A “mix‐and‐use” approach for formulation of human clinical doses of 177Lu‐DOTMP at hospital radiopharmacy for management of pain arising from skeletal metastases

Use of bone‐seeking radiopharmaceuticals is an established modality in the palliative care of pain due to skeletal metastases. ¹⁷⁷Lu‐DOTMP is a promising radiopharmaceutical for this application owing to the ideally suited decay properties of ¹⁷⁷Lu and excellent thermodynamic stability and kinetic rigidity of the macrocyclic complex. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of clinical doses of ¹⁷⁷Lu‐DOTMP at hospital radiopharmacy. After extensive radiochemical studies, an optimized strategy for formulation of clinical doses of ¹⁷⁷Lu‐DOTMP was developed, which involves simple mixing of approximately 3.7 GBq of ¹⁷⁷Lu activity as ¹⁷⁷LuCl₃ solution to an aqueous solution containing 5 mg of DOTMP and 8 mg of NaHCO₃. The proposed protocol yielded ¹⁷⁷Lu‐DOTMP with >98% radiochemical purity, and the resultant formulation showed excellent in vitro stability and desired pharmacokinetic properties in animal model. Preliminary clinical investigations in 5 patients showed specific skeletal accumulation with preferential localization in the osteoblastic lesion sites and almost no uptake in soft tissue or any other major nontarget organ. The developed “mix‐and‐use” strategy would be useful for large number of nuclear medicine centers having access to ¹⁷⁷Lu activity and would thereby accelerate the clinical translation of ¹⁷⁷Lu‐DOTMP.     

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.     

Single vial kit formulation of DOTATATE for preparation of 177Lu‐labeled therapeutic radiopharmaceutical at hospital radiopharmacy

The clinical applications of radiolabeled somatostatin analogue ¹⁷⁷Lu‐DOTA‐Tyr³‐Thr⁸‐Octreotide (¹⁷⁷Lu‐DOTATATE) constitute a promising treatment option for patients with disseminated and inoperable neuroendocrine (NET) tumors. Formulation of ¹⁷⁷Lu‐DOTATATE in hospital radiopharmacy under aseptic conditions in a safe and reliable manner is a major constraint for its extensive use. The present work was intended to develop a kit for the safe preparation of the therapeutic radiopharmaceutical, viz. ¹⁷⁷Lu‐DOTATATE of high quality that can be easily adapted at conventional hospital radiopharmacies. Single vial kits of DOTATATE were formulated and evaluated for suitability for radiolabeling as well as stability on its storage. Patient dose of ¹⁷⁷Lu‐DOTATATE (7.4 GBq) could be successfully prepared using semi‐automated in‐house setup that assures safe handling and high yields of product of pharmaceutical purity suitable for clinical use. Fast clearance of activity via renal route was observed in preclinical biodistribution studies of ¹⁷⁷Lu‐DOTATATE carried out in normal Swiss mice. Deployment of in‐house produced ¹⁷⁷LuCl₃, cold kits and easy adaptability of synthesis setup at hospital radiopharmacy for preparation is likely to expand applications of peptide receptor radionuclide therapy.     

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.     

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.     

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.     

177Lu‐labeled monomeric,dimeric and multimeric RGD peptides for the therapy of tumors expressing α(ν)β(3) integrins

The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target‐specific molecular recognition. Peptides based on the cyclic Arg‐Gly‐Asp (RGD) sequence have been reported as high‐affinity agents for the α(ν)β(3) integrin. The aim of this research was to prepare a multimeric system of ¹⁷⁷Lu‐labeled gold nanoparticles conjugated to c(RGDfK)C (cyclo(Arg‐Gly‐Asp‐Phe‐Lys)Cys) and to compare the radiation‐absorbed dose with that of ¹⁷⁷Lu‐labeled monomeric and dimeric RGD peptides to α(ν)β(3) integrin‐positive U87MG tumors in mice. DOTA‐GGC (1,4,7,10‐tetraazacyclododecane‐N‐N′,N″,N?‐tetraacetic acid‐Gly‐Gly‐Cys) and c(RGDfK)C peptides were synthesized and conjugated to AuNPs by a spontaneous reaction of the thiol groups. Transmission electron microscopy, ultraviolet–visible, X‐ray photoelectron spectroscopy, Raman and far‐infrared spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. For the ¹⁷⁷Lu‐AuNP‐c(RGDfK)C to be obtained, the ¹⁷⁷Lu‐DOTA‐GGC radiopeptide was first prepared and added to a solution of AuNPs followed by c(RGDfK)C (25 µl, 5 µ m ) at 18 °C for 15 min. ¹⁷⁷Lu‐DOTA‐GGC, ¹⁷⁷Lu‐DOTA‐cRGDfK and ¹⁷⁷Lu‐DOTA‐E‐c(RGDfK)₂ were prepared by adding ¹⁷⁷LuCl₃ (370 MBq) to 5 µl (1 mg/ml) of the DOTA derivative diluted with 50 µl of 1 m acetate buffer pH 5. The mixture was incubated at 90 °C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. Biokinetic studies were accomplished in athymic mice with U87MG‐induced tumors. The radiochemical purity for all ¹⁷⁷Lu‐RGD derivatives was 96 ± 2%. ¹⁷⁷Lu‐absorbed doses per injected activity delivered to U87MG tumors were 0.357 ± 0.052 Gy/MBq (multimer), 0.252 ± 0.027 Gy/MBq (dimer) and 0.102 ± 0.018 Gy/MBq (monomer). ¹⁷⁷Lu‐labeled dimeric and multimeric RGD peptides demonstrated properties suitable for targeted radionuclide therapy of tumors expressing α(ν)β(3) integrins. Copyright © 2012 John Wiley & Sons, Ltd.     

Preparation of 3′‐deoxy‐3′‐[18F]fluorothymidine ([18F]FLT) in ionic liquid, [bmim][OTf]

Although 3′‐deoxy‐3′‐[¹⁸F]fluorothymidine ([¹⁸F]FLT) is a prospective radiopharmaceutical for the imaging of proliferating tumor cell, it is difficult to prepare large amount of [¹⁸F]FLT. We herein describe the preparation of [¹⁸F]FLT in an ionic liquid, [bmim][OTf] (1‐butyl‐3‐methyl‐imidazolium trifluoromethanesulfonate). At optimized condition, [¹⁸F]fluorinationin ionic liquid with 5 µl of 1 M KHCO₃ and 5 mg of the precursor yielded 61.5 ± 4.3% (n=10). Total elapsed time was about 70 min including HPLC purification. The rapid synthesis of [¹⁸F]FLT can be achieved by removing all evaporation steps. Overall radiochemical yield and radiochemical purity were 30 ± 5% and >95%, respectively. This method can use a small amount of a nitrobenzenesulfonate precursor and can be adapted for automated production. Copyright © 2006 John Wiley & Sons, Ltd.     

2‐Amino‐3‐(1‐(4‐(4‐(2‐methoxyphenyl) piperazine‐1‐yl)butyl)‐1H‐1,2,3‐triazol‐4‐yl) propanoic acid: synthesized, 99mTc‐tricarbonyl labeled,and bioevaluated as a potential 5HT1A receptor ligand

To develop a novel 5HT_1A receptor imaging agent, a new methoxyphenyl piperazine derivative was synthesized and radiolabeled with ^99mTc‐tricarbonyl precursor. We used the Cu (I)‐catalyzed cycloaddition of azide and terminal alkynes to synthesize 1, 2, 3 triazole as the metal chelating system. This synthesis provided reliable and reproducible method to attach technetium to the methoxyphenyl piperazine moiety. ^99mTc‐tricabonyl labeling of ligand was performed at high radiochemical purity (greater than 95%). The radiolabeled compound was stable at least 24 h in room temperature. In vitro stability study in human serum albumin showed more than 90% stability in 37 °C incubation for 6 h. Biodistribution studies in rat have shown brain hippocampus uptake of 0.31 ± 0.02 %ID/g at 5‐min post‐injection. The favorable in vitro/in vivo stability, lipophilicity, and biodistribution profiles suggest that this radioconjugate is a good candidate for further exploration of its potential clinical application. Copyright © 2012 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.     

Preclinical evaluation of new GnRH‐I receptor radionuclide therapy with 177Lu‐peptide tracer

The purpose of this study was to develop preclinical evaluation of a novel radiolabeled gonadotropin‐releasing hormone (GnRH) receptor targeting peptide for prostate cancer therapy. The new antiproliferative agent of GnRH‐I analogue was developed on the basis of the D‐Trp⁶‐GnRH‐I scaffold, and in vivo pharmacokinetics and receptor binding affinity were enhanced by the substitution of Gly‐NHNH₂ for Gly‐NH₂ at position 10 in D‐Trp⁶‐GnRH‐I. To evaluate ¹⁷⁷Lu‐DOTA‐triptorelin‐hydrazide as radionuclide therapy of tumor, the quality control tests and preclinical stage assessment were carried out. Solid‐phase method was used to synthesize new peptide. Characterization and purity of peptide were done by mass spectroscopy and high‐performance liquid chromatography (HPLC). In order to be utilized in targeted therapy, the new GnRH‐I agonist was coupled with pSCN‐Bn‐DOTA. The precipitate crude of DOTA‐triptorelin‐hydrazide was then purified via preparative HPLC. At optimal conditions of time, temperature, ligand amount, and lutetium content, DOTA‐triptorelin‐hydrazide was labeled with ¹⁷⁷Lu (specific activity not less than 925 GBq/mg). Investigation of the in vivo biodistribution and in vitro studies for ¹⁷⁷Lu‐DOTA‐TRPHYD was performed in three different ways, and the binding of radiopeptide to GnRH receptors was expressed on the human cell lines using ¹²⁵I‐labeled D‐TRP⁶GnRH‐I as a tracer, respectively. Synthesized novel GnRH‐I was obtained with purity greater than 98%. Paper chromatography was found to be the most suitable with R_f of the complex and observed radiochemical purity of RTLC and HPLC greater than 97%. For in vivo studies, ¹⁷⁷Lu‐DOTA‐triptorelin‐hydrazide showed promising results with fast clearance from the blood and resulted in good T/NT ratios at 1, 4, and 24 hours postinjection and satisfactory biodistribution with no significant activity seen in normal tissue. The values of internalization efficiency and receptor affinity of new radiopeptide binding were IC₅₀ = 0.47 ± 0.06 vs 0.13 ± 0.01 nM for triptorelin and cellular uptake: 3.4 ± 0.7% at 1 hour and 6.8 ± 1.17% at 4 hours of the internal reference. The results showed a good stability and radiochemical purity of the obtained radioconjugate. For in vivo and in vitro studies, new radiopeptide showed a high uptake of ¹⁷⁷Lu conjugate in tumor and rapid clearance from the blood stream almost entirely via the renal/urinary pathway and binding to the GnRH receptors with high specificity and affinity, respectively.     

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.     

Synthesis of [18F] 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression

To synthesize ¹⁸F‐labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting ¹⁸F into a target molecule are necessary. The ¹⁸F‐fluorobenzene moiety has been widely utilized in the synthesis of ¹⁸F‐labeled compounds. The present study utilized [¹⁸F]‐labeled aniline as intermediate in [¹⁸F]‐radiolabeling chemistry for the facile radiosynthesis of 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide ([¹⁸F]IDO5L) as indoleamine 2,3‐dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC₅₀. [¹⁸F]IDO5L was synthesized via coupling [¹⁸F]3‐chloro‐4‐fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [¹⁸F]IDO5L was obtained with specific radioactivity ranging from 11 to 15 GBq/µmol at the end of synthesis within ~90 min, and the decay‐corrected radiochemical yield was 18.2 ± 2.1% (n = 4).     

Synthesis and evaluation of a new 99mTc(I)‐tricarbonyl complex bearing the 5‐nitroimidazol‐1‐yl moiety as potential hypoxia imaging agent

The objective of this work was to develop a novel ^99mTc complex bearing the 5‐nitroimidazol‐1‐yl moiety with recognised selectivity towards hypoxic tissue, as a potential radiopharmaceutical for imaging tumour hypoxia. The new metronidazole derivative (2‐amine‐3‐[2‐(2‐methyl‐5‐nitro‐1H‐imidazol‐1‐yl)ethylthio]propanoic acid) (L) containing adequate groups to coordinate technetium through the formation of a Tc(I)‐tricarbonyl complex was synthesised with adequate yield (33%) and characterised by spectroscopy. Labelling was performed by substitution of three labile water molecules of the technetium tricarbonyl precursor, fac‐[^99mTc(CO)₃(H₂O)₃]⁺ with the ligand. A radiochemical purity higher than 90% was achieved and remained unchanged for more than 4 h. The complex has a high stability in plasma, a moderate plasma protein binding and a moderate hydrophilicity. In vitro cell uptake studies showed a ratio between the activity taken up by cells in hypoxia/normoxia of 1.6 ± 0.4 (p < 0.5). Biodistribution in normal mice showed rapid depuration and low uptake in all organs and tissues except liver. Biodistribution in mice bearing induced tumours showed a low tumour uptake, but tumour/muscle ratio was favourable thanks to depuration. Comparison with biological results of other metronidazole derivatives clearly shows that modifications of the chelator are very important and contribute to improve the biological behaviour.     

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.     

Two‐step radiosynthesis of [18F]N‐succinimidyl‐4‐fluorobenzoate ([18F]SFB)

The acylation reagent [¹⁸F]N‐succinimidyl‐4‐fluorobenzoate (¹⁸F‐SFB) has been prepared using a new two‐step approach. The starting material p‐[¹⁸F]fluorobenzaldehyde (¹⁸F‐FBA) was obtained by an improved radiosynthesis with a decay‐corrected radiochemical yield of 66±6 % (n=3). Reaction of ¹⁸F‐FBA with (diacetoxyiodine)benzene and N‐hydroxysuccinimide and preparative HPLC purification furnished ¹⁸F‐SFB in an r.c.y. of 49±6 % (n=3), based on the starting radioactivity of ¹⁸F‐FBA. The radiochemical purity of ¹⁸F‐SFB was >99%. Alternatively, purification by solid phase extraction gave ¹⁸F‐SFB with an r.c.y. of 77±9% (n=4) and a radiochemical purity of 89±5% (n=4). This radiochemical synthesis only used non‐aqueous solvents, which simplifies the method and facilitates subsequent applications of ¹⁸F‐SFB. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis and in vivo study of [18F]1‐(2‐fluoroethyl)‐4‐[(4‐cyanophenoxy)methyl]piperidine: a promising new sigma‐1 receptor ligand

The novel sigma‐1 receptor PET radiotracer [¹⁸F]1‐(2‐fluoroethyl)‐4‐[(4‐cyanophenoxy)methyl]piperidine ([¹⁸F]WLS1.002, [¹⁸F]‐2) was synthesized (n=6) by heating the corresponding N‐ethylmesylate precursor in an anhydrous acetonitrile solution containing [¹⁸F]fluoride, Kryptofix K₂₂₂ and potassium carbonate for 15 min. Purification was accomplished by reverse‐phase HPLC methods, providing [¹⁸F]‐2 in 59±8% radiochemical yield (EOB), with specific activity of 2.89±0.80 Ci/µmol (EOS) and radiochemical purity of 98.3±2.1%. Rat biodistribution studies revealed relatively high uptake in many organs known to contain sigma‐1 receptors, including the lungs, kidney, heart, spleen, and brain. Good clearance from normal tissues was observed over time. Blocking studies (60 min) demonstrated high (>80%) specific binding of [¹⁸F]‐2 in the brain, with reduction also noted in other organs known to express these sites. Copyright © 2005 John Wiley & Sons, Ltd.     

Quality control methods for 99mTc‐labeled exogenous natural surfactant (99mTc‐ENS)

To standardize the quality control for ^99mTc‐ENS, the following methods were studied: (1) physical properties and pH, (2) radiochemical purity (chromatographic studies on Whatman‐1 paper, or instant thin‐layer chromatography and solvent extraction using different solvents and (3) rat biodistribution studies by intratracheal injection. The tolerance limits were fixed for each method. The radiopharmaceutical stability was also evaluated. The results showed that ^99mTc‐ENS was a white suspension with a pH between 4.0 and 6.0. The limit for radiochemical impurities in Whatman‐1 paper/acetone was fixed at lower than 2% and the established limit for the organic aliquot in cyclohexane extraction was greater than 2%. In the biodistribution studies, the limits for activity concentration were fixed at greater than 90% for lungs, less than 9% for the gastrointestinal system and less than 1% for the sum of the other organs studied. After a storage time of 6 h at room temperature or in a refrigerator, ^99mTc‐ENS physical properties and pH, radiochemical and biodistribution results were within the established values. In conclusion, the quality control methods for ^99mTc‐ENS are tests on physical properties and pH, radiochemical purity by Whatman‐1 paper/acetone chromatography and cyclohexane extraction and biodistribution studies in rats. The stability of this radiopharmaceutical is at least 6 h at room temperature. Copyright © 2003 John Wiley & Sons, Ltd.     

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.     

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.