Dosimetric implications of the potential radionuclidic impurities in 153Sm-DOTMP.

Thehuman internal dosimetry of the radionuclidic impurities of samarium-153 in a new bone-seeking radiopharmaceutical, 153Sm-1,4,7,10tetraazacyclododecanetetramethylenephosponic acid (153Sm-DOTMP), has been estimated from preclinical data. The effective dose from the impurities in lower-specific-activity 153Sm is less than 17% of the effective dose from pure Sm-153. It has a background-equivalent radiation time for a dosage of 37 MBq/kg of less than one-half year.

Recovery, recycling and re-irradiation of enriched 104Ru metal targets for cost effective production of 105Rh.

Rhodium-105 (0.567 MeV ß-, 319 keV γ, 35.4 h half-life) was produced by neutron irradiation of enriched 104Ru (>99%) over multiple decades. A method is reported to recover the previously irradiated 104Ru (trapped in HCl as RuO42-) as the metal. The 104Ru was recovered in >93% yield and >98% enrichment. Neutron re-irradiation of the recycled 104Ru produced 105Rh, which was successfully radiolabeled with tetrathioethers in high yield. This recovery and recycling method for enriched 104Ru makes 105Rh production and utilization economical.

Evaluation of 72Se/72As generator and production of 72Se for supplying 72As as a potential PET imaging radionuclide.

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, 2 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.

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.

Chemistry and radiochemistry of As, Re and Rh isotopes relevant to radiopharmaceutical applications: high specific activity radionuclides for imaging and treatment.

The chemistry and radiochemistry of high specific activity radioisotopes of arsenic, rhenium and rhodium are reviewed with emphasis on University of Missouri activities over the past several decades, and includes recent results. The nuclear facilities at the University of Missouri (10 MW research reactor and 16.5 MeV GE PETtrace cyclotron) allow research and development into novel theranostic radionuclides. The production, separation, enriched target recovery, radiochemistry, and chelation chemistry of 72,77As, 186,188Re and 105Rh are discussed.

Bulk production and evaluation of high specific activity 186gRe for cancer therapy using enriched 186WO3 targets in a proton beam.

INTRODUCTION: Rhenium-186g (t1/2 = 3.72 d) is a ß- emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction 185Re(n,γ)186gRe, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched 186W results in a 186gRe product with a higher specific activity, allowing it to be used more broadly for targeted radiotherapy applications. This targets the unmet clinical need for more efficient radiotherapeutics. METHODS: A target consisting of highly enriched, pressed 186WO3 was irradiated with protons at the Los Alamos National Laboratory Isotope Production Facility (LANL-IPF) to evaluate 186gRe product yield and quality. LANL-IPF was operated in a dedicated nominal 40 MeV mode. Alkaline dissolution followed by anion exchange chromatography was used to isolate 186gRe from the target material. Phantom and radiolabeling studies were conducted with the produced 186gRe activity. RESULTS: A 186gRe batch yield of 1.38 ± 0.09 MBq/µAh or 384.9 ± 27.3 MBq/C was obtained after 16.5 h in a 205 µA average/230µA maximum current proton beam. The chemical recovery yield was 93% and radiolabeling was achieved with efficiencies ranging from 60-80%. True specific activity of 186gRe at EOB was determined via ICP-AES and amounted to 0.788 ± 0.089 GBq/µg (0.146 ± 0.017 GBq/nmol), which is approximately seven times higher than the product obtained from neutron capture in a reactor. Phantom studies show similar imaging quality to the gold standard 99mTc. CONCLUSIONS: We report a preliminary study of the large-scale production and novel anion exchange based chemical recovery of high specific activity 186gRe from enriched 186WO3 targets in a high-intensity proton beam with exceptional chemical recovery and radiochemical purity.

Deuteron irradiation of W and WO3 for production of high specific activity (186)Re: Challenges associated with thick target preparation.

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity (186)Re using deuteron irradiation of enriched (186)W via the (186)W(d,2n)(186)Re reaction. Thick W and WO3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO3, or 96.86% enriched (186)W, into Al target supports. Alternatively, thick targets were prepared by pressing (186)W between two layers of graphite powder or by placing pre-sintered (1105°C, 12h) natural abundance WO3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24h post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO3 targets prepared and studied were unacceptable. By contrast, (186)W metal was found to be a viable target material for (186)Re production. Thick targets prepared with powdered (186)W pressed between layers of graphite provided a particularly robust target configuration.

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.

Accelerator-based production of the (99m)Tc-(186)Re diagnostic-therapeutic pair using metal disulfide targets (MoS2, WS2, OsS2).

Novel, natural abundance metal disulfide targets were irradiated for 1h with a 10µA proton beam in a small, medical cyclotron. Osmium disulfide was synthesized by simple distillation and precipitation methods while MoS2 and WS2 were commercially available. The targets dissolved under mild conditions and were analyzed by γ-spectroscopy. Production rates and potential applications are discussed, including target recovery and recycling schemes for OsS2 and WS2.

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.

Comparison of pretargeted and conventional CC49 radioimmunotherapy using 149Pm, 166Ho, and 177Lu.

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.

Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu.

The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas.

Biological comparison of 149Pm-, 166Ho-, and 177Lu-DOTA-biotin pretargeted by CC49 scFv-streptavidin fusion protein in xenograft-bearing nude mice.

The radiolanthanides (149)Pm, (166)Ho, and (177)Lu possess a range of half-lives and alpha(-) beta(-) energies for targeted radiotherapy of cancer. (149)Pm-, (166)Ho-, and (177)Lu-DOTA-biotin were pretargeted to LS174T colorectal tumors in nude mice with CC49 scFvSA antibody-streptavidin fusion protein. Tumor uptakes of (149)Pm (22.9% ID/g), (166)Ho (30.2% ID/g), and (177)Lu (35.4% ID/g) peaked at 1-4 h. Rapid blood disappearance was accompanied by urinary excretion of 59-66% ID within 1 h. Biodistributions of these agents show promise for pretargeted radioimmunotherapy of cancer.

Aminocarboxylate complexes and octreotide complexes with no carrier added 177Lu, 166Ho and 149Pm.

Several aminocarboxylate complexes of the "no carrier added" (NCA) radiolanthanides (149)Pm, (166)Ho and (177)Lu were evaluated using our in vitro hydroxyapatite and serum stability model and in vivo in normal CF-1 mice [10]. The aminocarboxylate chelates evaluated with the NCA radiolanthanides for in vitro stability were EDTA, CDTA, DTPA, MA-DTPA and DOTA. In addition, the NCA radiolanthanide complexes with DTPA-octreotide (DTPA-OCT) were synthesized and evaluated, as a model for a peptide conjugated aminocarboxylate complex. The biodistribution studies of the NCA complexes with DTPA, DOTA and DTPA-OCT showed that the in vitro model correctly predicted the in vivo stability of the radiolanthanide complexes, with Ln-DOTA > Ln-DTPA > Ln-DTPA-OCT.

Chemistry in Environmentally Benign Media. 7.(1) Chelating Hydroxymethyl-Functionalized Bisphosphines as Building Blocks to Water-Soluble and in-Vitro-Stable Gold(I) Complexes. Synthesis, Characterization, and X-ray Crystal Structures of [Au{(HOH(2)C)(2)PC(6)H(4)P(CH(2)OH)(2)}(2)]Cl and [Au(2){(HOH(2)C)(2)PCH(2)CH(2)P(CH(2)OH)(2)}(2)]Cl(2).

The reactions of water-soluble bisphosphines (HOH(2)C)(2)PC(6)H(4)P(CH(2)OH)(2) (1) and (HOH(2)C)(2)PCH(2)CH(2)P(CH(2)OH)(2) (2) with NaAuCl(4), in aqueous media, or AuClPPh(3), in biphasic media (aqueous/organic), produced the water/alcoholic-soluble Au(I) complexes [Au{(HOH(2)C)(2)PC(6)H(4)P(CH(2)OH)(2)}(2)]Cl (3), [Au{(HOH(2)C)(2)PCH(2)CH(2)P(CH(2)OH)(2)}(2)]Cl (4), and [Au(2){(HOH(2)C)(2)PCH(2)CH(2)P(CH(2)OH)(2)}(2)]Cl(2) (5) in near quantitative yields. Stability and cysteine-challenge studies of 3 indicate the kinetic inertness of these new complexes. Complex 5 is luminescent in the solid state at room temperature. When excited at 280 nm in non-degassed water at room temperature, the emission spectrum shows a high-energy band at 310 nm and a low-energy band at 560 nm. The large Stokes shift for the low-energy band implies that the emission is phosphorescence. The X-ray structures of 3 and 5, reported in this paper, confirm the gold(I) structures of this new generation of water-soluble transition metal complexes. All compounds were characterized by (31)P and (1)H NMR spectroscopy and mass spectroscopy. X-ray data for 3: monoclinic, P2(1)/m, a = 9.8715(5) Å, b = 9.9465(5) Å, c = 14.5621(8) Å, beta = 106.5930(10) degrees, Z = 2, R = 0.032 (R(w) = 0.050). X-ray data for 5: monoclinic, C2/c, a = 29.7128(14) Å, b = 16.7062(8) Å, c = 22.3762 (11) Å, beta = 117.6970(10) degrees, Z = 16, R = 0.051 (R(w) = 0.072).