetry study for human based on biodistribution data in Wistar rats. The moderate energy β⁻ emitter, ¹⁷⁷Lu (T _½ = 6.7 days, E _βmax = 497 keV), has been considered as a potential agent for development of bone‐seeking radiopharmaceuticals. Because the specific activity of the radiolabeled carrier molecules should be high, the NCA radionuclides have an effective role in nuclear medicine. Many researchers illustrated an NCA ¹⁷⁷Lu production; among these separation techniques, extraction chromatography has been considered more capable than other methods. The NCA ¹⁷⁷Lu was produced with specific activity of 48 Ci/mg and radionuclidic purity of 99.99% by the irradiation of enriched ¹⁷⁶Yb target in thermal neutron flux of 4 × 10¹³ n·cm⁻²·s⁻¹ for 14 days. The NCA ¹⁷⁷Lu was mixed to a desired amount of sodium risedronate (15 mg/mL, 200 μL) and incubated with stirring at 95°C for 30 minutes. The radiochemical purity of ¹⁷⁷Lu‐risedronate was determined by radio thin‐layer chromatography, and high radiochemical purities (>97%) were obtained under optimized reaction conditions . The complex was injected to Wistar rats, and complex biodistribution was performed 4 hours to 7 days postinjections showing high bone uptake (9.8% ± 0.24% ID/g at 48 hours postinjection). Also, modeling the radiation dose delivery by RADAR software for the absorbed dose evaluation of each human organ showed a major accumulation of the radiocomplex in bone tissue.     

Synthesis and evaluation of an 18F‐labeled trifluoroborate derivative of 2‐nitroimidazole for imaging tumor hypoxia with positron emission tomography

2‐Nitroimidazole‐based hypoxia imaging tracers such as ¹⁸F‐FMISO are normally imaged at late time points (several hours post‐injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion‐based ammoniomethyl‐trifluoroborate derivative of 2‐nitroimidazole, ¹⁸F‐AmBF₃‐Bu‐2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF₃‐Bu‐2NI was prepared in 4 steps. ¹⁸F labeling was conducted via ¹⁸F‐¹⁹F isotope exchange reaction, and ¹⁸F‐AmBF₃‐Bu‐2NI was obtained in 14.8 ± 0.4% (n = 3) decay‐corrected radiochemical yield with 24.5 ± 5.2 GBq/μmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT‐29 tumor‐bearing mice showed that ¹⁸F‐AmBF₃‐Bu‐2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post‐injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post‐injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl‐trifluoroborate that prevents free diffusion of ¹⁸F‐AmBF₃‐Bu‐2NI across the cell membrane. Our results suggest that highly hydrophilic ¹⁸F‐labeled ammoniomethyl‐trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target.     

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.     

cGMP production of the radiopharmaceutical [18F]MK‐6240 for PET imaging of human neurofibrillary tangles

Fluorine‐18–labelled 6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine ([¹⁸F]MK‐6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2‐step radiosynthesis of [¹⁸F]MK‐6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FX_FN. Nucleophilic fluorination of the 5‐diBoc‐6‐nitro precursor with potassium cryptand [¹⁸F]fluoride (K[¹⁸F]/K₂₂₂) was performed by conventional heating, followed by acid deprotection and semipreparative high‐performance liquid chromatography under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices, and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 to 9.3 GBq (170‐250 mCi) of [¹⁸F]MK‐6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5% ± 1.9% (relative to starting [¹⁸F]fluoride) with a specific activity of 222 ± 67 GBq/μmol (6.0 ± 1.8 Ci/μmol) at the end of synthesis (90 minutes; n = 3). [¹⁸F]MK‐6240 was successfully validated for human PET studies meeting all Food and Drug Administration and United States Pharmacopeia requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.     

A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [18F]‐THK‐5351

The radiotracer, [¹⁸F]‐THK‐5351, is a highly selective and high‐binding affinity PET imaging agent for aggregates of hyper‐phosphorylated tau protein. Our report is a simplified 1‐pot, 2‐step radiosynthesis of [¹⁸F]‐THK‐5351. This report is broadly applicable for routine clinical production and multi‐center trials on account of favorable half‐life of flourine‐18 and the use of a commercially available radiosynthesis module, the GE TRACERlab™ FX_FN. First, the O‐THP protected tosyl precursor underwent nucleophilic fluorinating reaction with potassium cryptand fluoride ([¹⁸F] fluoride (K[¹⁸F]/K₂₂₂)) in Dimethyl sulfoxide at 110°C for 10 minutes followed by O‐THP removal by using diluted hydrochloric acid (HCl) at same temperature. [¹⁸F]‐THK‐5351 was purified via semi‐preparative high‐performance liquid chromatography and formulated by using 10% EtOH, United States Pharmacopeia (USP) in 0.9% sodium chloride for injection, USP and an uncorrected radiochemical yield of 21 ± 3.5%, with a specific activity of 153.11 ± 25.9 GBq/μmol (4138 ± 700 mCi/μmol) at the end of synthesis (63 minutes; n  = 3).