ABSTRACT
Three isotopes of scandiumâ43Sc, 44Sc, and 47Scâhave attracted increasing attention as potential candidates for use in imaging and therapy, respectively, as well as for possible theranostic use as an elementally matched pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO), an effective chelator for hard cations, as a potential ligand for use in radioscandium constructs with simple radiolabeling under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully characterized, both experimentally and theoretically. [47Sc]Sc-HOPO exhibited good stability in chemical and biological challenges over 7 days. In healthy mice, [43,47Sc]Sc-HOPO cleared the body rapidly with no signs of demetalation. HOPO is a strong candidate for use in radioscandium-based radiopharmaceuticals.
Subject(s)
Pyridones , Radiopharmaceuticals , Animals , Mice , Radiopharmaceuticals/chemistry , Pyridones/chemistry , Chelating Agents/chemistry , Positron-Emission Tomography/methods , LigandsABSTRACT
The continual development of radiopharmaceutical agents for the field of nuclear medicine is integral to promoting the necessity of personalized medicine. One way to greatly expand the selection of radiopharmaceuticals available is to broaden the range of radionuclides employed in such agents. Widening the scope of development to include radiometals with their variety of physical decay characteristics and chemical properties opens up a myriad of possibilities for new actively targeted molecules and bioconjugates. This is especially true to further advance the imaging and treatment of disease in the brain. Over the past few decades, imaging of disease in the brain has heavily relied on agents which exploit metabolic uptake. However, through utilizing the broad range of physical characteristics that radiometals offer, the ability to target other processes has become more available. The varied chemistries of radiometals also allows for them to incorporated into specifically designed diverse constructs. A major limitation to efficient treatment of disease in the brain is the ability for relevant agents to penetrate the blood-brain barrier. Thus, along with efficient disease targeting, there must be intentional thought put into overcoming this challenge. Here, we review the current field of radiometal-based agents aimed at either imaging or therapy of brain disease that have been evaluated through at least in vivo studies.
Subject(s)
Brain Diseases/diagnosis , Brain Diseases/radiotherapy , Metals/metabolism , Radiopharmaceuticals/metabolism , Brain Diseases/metabolism , Chelating Agents/chemistry , HumansABSTRACT
Positron-emitting 72As is the PET imaging counterpart for beta-emitting 77As. Its parent, no carrier added (n.c.a.) 72Se, was produced for a 72Se/72As generator by irradiating an enriched 7°Ge metal-graphite target via the 70Ge(α, 2â¯n)72Se reaction. Target dissolution used a fast, environmentally friendly method with 93% radioactivity recovery. Chromatographic parameters of the 72Se/72As generator were evaluated, the eluted n.c.a. 72As was characterized with a phantom imaging study, and the previously reported trithiol and aryl-dithiol ligand systems were radiolabeled with the separated n.c.a. 72As in high yield.
Subject(s)
Arsenic/isolation & purification , Radioisotopes/isolation & purification , Radionuclide Generators , Radiopharmaceuticals/isolation & purification , Selenium Radioisotopes/isolation & purification , Germanium/chemistry , Germanium/isolation & purification , Germanium/radiation effects , Humans , Isotopes/chemistry , Isotopes/isolation & purification , Isotopes/radiation effects , Phantoms, Imaging , Positron-Emission Tomography , Radioligand Assay , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistryABSTRACT
INTRODUCTION: Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49â¯MeV ß+, 26â¯h; 77As: 0.683â¯MeV ß-, 38.8â¯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 48â¯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.
Subject(s)
Arsenic/chemistry , Positron-Emission Tomography/methods , Radioisotopes/chemistry , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/therapeutic use , Animals , Bombesin/chemistry , Drug Stability , Isotope Labeling , Male , Mice , Models, Molecular , Molecular Conformation , Radiochemistry , Sulfhydryl Compounds/pharmacokinetics , Tissue DistributionABSTRACT
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.
Subject(s)
Arsenicals/chemistry , Radiopharmaceuticals/chemistry , Arsenicals/chemical synthesis , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Molecular Structure , Radiopharmaceuticals/chemical synthesis , Spectrometry, Mass, Electrospray Ionization , Toluene/analogs & derivatives , Toluene/chemistryABSTRACT
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].
