Synthesis and preclinical evaluation of 11C-labeled 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine radioligands for RIPK1 positron emission tomography imaging.

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic strategy for various neurodegenerative disorders. The development of a positron emission tomography (PET) probe for brain RIPK1 imaging could offer a valuable tool to assess therapeutic effectiveness and uncover the neuropathology associated with RIPK1. In this study, we present the development and characterization of two new PET radioligands, [11C]PB218 and [11C]PB220, which have the potential to facilitate brain RIPK1 imaging. [11C]PB218 and [11C]PB220 were successfully synthesized with a high radiochemical yield (34 % - 42 %) and molar activity (293 - 314 GBq/µmol). PET imaging characterization of two radioligands was conducted in rodents, demonstrating that both newly developed tracers have good brain penetration (maximum SUV = 0.9 - 1.0) and appropriate brain clearance kinetic profiles. Notably, [11C]PB218 has a more favorable binding specificity than [11C]PB220. A PET/MR study of [11C]PB218 in a non-human primate exhibited good brain penetration, desirable kinetic properties, and a safe profile, thus supporting the translational applicability of our new probe. These investigations enable further translational exploration of [11C]PB218 for drug discovery and PET probe development targeting RIPK1.

Arginine-Selective Bioconjugation Reagent for Effective 18F-labeling of Native Proteins.

Protein-based 18F-PET tracers offer new possibilities in early disease detection and personalized medicine. Their development relies heavily on the availability and effectiveness of 18F-prosthetic groups. We prepared and evaluated a novel arginine-selective prosthetic group, 4-[18F]fluorophenylglyoxal ([18F]FPG). [18F]FPG was radiosynthesized by a one-pot, two-step procedure with a non-decay-corrected (n.d.c.) isolated radiochemical yield (RCY) of 41 ± 8% (n = 10). [18F]FPG constitutes a generic tool for 18F-labeling of various proteins, including human serum albumin (HSA), ubiquitin, interleukin-2, and interleukin-4 in ∼30-60% n.d.c. isolated RCYs. [18F]FPG conjugation with arginine residues is highly selective, even in the presence of a large excess of lysine, cysteine, and histidine. [18F]FPG protein conjugates are able to preserve the binding affinity of the native proteins while also demonstrating excellent in vivo stability. The [18F]FPG-HSA conjugate has prolonged blood retention, which can be applied as a potential blood pool PET imaging agent. Thus, [18F]FPG is an arginine-selective bioconjugation reagent that can be effectively used for the development of 18F-labeled protein radiopharmaceuticals.

Automated radiosynthesis of mGluR5 PET tracer [18F]FPEB from aryl-chloro precursor and validation for clinical application.

The radioligand [18F]FPEB, used for PET imaging of the brain's metabotropic glutamate receptor subtype 5 (mGluR5), undergoes a thorough validation process to ensure its safety, efficacy, and quality for clinical use. The process starts by optimizing the synthesis of [18F]FPEB to achieve high radiochemical yield and purity. This study focuses on optimizing the radiolabeling process using an aryl-chloro precursor and validating the GMP production for clinical applications. Fully automated radiolabeling was achieved via one-step nucleophilic substitution reaction. [18F]FPEB was produced and isolated in high radioactivity and radiochemical purity. Throughout the validation process, thorough quality control measures are implemented. Radiopharmaceutical batch release criteria are established, including testing for physical appearance, filter integrity, pH, radiochemical purity, molar activity, radiochemical identity, chemical impurity, structural identity, stability, residual solvent, sterility, and endotoxin levels. In conclusion, the validation of [18F]FPEB involved a comprehensive process of synthesis optimization, quality control, which ensure the safety, efficacy, and quality of [18F]FPEB, enabling its reliable use in clinical PET. Here, we successfully radiolabeled and validated [18F]FPEB using aryl-chloro precursor according to GMP production for clinical application.

Radiochemistry and In Vivo Imaging of [45Ti]Ti-THP-PSMA.

Titanium-45 (45Ti) is a radionuclide with excellent physical characteristics for use in positron emission tomography (PET) imaging, including a moderate half-life (3.08 h), decay by positron emission (85%), and a low mean positron energy of 0.439 MeV. However, challenges associated with titanium chemistry have led to the underdevelopment of this radionuclide for incorporation into radiopharmaceuticals. Expanding on our recent studies, which showed promising results for the complexation of 45Ti with the tris hydroxypyridinone (THPMe) chelator, the current work aimed to optimize the chemistry and imaging attributes of [45Ti]Ti-THP-PSMA as a new PET radiopharmaceutical. Methods. Radiolabeling of THP-PSMA was optimized with [45Ti]Ti-citrate at varying pHs and masses of the precursor. The stability of the radiolabeled complex was assessed in mouse serum for up to 6 h. The affinity of [45Ti]Ti-THP-PSMA for prostate-specific membrane antigen (PSMA) was assessed using LNCaP (PSMA +) and PC3 (PSMA -) cell lines. In vivo imaging and biodistribution analysis were performed in tumor-bearing xenograft mouse models to confirm the specificity of the tumor uptake. Results. > 95% of radiolabeling was achieved with a high specific activity of 5.6 MBq/nmol under mild conditions. In vitro cell binding studies showed significant binding of the radiolabeled complex with the PSMA-expressing LNCaP cell line (11.9 ± 1.5%/mg protein-bound activity) compared to that with the nonexpressing PC3 cells (1.9 ± 0.4%/mg protein-bound activity). In vivo imaging and biodistribution studies confirmed specific uptake in LNCaP tumors (1.6 ± 0.27% ID/g) compared to that in PC3 tumors (0.39 ± 0.2% ID/g). Conclusion. This study showed a simple one-step radiolabeling method for 45Ti with THP-PSMA under mild conditions (pH 8 and 37 °C). In vitro cell studies showed promise, but in vivo tumor xenograft studies indicated low tumor uptake. Overall, this study shows the need for more chelators for 45Ti for the development of a PET radiopharmaceutical for cancer imaging.

Scalable droplet-based radiosynthesis of [18F]fluorobenzyltriphenylphosphonium cation ([18F]FBnTP) via a "numbering up" approach.

The [18F]fluorobenzyltriphenylphosphonium cation ([18F]FBnTP) has emerged as a highly promising positron emission tomography (PET) tracer for myocardial perfusion imaging (MPI) due to its uniform distribution in the myocardium and favorable organ biodistribution demonstrated in preclinical studies. However, a complex and low-efficiency radiosynthesis procedure has significantly hindered its broader preclinical and clinical explorations. Recently, Zhang et al. developed a pinacolyl arylboronate precursor, enabling a one-step synthesis process that greatly streamlines the production of [18F]FBnTP. Building upon this progress, our group successfully adapted the approach to a microdroplet reaction format and demonstrated improved radiosynthesis performance in a preliminary optimization study. However, scaling up to clinical dose amounts was not explored. In this work, we demonstrate that scale-up can be performed in a straightforward manner using a "numbering up" strategy (i.e. performing multiple droplet reactions in parallel and pooling the crude products). The resulting radiochemical yield after purification and formulation was high, up to 66 ± 1% (n = 4) for a set of experiments involving pooling of 4 droplet reactions, accompanied by excellent radiochemical purity (>99%) and molar activity (339-710 GBq µmol-1). Notably, we efficiently achieved sufficient activity yield (0.76-1.84 GBq) for multiple clinical doses from 1.6 to 3.7 GBq of [18F]fluoride in just 37-47 min.

Light-Driven Radiochemistry with Fluorine-18, Carbon-11 and Zirconium-89.

This review discusses recent advances in light-driven radiochemistry for three key isotopes: fluorine-18, carbon-11, and zirconium-89, and their applications in positron emission tomography (PET). In the case of fluorine-18, the predominant approach involves the use of cyclotron-produced [18F]fluoride or reagents derived thereof. Light serves to activate either the substrate or the fluorine-18 labeled reagent. Advancements in carbon-11 photo-mediated radiochemistry have been leveraged for the radiolabeling of small molecules, achieving various transformations, including 11C-methylation, 11C-carboxylation, 11C-carbonylation, and 11C-cyanation. Contrastingly, zirconium-89 photo-mediated radiochemistry differs from fluorine-18 and carbon-11 approaches. In these cases, light facilitates a postlabeling click reaction, which has proven valuable for the labeling of large biomolecules such as monoclonal antibodies (mAbs). New technological developments, such as the incorporation of photoreactors in commercial radiosynthesizers, illustrate the commitment the field is making in embracing photochemistry. Taken together, these advances in photo-mediated radiochemistry enable radiochemists to apply new retrosynthetic strategies in accessing novel PET radiotracers.

Fully automated dual-run manufacturing of [11C]PIB on FASTlab.

This report describes an updated, fully automated method for the production of [11C]PIB on a cassette-based automated synthesis module. The method allows for two separate productions of [11C]PIB, both of which meet all specification for use in clinical studies. The GE FASTlab developer system was used to create the cassette design as well as the controlling tracer package. The method takes 16 min from the delivery of [11C]MeOTf to the FASTlab, or 35 min from the End of Bombardment; and reliably produces 3547 ± 586 MBq of [11C]PIB in high radiochemical purity (> 98 %). This methodology increases the production capacity of radiopharmaceutical facilities for [11C]PIB, and can easily produce 4 batches in a single day with limited infrastructure footprint.

Automated radiosynthesis of [18 F]CETO, a PET radiotracer for imaging adrenal glands, on Synthra RNplus.

Primary aldosteronism (PA) is the leading secondary cause of hypertension. Determining whether one (unilateral) or both (bilateral) adrenal glands are the source of PA in a patient remains challenging, and yet it is a critical step in the decision whether to recommend potentially curative surgery (adrenalectomy) or lifelong medical therapy (typically requiring multiple drugs). Recently, we have developed a fluorine-18 radiopharmaceutical [18 F]CETO to permit greater access to PA molecular imaging. Herein, we report an automated synthesis of this radiotracer. To manufacture the radiopharmaceutical routinely for clinical PET studies, we implemented an automated radiosynthesis method on a Synthra RNplus© synthesiser for which Cl-tosyletomidate was used as the precursor for radiolabelling via nucleophilic [18 F]fluorination. [18 F]CETO was produced with 35 ± 1% (n = 7), decay corrected and 25 ± 4% (n = 7) non-decay corrected radiochemical yield with molar activities ranging from 150 to 400 GBq/µmol. The GMP compliant manufacturing process produces a sterile formulated [18 F]CETO injectable solution for human use as demonstrated by the results of quality control. Automation of the radiosynthesis of [18 F]CETO should facilitate uptake by other adrenal centres and increase access to molecular imaging in PA.

Production, isolation, and shipment of clinically relevant quantities of astatine-211: A simple and efficient approach to increasing supply.

The alpha emitter astatine-211 (211At) is a promising candidate for cancer treatment based on Targeted Alpha (α) Therapy (TAT). A small number of facilities, distributed across the United States, are capable of accelerating α-particle beams to produce 211At. However, challenges remain regarding strategic methods for shipping 211At in a form adaptable to advanced radiochemistry reactions and other uses of the radioisotope. PURPOSE: Our method allows shipment of 211At in various quantities in a form convenient for further radiochemistry. PROCEDURES: For this study, a 3-octanone impregnated Amberchrom CG300M resin bed in a column cartridge was used to separate 211At from the bismuth matrix on site at the production accelerator (Texas A&M) in preparation for shipping. Aliquots of 6 M HNO3 containing up to ≈2.22 GBq of 211At from the dissolved target were successfully loaded and retained on columns. Exempt packages (<370 MBq) were shipped to a destination radiochemistry facility, University of Texas MD Anderson Cancer Center, in the form of a convenient air-dried column. Type A packages have been shipped overnight to University of Alabama at Birmingham. MAIN FINDINGS: Air-dried column hold times of various lengths did not inhibit simple and efficient recovery of 211At. Solution eluted from the column was sufficiently high in specific activity to successfully radiolabel a model compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1), with 211At. The method to prepare and ship 211At described in this manuscript has also been used to ship larger quantities of 211At a greater distance to University of Alabama at Birmingham. PRINCIPAL CONCLUSIONS: The successful proof of this method paves the way for the distribution of 211At from Texas A&M University to research institutions and clinical oncology centers in Texas and elsewhere. Use of this simple method at other facilities has the potential increase the overall availability of 211At for preclinical and clinical studies.

Click Chemistry and Radiochemistry: An Update.

The term "click chemistry" describes a class of organic transformations that were developed to make chemical synthesis simpler and easier, in essence allowing chemists to combine molecular subunits as if they were puzzle pieces. Over the last 25 years, the click chemistry toolbox has swelled from the canonical copper-catalyzed azide-alkyne cycloaddition to encompass an array of ligations, including bioorthogonal variants, such as the strain-promoted azide-alkyne cycloaddition and the inverse electron-demand Diels-Alder reaction. Without question, the rise of click chemistry has impacted all areas of chemical and biological science. Yet the unique traits of radiopharmaceutical chemistry have made it particularly fertile ground for this technology. In this update, we seek to provide a comprehensive guide to recent developments at the intersection of click chemistry and radiopharmaceutical chemistry and to illuminate several exciting trends in the field, including the use of emergent click transformations in radiosynthesis, the clinical translation of novel probes synthesized using click chemistry, and the advent of click-based in vivo pretargeting.

One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development.

We report the first one-pot formal alkene carboradiofluorination reaction employing easily accessible alkenes as both prosthetic group precursors and coupling partners. The methodology features rapid sequential Markovnikov-selective iodofluorination and photoinduced Pd(0/I/II)-catalyzed alkyl Heck reaction as a mild and robust fluorine-18 (18F) radiochemical approach for positron emission tomography (PET) imaging probe development. A new class of prosthetic groups for PET imaging probe synthesis was isolated as iodofluorinated intermediates in moderate to excellent yields. The one-pot formal alkenylfluorination reaction was carried out to produce over 30 analogues of a wide range of bioactive molecules. Further application of the Pd(0/I/II) manifold in PET probe development was illustrated by the direct carbo(radio)fluorination of electron-rich alkenes. The methods were successfully translated to radiolabel a broad scope of medicinally relevant small molecules in generally good radiochemical conversion. The protocol was further optimized to accommodate no-carrier-added conditions with similar efficiency for future (pre)clinical translation. Moreover, the radiosynthesis of prosthetic groups was automated in a radiochemistry module to facilitate its practical use in multistep radiochemical reactions.

MRI magnitude signal-based proton beam visualisation in water phantoms reflects composite effects of beam-induced buoyant convection and radiation chemistry.

Objective. Local magnetic resonance (MR) signal loss was previously observed during proton beam irradiation of free-floating water phantoms at ambient temperature using a research prototype in-beam magnetic resonance imaging (MRI) scanner. The emergence of this MR signal loss was hypothesised to be dependent on beam-induced convection. The aim of this study was therefore to unravel whether physical conditions allowing the development of convection must prevail for the beam-induced MRI signatures to emerge.Approach. The convection dependence of MRI magnitude signal-based proton beam visualisation was investigated in combined irradiation and imaging experiments using a gradient echo (GE)-based time-of-flight (ToF) angiography pulse sequence, which was first tested for its suitability for proton beam visualisation in free-floating water phantoms at ambient temperature. Subsequently, buoyant convection was selectively suppressed in water phantoms using either mechanical barriers or temperature control of water expansivity. The underlying contrast mechanism was further assessed using sagittal imaging and variation of T1 relaxation time-weighting.Main results. In the absence of convection-driven water flow, weak beam-induced MR signal changes occurred, whereas strong changes did occur when convection was not mechanically or thermally inhibited. Moreover, the degree of signal loss was found to change with the variation of T1-weighting. Consequently, beam-induced MR signal loss in free-floating water phantoms at ambient temperature does not exclusively originate from buoyant convection, but is caused by local composite effects of beam-induced motion and radiation chemistry resulting in a local change in the water T1 relaxation time.Significance. The identification of ToF angiography sequence-based proton beam visualisation in water phantoms to result from composite effects of beam-induced motion and radiation chemistry represents the starting point for the future elucidation of the currently unexplained motion-based MRI contrast mechanism and the identification of the proton beam-induced material change causing T1 relaxation time lengthening.

Molecular Imaging, Radiochemistry, and Environmental Pollutants.

The worldwide proliferation of persistent environmental pollutants is accelerating at an alarming rate. Not surprisingly, many of these pollutants pose a risk to human health. In this review, we examine recent literature in which molecular imaging and radiochemistry have been harnessed to study environmental pollutants. Specifically, these techniques offer unique ways to interrogate the pharmacokinetic profiles and bioaccumulation patterns of pollutants at environmentally relevant concentrations, thereby helping to determine their potential health risks.

Alpha-induced production and robust radiochemical separation of 43Sc as an emerging radiometal for formulation of PET radiopharmaceuticals.

Scandium-43 is an emerging PET radiometal that was produced by α-particle bombardment on natural CaCO3 target via natCa (α,p) 43Sc and natCa (α,n) 43Ti→43Sc reactions using K-130 cyclotron at VECC. A robust radiochemical procedure based on selective precipitation of 43Sc as Sc(OH)3 was developed for separation of the radioisotope from the irradiated target. The overall yield of the separation process was >85% and it was obtained in a form suitable for preparation of target specific radiopharmaceuticals for PET imaging of cancer.

Radiochemistry for positron emission tomography.

Positron emission tomography (PET) constitutes a functional imaging technique that is harnessed to probe biological processes in vivo. PET imaging has been used to diagnose and monitor the progression of diseases, as well as to facilitate drug development efforts at both preclinical and clinical stages. The wide applications and rapid development of PET have ultimately led to an increasing demand for new methods in radiochemistry, with the aim to expand the scope of synthons amenable for radiolabeling. In this work, we provide an overview of commonly used chemical transformations for the syntheses of PET tracers in all aspects of radiochemistry, thereby highlighting recent breakthrough discoveries and contemporary challenges in the field. We discuss the use of biologicals for PET imaging and highlight general examples of successful probe discoveries for molecular imaging with PET - with a particular focus on translational and scalable radiochemistry concepts that have been entered to clinical use.

Production and radiochemistry of antimony-120m: Efforts toward Auger electron therapy with 119Sb.

Targeted Meitner-Auger Therapy (TMAT) has potential for personalized treatment thanks to its subcellular dosimetric selectivity, which is distinct from the dosimetry of ß- and α particle emission based Targeted Radionuclide Therapy (TRT). To date, most clinical and preclinical TMAT studies have used commercially available radionuclides. These studies showed promising results despite using radionuclides with theoretically suboptimal photon to electron ratios, decay kinetics, and electron emission spectra. Studies using radionuclides whose decay characteristics are considered more optimal are therefore important for evaluation of the full potential of Meitner-Auger therapy; 119Sb is among the best such candidates. In the present work, we develop radiochemical purification of 120Sb from irradiated natural tin targets for TMAT studies with 119Sb.

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations.

G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3's high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3's high specificity.

Cyclotron production of 103Pd using a liquid target.

INTRODUCTION: In this work, we present the first feasibility study on the production of the medically important radionuclide 103Pd via the 103Rh(p,n)103Pd reaction by cyclotron irradiation of a liquid target. Using a liquid target removes the time consuming and complex dissolution process of rhodium post-irradiation due to its chemically inactive nature and thereby will improve the accessibility of this radioisotope. METHODS: Liquid targets made from Rh(NO3)3·×H2O salt dissolved in de-ionized water were irradiated using a 12 MeV beam at the TR13 cyclotron at TRIUMF, Vancouver. RESULTS: A maximum EOB activity of 1.03 ± 0.05 MBq was achieved with the tested conditions, sufficient for basic radiochemistry studies. An effective separation method using anion exchange chromatography is reported using 1 M HNO3 as an eluent for rhodium (90.1 ± 2.1 % recovery) and a 1:1 mixture of 0.5 M NH3 + NH4Cl palladium eluent (103.8 ± 2.3 % recovery). The solution showed good in-target pressure stability. However, the production efficiency decreased significantly with higher solution concentrations and irradiation lengths which puts into question the scaling potential of this method. CONCLUSION: This proof-of-concept study has demonstrated the potential for using liquid targets as complementary production method of 103Pd for research purposes. The liquid target route faces several scaling challenges but can nonetheless improve the availability of 103Pd and consequently aid in widening its utility for radiopharmaceuticals.

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies.

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (11C; t½ = 20.4 min) offers other advantages for imaging including multiple PET scans in the same subject on the same day, its use is limited to facilities that have an on-site cyclotron, and the radiochemical transformations are consequently more restrictive. Many researchers have embraced this challenge by discovering novel carbon-11 radiolabelling methodologies to broaden the synthetic versatility of this radionuclide. This review presents new carbon-11 building blocks and radiochemical transformations as well as PET tracers that have advanced to first-in-human studies over the past five years.

High-yield cyclotron production of 203Pb using a sealed 205Tl solid target.

INTRODUCTION: 203Pb (t1/2 = 51.9 h, 279 keV (81 %)) is a diagnostic SPECT imaging radionuclide ideally suited for theranostic applications in combination with 212Pb for targeted alpha particle therapy. Our objectives were to develop a high-yield solid target 203Pb cyclotron production route using isotopically enriched 205Tl target material and the 205Tl(p,3n)203Pb reaction as an alternative to lower energy production via the 203Tl(p,n)203Pb reaction. METHODS: 250 mg 205Tl metal (99.9 % isotopic enrichment) was pressed using a hardened stainless steel die. Aluminum target discs were machined with a central depression and annulus groove. The flattened 205Tl pellet was placed into the central depression of the Al disc and a circle of indium wire was laid in the machined annulus surrounding the pellet. An aluminum foil cover was then pressed onto the target disc to create an airtight bond. Targets were irradiated at 23.3 MeV for up to 516 min on a TR-24 cyclotron at currents up to 60 µA to produce 203Pb via the 205Tl(p,3n)203Pb nuclear reaction. Following a cool-down period of >12 h, the target was removed and 205Tl dissolved in 4 M HNO3. A NEPTIS Mosaic-LC synthesis unit performed automated separation using Eichrom Pb resin, and 203Pb was eluted using 8 M HCl or 1 M NH4OAc. 205Tl was diverted to a vial for recovery in an electrolytic cell. 203Pb product radionuclidic purity was assessed by HPGe gamma spectroscopy, while elemental purity was assessed by ICP-OES. Radiolabeling and stability studies were performed with PSC, TCMC, and DOTA chelators, and 203Pb incorporation was verified by radio-TLC analysis. RESULTS: Cyclotron irradiations performed at 60 µA proton beam current and 23.3 MeV (205Tl incident energy) had a 203Pb saturated yield of 4658 ± 62 MBq/µA (n = 3). Automated NEPTIS separation took <4 h from the start of target dissolution to product elution, yielding >85 % decay-corrected [203Pb]PbCl2 with a radionuclidic purity of >99.9 %. Purified [203Pb]PbCl2 yields of up to 12 GBq 203Pb were attained (15.8 GBq at EOB). The [203Pb]PbCl2 and [203Pb]Pb(OAc)2 products contained no detectable radionuclidic impurities besides 201Pb (<0.1 %), and <0.4 ppm stable Pb. 205Tl metal was recovered with a 92 % batch yield. Aliquots of 100 µL [203Pb]Pb(OAc)2 were used for radiolabeling PSC-Bn-NCS, TCMC-NCS, and DOTA-NCS chelators at pH 4.5 and 22 °C for 30 min, with maximum respective molar activities of 461 ± 30 GBq/µmol, 195 ± 37 GBq/µmol, and 83 ± 12 GBq/µmol. PSC, TCMC, and DOTA chelators exhibited >99.9 % incorporation after a 120-hour incubation in human serum at 37 °C. CONCLUSIONS: Nuclear medicine centers with access to higher energy cyclotrons can produce large 203Pb activities sufficient for clinical applications, with a convenient separation technique producing highly pure [203Pb]PbCl2 or [203Pb]Pb(OAc)2 for direct radiolabeling. This represents an attractive route to produce 203Pb for diagnostic SPECT imaging alongside 212Pb targeted alpha particle therapy. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our high-yield 203Pb production technique significantly enhances 203Pb production capabilities to meet the growing preclinical and clinical demand for 203Pb radiopharmaceuticals alongside 212Pb target alpha particle therapy.