203/212Pb Theranostic Radiopharmaceuticals for Image-guided Radionuclide Therapy for Cancer.

Receptor-targeted image-guided Radionuclide Therapy (TRT) is increasingly recognized as a promising approach to cancer treatment. In particular, the potential for clinical translation of receptor-targeted alpha-particle therapy is receiving considerable attention as an approach that can improve outcomes for cancer patients. Higher Linear-energy Transfer (LET) of alpha-particles (compared to beta particles) for this purpose results in an increased incidence of double-strand DNA breaks and improved-localized cancer-cell damage. Recent clinical studies provide compelling evidence that alpha-TRT has the potential to deliver a significantly more potent anti-cancer effect compared with beta-TRT. Generator-produced 212Pb (which decays to alpha emitters 212Bi and 212Po) is a particularly promising radionuclide for receptor-targeted alpha-particle therapy. A second attractive feature that distinguishes 212Pb alpha-TRT from other available radionuclides is the possibility to employ elementallymatched isotope 203Pb as an imaging surrogate in place of the therapeutic radionuclide. As direct non-invasive measurement of alpha-particle emissions cannot be conducted using current medical scanner technology, the imaging surrogate allows for a pharmacologically-inactive determination of the pharmacokinetics and biodistribution of TRT candidate ligands in advance of treatment. Thus, elementally-matched 203Pb labeled radiopharmaceuticals can be used to identify patients who may benefit from 212Pb alpha-TRT and apply appropriate dosimetry and treatment planning in advance of the therapy. In this review, we provide a brief history on the use of these isotopes for cancer therapy; describe the decay and chemical characteristics of 203/212Pb for their use in cancer theranostics and methodologies applied for production and purification of these isotopes for radiopharmaceutical production. In addition, a medical physics and dosimetry perspective is provided that highlights the potential of 212Pb for alpha-TRT and the expected safety for 203Pb surrogate imaging. Recent and current preclinical and clinical studies are presented. The sum of the findings herein and observations presented provide evidence that the 203Pb/212Pb theranostic pair has a promising future for use in radiopharmaceutical theranostic therapies for cancer.

A trithiol bifunctional chelate for 72,77As: A matched pair theranostic complex with high in vivo stability.

INTRODUCTION: Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV ß+, 26 h; 77As: 0.683 MeV ß-, 38.8 h) to form potential theranostic radiopharmaceuticals for PET imaging and therapy. To investigate the in vivo stability of trithiol chelates complexed with no carrier added (nca) radioarsenic, a bifunctional trithiol chelate was developed, and conjugated to bombesin(7-14)NH2 as a model peptide. METHODS: A trithiol-BBN(7-14)NH2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol-BBN(7-14)NH2 conjugate was radiolabeled with 77As, its in vitro stability assessed, and biodistribution studies were performed in CF-1 normal mice of free [77As]arsenate and 77As-trithiol- BBN(7-14)NH2. RESULTS: The trithiol-BBN(7-14)NH2 conjugate, its precursors and its As-trithiol-BBN(7-14)NH2 complex were fully characterized. Radiolabeling studies with nca 77As resulted in over 90% radiochemical yield of 77As-trithiol-BBN, which was stable for over 48 h. Biodistribution studies were performed with both free [77As]arsenate and Sep-Pak® purified 77As-trithiol-BBN(7-14)NH2. Compared to the fast renal clearance of free [77As]arsenate, 77As-trithiol-BBN(7-14)NH2 demonstrated increased retention with clearance mainly through the hepatobiliary system, consistent with the lipophilicity of the 77As-trithiol-BBN(714)NH2 complex. CONCLUSION: The combined in vitro stability of 77As-trithiol-BBN(7-14)NH2 and the biodistribution results demonstrate its high in vivo stability, making the trithiol a promising platform for developing radioarsenic-based theranostic radiopharmaceuticals.

Dithiol Aryl Arsenic Compounds as Potential Diagnostic and Therapeutic Radiopharmaceuticals.

Arsenic-72 ((72)As) and (77)As have nuclear properties useful for positron emission tomography (PET) and radiotherapy, respectively. The thiophilic nature of arsenic led to the evaluation of dithioarylarsines for potential use in radiopharmaceuticals. Several dithioarylarsines were synthesized from their arylarsonic acids and dithiols and were fully characterized by NMR, ESI-MS, and X-ray crystallography. This chemistry was translated to the no-carrier-added (nca) (77)As level. Because arsenic was available at the nca nanomolar level only as [(77)As]arsenate, this required addition of an aryl group directly to the As to form the [(77)As]arylarsonic acid. The [(77)As]arsenate was reduced from (77)As (V) to (77)As (III), and a modified Bart reaction was used to incorporate the aryl ring onto the (77)As, which was followed by dithiol addition. Various modifications and optimizations resulted in 95% radiochemical yield of nca [(77)As]p-ethoxyphenyl-1,2-ethanedithiolatoarsine.

Trithiols and their arsenic compounds for potential use in diagnostic and therapeutic radiopharmaceuticals.

INTRODUCTION: Arsenic-72 ((72)As; 2.49MeV ß(+), 26h) and (77)As (0.683MeV ß(-), 38.8h) have nuclear properties useful for positron emission tomography (PET) and radiotherapy applications, respectively. Their half-lives are sufficiently long for targeting tumors with antibodies, as well as peptides. Potential radiopharmaceuticals based on radioarsenic require development of suitable bifunctional chelates for stable conjugation of arsenic to vectors under in vivo conditions at high dilution. METHODS: The thiophilic nature of arsenic led to the synthesis and characterization of a simple trithiol ligand and its arsenic complex, and radiolabeling studies at the no carrier added (NCA) (77)As level. RESULTS: (1)H- and (13)C-NMR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), and single crystal X-ray diffraction were used to characterize the trithiol ligand and its arsenic(III) complex. Radiotracer studies with no carrier added (NCA) (77)As resulted in high radiolabeling yields (>96%) with high in vitro stability. CONCLUSIONS: The high yield and stability of a single NCA (77)As trithiol complex indicates that this framework is suitable for developing matched pair agents for non-invasive in vivo PET imaging and radiotherapy of tumors with (72,77)As. This is the first reported chelate developed for NCA radioarsenic and studies are underway for developing a trithiol bifunctional chelate conjugated to a targeting vector, such as a peptide or monoclonal antibody.

Chromatographic separation of germanium and arsenic for the production of high purity (77)As.

A simple column chromatographic method was developed to isolate (77)As (94±6% (EtOH/HCl); 74±11 (MeOH)) from germanium for potential use in radioimmunotherapy. The separation of arsenic from germanium was based on their relative affinities for different chromatographic materials in aqueous and organic environments. Using an organic or mixed mobile phase, germanium was selectively retained on a silica gel column as germanate, while arsenic was eluted from the column as arsenate. Subsequently, enriched (76)Ge (98±2) was recovered for reuse by elution with aqueous solution (neutral to basic). Greater than 98% radiolabeling yield of a (77)As-trithiol was observed from methanol separated [(77)As]arsenate [17].

Chromatographic separation of selenium and arsenic: A potential (72)Se/(72)As generator.

An anion exchange method was developed to separate selenium and arsenic for potential utility in a (72)Se/(72)As generator. The separation of the daughter (72)As from the (72)Se parent is based on the relative acid-base behavior of the two oxo-anions in their highest oxidation states. At pH 1.5, selenate is retained on strongly basic anion exchange resin as HSeO4(-) and SeO4(2-), while neutral arsenic acid, H3AsO4, is eluted.