Specific Cytotoxicity of Targeted 177Lu and 212Pb-Based Radiopharmaceuticals.

Two radiopharmaceutical preparations were developed on the basis of artificial targeted polypeptide ZHER2 specific to HER2/neu tumor marker and radionuclides 177Lu (ZHER2-HSA-chelator-177Lu) or 212Pb (ZHER2-HSA-chelator-212Pb). The objective was to evaluate in vitro the cytotoxic activity of the targeted radiopharmaceuticals using two cultured human breast cancer cell lines with different expression of HER2/neu: SK-BR3 (high expression of HER2/neu) and MCF-7 (low expression of HER2/neu). It was shown that the cytotoxic effect of both preparations was significantly higher against the SK-BR-3 cells. The cytotoxicity correlated with the incubation period (it was higher after 72 h than after 24 h) and was significantly more pronounced in comparison with activity of radionuclide salts without a specific ligand. In vivo preclinical study of these pharmaceuticals seems to be very promising in animals with xenografted tumors showing high expression of HER2/neu marker.

Getting a lead on Pb2+-amide chelators for 203/212Pb radiopharmaceuticals.

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [nat/203Pb]Pb2+ ions for potential radiopharmaceutical applications. 1H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The 1H NMR spectrum of [Pb(DTPAm)]2+ revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)]2+ and [Pb(ampam)]2+, both of which showed fewer spectral changes indicative of less static behaviour. The solid-state coordination properties of each complex were also examined from single crystal structures that were studied by X-ray diffraction (XRD). In the solid-state, octadentate DTPAm coordinated Pb2+ to form an eight-coordinate hemidirected complex; octadentate EGTAm coordinated Pb2+ forming a ten-coordinate holodirected complex with a bidentate NO3- ion also coordinated to the metal centre; decadentate ampam completely encapsulated the Pb2+ ion to form a ten-coordinate holodirected complex with a C2 axis of symmetry. Potentiometric titrations were carried out to assess the thermodynamic stability of each metal-ligand complex. The pM values obtained for [Pb(DTPAm)]2+, [Pb(EGTAm)]2+ and [Pb(ampam)]2+ were 9.7, 7.2 and 10.2, respectively. The affinity of each chelator for Pb2+ ions was tested by [203Pb]Pb2+ radiolabeling studies to evaluate their prospects as chelators for [203/212Pb]Pb2+-based radiopharmaceuticals. DTPAm radiolabeled [203Pb]Pb2+ ions achieving molar activities as high as 3.5 MBq µmol-1 within 15 minutes, at 25 °C, whereas EGTAm and ampam produced lower molar activities of 0.25 MBq µmol-1 within 30 minutes, at 37 °C. EGTAm and ampam were therefore deemed unsuitable for [203/212Pb]Pb2+-based radiopharmaceutical applications, while DTPAm warrants further studies.

On the role of 210Bi in the apparent disequilibrium of 210Pb-210Po at sea.

The disequilibrium of the grandparent-daughter pair 210Pb (t1/2=22.3 years)-210Po (t1/2=138 days) has been used to estimate the export fluxes of particulate organic carbon in the ocean using particulate-matter-associated 210Po. 210Po is produced from 210Bi, not from 210Pb. The half-life of 210Bi (t1/2=5.01 days) is sufficiently long compared to the rates of biological particle formation and decomposition or dissolution occurring at sea. The role of 210Bi has not yet been assessed quantitatively in the apparent disequilibrium between 210Pb and 210Po, partly due to the non-existence of 210Bi depth profile measurements at sea up to now. However, greater affinity of 210Bi over 210Po and 210Pb was found recently in coastal waters and phytoplankton 207Bi uptake experiments. Build upon these findings, we developed a primitive and simple analytical approach to elucidate the role of 210Bi in the 210Po-210Pb pair in the ocean using a simplified two-box irreversible steady-state ocean model. We assumed that the activity concentrations in the dissolved and particulate phases of 210Pb, 210Bi, and 210Po in a given water column are solely determined by the concentration of the particles, their input and output, the distribution coefficients between dissolved and particulate phases, and decay constants of these radionuclides in the steady-state ocean. The 210Bi contribution to the 210Pb-210Po activity difference in seawater is found to be significant, therefore, it needs to be considered in estimating particle fluxes using 210Pb-210Po secular equilibrium at sea.

Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma.

Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAFi) and histone deacetylase inhibitors (HDACi) to enhance the delivery of MC1R-targeted radiolabeled peptide ([212Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAFV600E cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [212Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAFi and/or HDACi was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAFi and HDACi significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAFV600E and BRAFWT cells. Combining [212Pb]DOTA-MC1L with BRAFi and/or HDACi improved the tumor response by increasing the delivery of 212Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDACi and BRAFi could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.

Evaluation of a Novel Pb-203-Labeled Lactam-Cyclized Alpha-Melanocyte-Stimulating Hormone Peptide for Melanoma Targeting.

The purpose of this study is to examine the melanocortin-1 receptor (MC1R) targeting and specificity of 203Pb-DOTA-GGNle-CycMSHhex in melanoma cells and tumors to facilitate its potential therapeutic application when labeled with 212Pb. The MC1R-specific targeting and imaging properties of 203Pb-DOTA-GGNle-CycMSHhex were determined on B16/F1 and B16/F10 murine melanoma cells and in B16/F1 flank melanoma-, B16/F10 flank melanoma-, and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. 203Pb-DOTA-GGNle-CycMSHhex displayed MC1R-specific binding on B16/F1 and B16/F10 melanoma cells and tumors. B16/F1 flank melanoma, B16/F10 flank melanoma, and B16/F10 pulmonary metastatic melanoma lesions could be clearly imaged by single photon emission computed tomography (SPECT) using 203Pb-DOTA-GGNle-CycMSHhex as an imaging probe. The favorable melanoma targeting and imaging properties highlighted the potential of 203Pb-DOTA-GGNle-CycMSHhex as a MC1R-targeting melanoma imaging probe and warranted the evaluation of 212Pb-DOTA-GGNle-CycMSHhex for melanoma therapy in future studies.

210Po and 210Pb in forest mushrooms of genus Leccinum and topsoil from northern Poland and its contribution to the radiation dose.

Wild growing mushrooms are traditional food items for man and also an important source of nutrients for small and big wildlife. Nevertheless, they can be species - specifically vulnerable for contamination with heavy metals and radionuclides. We studied a less known phenomenon of accumulation of highly toxic, the alpha-radiation emitter such as 210Po and the beta emitter 210Pb by three Leccinum mushrooms: orange oak bolete L. aurantiacum (Bull.) Gray (previous name Leccinum aurantiacum var. quercinum Pilát), foxy bolete L. vulpinum Watling and slate bolete L. duriusculum (Schulzer ex Kalchbr.) Singer. Fungal and soil materials were collected from areas of a different geochemical composition in the northern regions of Poland. In parallel evaluated was the risk to human consumer due to possible intake of 210Po and 210Pb with a mushroom meal. Results showed a heterogeneous distribution of 210Po and 210Pb activity concentrations within caps and stipes of fruiting bodies. Overall activity concentration for whole dried fungi material ranged from 0.59 ±â€¯0.38 to 3.2 ±â€¯0.2 Bq 210Po kg-1 and from 0.45 ±â€¯0.04 to 3.1 ±â€¯0.2 Bq 210Pb kg-1. Evaluation showed that Leccinum mushrooms consumed by locals in typical quantity of 0.5 kg (dry biomass) can contribute into annual effective radiation dose at 0.90-3.81 µSv from 210Po decay and 0.31-2.14 µSv from 210Pb decay, which is a small portion of the annual effective radiation dose of 210Po and 210Pb for human inhabiting the northern regions of Poland.

212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC. The purpose of this study was to determine whether α-particle radioimmunotherapy (RIT) targeting TNBC cells using the CSPG4-specific monoclonal antibody (mAb) 225.28 as a carrier was effective at eliminating TNBC tumors in preclinical models. To this end, mAb 225.28 labeled with 212Pb (212Pb-225.28) as a source of α-particles for RIT was used for in vitro Scatchard assays and clonogenic survival assays with human TNBC cells (SUM159 and 2LMP) grown as adherent cells or non-adherent CIC-enriched mammospheres. Immune-deficient mice bearing orthotopic SUM159 or 2LMP xenografts were injected i.v. with the targeted (225.28) or irrelevant isotype-matched control (F3-C25) mAbs, labeled with 99mTc, 125I, or 212Pb for in vivo imaging, biodistribution, or tumor growth inhibition studies. 212Pb-225.28 bound to adherent SUM159 and 2LMP cells and to CICs from SUM159 and 2LMP mammospheres with a mean affinity of 0.5 nM. Nearly ten times more binding sites per cell were present on SUM159 cells and CICs compared with 2LMP cells. 212Pb-225.28 was six to seven times more effective than 212Pb-F3-C25 at inhibiting SUM159 cell and CIC clonogenic survival (p < 0.05). Radiolabeled mAb 225.28 showed significantly higher uptake than radiolabeled mAb F3-C25 in SUM159 and 2LMP xenografts (p < 0.05), and the uptake of 212Pb-225.28 in TNBC xenografts was correlated with target epitope expression. 212Pb-225.28 caused dose-dependent growth inhibition of SUM159 xenografts; 0.30 MBq 212Pb-225.28 was significantly more effective than 0.33 MBq 212Pb-F3-C25 at inhibiting tumor growth (p < 0.01). These results suggest that CSPG4-specific 212Pb-225.28 is a useful reagent for RIT of CSPG4-expressing tumors, including metastatic TNBC.

Preparation of 212Pb-labeled monoclonal antibody using a novel 224Ra-based generator solution.

INTRODUCTION: Alpha-emitting radionuclides have gained considerable attention as payloads for cancer targeting molecules due to their high cytotoxicity. One attractive radionuclide for this purpose is 212Pb, which by itself is a ß-emitter, but acts as an in vivo generator for its short-lived α-emitting daughters. The standard method of preparing 212Pb-labeled antibodies requires handling and evaporation of strong acids containing high radioactivity levels by the end user. An operationally easier and more rapid process could be useful since the 10.6h half-life of 212Pb puts time constraints on the preparation protocol. In this study, an in situ procedure for antibody labeling with 212Pb, using a solution of the generator nuclide 224Ra, is proposed as an alternative protocol for preparing 212Pb-radioimmunoconjugates. METHODS: Radium-224, the generator radionuclide of 212Pb, was extracted from its parent nuclide, 228Th. Lead-212-labeling of the TCMC-chelator conjugated monoclonal antibody trastuzumab was carried out in a solution containing 224Ra in equilibrium with progeny. Subsequently, the efficiency of separating the 212Pb-radioimmunoconjugate from 224Ra and other unconjugated daughter nuclides in the solution using either centrifugal separation or a PD-10 desalting size exclusion column was evaluated and compared. RESULTS: Radiolabeling with 212Pb in 224Ra-solutions was more than 90% efficient after only 30min reaction time at TCMC-trastuzumab concentrations from 0.15mg/mL and higher. Separation of 212Pb-labeled trastuzumab from 224Ra using a PD-10 column was clearly superior to centrifugal separation. This method allowed recovery of approximately 75% of the 212Pb-antibody-conjugate in the eluate, and the remaining amount of 224Ra was only 0.9±0.8% (n=7). CONCLUSIONS: The current work demonstrates a novel method of producing 212Pb-based radioimmunoconjugates from a 224Ra-solution, which may be simpler and less time-consuming for the end user compared with the method established for use in clinical trials of 212Pb-TCMC-trastuzumab.

Linking sedimentary total organic carbon to 210Pbex chronology from Changshou Lake in the Three Gorges Reservoir Region, China.

The influences of total organic carbon (TOC) and total nitrogen (TN) on Lead-210 (210Pb) dating have recently been of increasing concern in lacustrine research. Sediment core from Changshou Lake in the Longxi catchment was investigated for influence of TOC on 210Pb dating. Lead-210 excess (210Pbex), Cesium-137 (137Cs) activities, TOC, TN, and particle size were measured. We proposed a dating index based on 137Cs chronology and particle size distribution of the lake sediment profile and rainfall erosivities calculated from Longxi catchment metrological records. Increasing trends in TOC and TN were specifically caused by commercial cage fish farming after 1989. The statistically significant correlation between 210Pbex activity, TOC (0.61, p = 0.04) and TN (0.51, p = 0.04), respectively explained post-1989 210Pb scavenging. The 210Pbex activity was closely related with coupled peaks of TOC and TN from mass depth 5-10 g cm-2. Higher TOC/TN ratio (8.33) indicated submerged macrophytes and native aquatic algal growth as main source of carbon from enhanced primary productivity because of massive fertilizer use and coherent climate warming. The study supported key hypothesis on vital role of fertilizer usage and algal derived TOC in controlling sedimentary 210Pbex activity at Changshou Lake sediment. 137Cs profile and erosive events as time markers provided reliable and consistent sedimentation rate of (1.6 cm y-1). 210Pbex activity decayed exponentially after peak at mass depth 5.68 g cm-2. Therefore, violation of 210Pb dating primary assumptions made it inappropriate for sediment dating at Changshou Lake. TOC content must be considered while using 210Pb as dating tool for lake sediment profiles.

Monitoring steel bridge renovation using lead isotopic tracing.

Monitoring removal of lead (Pb) paint from steel structures usually involves analysis of environmental samples for total lead and determination of blood Pb levels of employees involved in the Pb paint removal. We used high precision Pb isotopic tracing for a bridge undergoing Pb paint removal to determine if Pb in the environmental and blood samples originated from the bridge paint. The paint system on the bridge consisted of an anti-corrosive red Pb primer top-coated with a Micaceous Iron Oxide (MIO) alkyd. Analysis of the red Pb primer gave uniform isotopic ratios indicative of Pb from the geologically-ancient Broken Hill mines in western New South Wales, Australia. Likewise waste abrasive material, as anticipated, had the same isotopic composition as the paint. The isotopic ratios for other samples lay on 2 separate linear arrays on a207Pb/204Pb versus 206Pb/204Pb diagram, one largely defined by gasoline and the majority of the ambient air data, and the other by data for one sample each of gasoline and ambient air and underwater sediments. Isotopic ratios in background ambient air samples for the project were characteristic of leaded gasoline. Air sampling during paint removal showed a contribution of paint Pb ranging from about 20 to 40%. Isotopic ratios in the blood of 8 employees prior to the commencement of work showed that 6 of these had been previously exposed to the Broken Hill Pb possibly from earlier bridge paint removal projects. One subject appeared to have increased exposure to Pb probably from the paint renovations.

Cherenkov light production from the α-emitting decay chains of 223Ra, 212Pb, and 149Tb for Cherenkov Luminescence Imaging.

Cherenkov Luminescence Imaging (CLI) is a new method to image radioactive therapeutic and diagnostic agents, primarily in preclinical studies. This study used Geant4 and Python to generate the predicted Cherenkov light production as a function of time for a set of isotopic chains of interest for targeted alpha therapy: 223Ra, 212Pb, and 149Tb. All are shown to produce substantial Cherenkov light, though time delays between initial decays and the production of Cherenkov light requires caution in interpreting CLI.

Historical decline and altered congener patterns of polychlorinated dibenzo-p-dioxins and dibenzofurans in fish and sediment in response to process changes at a pulp mill discharging into Jackfish Bay, Lake Superior.

Improved regulations for pulp and paper mill effluents and an industry shift away from elemental chlorine bleaching in the 1990s greatly reduced the release of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) into the environment. However, the high potential of these contaminants to persist in sediment and bioaccumulate in biota means that they have remained a concern. To document current contamination from bleached kraft pulp mill effluent, PCDD/Fs were measured in white sucker (Catostomus commersoni) collected from Jackfish Bay, Lake Superior. These values were contrasted to historically reported fish data as well as PCDD/F patterns from dated sediment cores. Patterns of PCDD/Fs in sediment cores from Jackfish Bay and reference sites demonstrated a relationship between contamination and mill process changes. During the peak PCDD/F contamination period (1991), when the mill was still using elemental chlorine, the contamination patterns in fish and sediment were distinct and dominated by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzofuran. Following the reduction in the use of elemental chlorine during the early 1990s, a rapid decline was observed in PCDD/F contamination of fish tissue, and levels are now approaching background conditions with congener patterns more reflective of atmospheric sources. Although surface sediments from Jackfish Bay continue to have elevated PCDD/Fs, with some locations exceeding sediment quality guidelines, they do not appear to be highly bioavailable to benthic fish.

PET and SPECT Imaging for the Acceleration of Anti-Cancer Drug Development.

Lead-compound optimization is an iterative process in the cancer drug development pipeline, in which small molecule inhibitors or biological compounds that are selected for their ability to bind specific targets are synthesised, tested and optimised. This process can be accelerated significantly using molecular imaging with nuclear medicine techniques, which aim to monitor the biodistribution and pharmacokinetics of radiolabelled versions of compounds. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be used to quantify fourdimensional (temporal and spatial) clinically relevant information, to demonstrate tumor uptake of, and monitor the response to treatment with lead-compounds. This review discusses the pre-clinical and clinical value of the information provided by nuclear medicine imaging compared to the histological analysis of biopsied tissue samples. Also, the role of nuclear medicine imaging is discussed with regard to the assessment of the treatment response, radiotracer biodistribution, tumor accumulation, toxicity, and pharmacokinetic parameters, with mention of microdosing studies, pre-targeting strategies, and pharmacokinetic modelling.

Preparation of a (219)Rn trap to measure the half-life of (211)Pb.

A Petri dish was filled with liquid scintillator and then used to trap (219)Rn from a (223)Ra source. The liquid scintillator was then transferred to a vial which was measured in a custom-built triple-to-double coincidence ratio (TDCR) counter. Two Cherenkov samples were prepared in a similar manner. The measurements were used to determine the (211)Pb half-life which was found to be 36.165(37)min.

Stratigraphic analysis of the Sterkfontein StW 573 Australopithecus skeleton and implications for its age.

StW 573, Little Foot, is the most complete Australopithecus skeleton yet discovered, with many of its bones found in their correct anatomical position. Since the discovery of the in situ skeleton in the Silberberg Grotto in 1997, several teams have attempted to date the fossil. This appeared a simple process because several flowstones are inter-bedded in the breccia above and below StW 573. Dating of these flowstones, using U-Pb (uranium-lead) isotope decay techniques, gave younger results than expected from the fauna and stratigraphic position, around 2.2 Ma (millions of years). Our recent stratigraphic, micromorphological and geochemical studies revealed that the stratigraphy is much more complicated than was previously thought, with localized post-depositional processes leading to the creation of voids within the breccia around the skeleton. These voids were then filled by multiple generations of flowstone growth. The research we present here demonstrates that the proposed dates based on the flowstone deposition can give only a minimum age for StW 573 and that the flowstone formation came after, and probably long after, the breccia deposition. If one takes account of the long evolution of these karst fillings, StW 573 appears to be significantly older than 2.2 Ma.

Assessment of soil contamination by (210)Po and (210)Pb around heavy oil and natural gas fired power plants.

Soil contamination by (210)Pb and (210)Po around heavy oil and natural gas power plants has been investigated; fly and bottom ash containing enhanced levels of (210)Pb and (210)Po were found to be the main source of surface soil contamination. The results showed that (210)Pb and (210)Po in fly-ash (economizer, superheater) is highly enriched with (210)Pb and (210)Po, while bottom-ash (boiler) is depleted. The highest (210)Pb and (210)Po activity concentrations were found to be in economizer ash, whereas the lowest activity concentration was in the recirculator ash. On the other hand, (210)Pb and (210)Po activity concentrations in soil samples were found to be higher inside the plant site area than those samples collected from surrounding areas. The highest levels were found in the vicinity of Mhardeh and Tishreen power plants; both plants are operated by heavy oil and natural fuels, while the lowest values were found to be in those samples collected from Nasrieh power plant, which is only operated by one type of fuel, viz. natural gas. In addition, the levels of surface soil contamination have decreased as the distance from the power plant site center increased.

Retention studies of recoiling daughter nuclides of 225Ac in polymer vesicles.

Alpha radionuclide therapy is steadily gaining importance and a large number of pre-clinical and clinical studies have been carried out. However, due to the recoil effects the daughter recoil atoms, most of which are alpha emitters as well, receive energies that are much higher than the energies of chemical bonds resulting in decoupling of the radionuclide from common targeting agents. Here, we demonstrate that polymer vesicles (i.e. polymersomes) can retain recoiling daughter nuclei based on an experimental study examining the retention of (221)Fr and (213)Bi when encapsulating (225)Ac.

Methodology for labeling proteins and peptides with lead-212 (212Pb).

INTRODUCTION: Alpha particles possess an exquisite degree of cytotoxicity when employed for targeted α-particle therapy (TAT) or radioimmunotherapy (RIT). (212)Pb, which acts as an in vivo generator of the α-emitting nuclide (212)Bi has shown great promise in pre-clinical studies when used to label the HER2 binding antibody, trastuzumab. Currently, the first RIT clinical trial employing (212)Pb radiolabeled trastuzumab is in progress. This report provides detailed current protocol operations and steps that were generated for use in the clinical trial as well as the relevant pre-clinical experimentation, and describes in detail the labeling of proteins or peptides with (212)Pb as provided via a (224)Ra based generator system. METHODS: (212)Pb was eluted from the (224)Ra/(212)Pb generator using hydrochloric acid (2M). The generator eluate was evaporated and digested with nitric acid (8M) followed by extraction of the (212)Pb with dilute nitric acid (0.1M). The dilute nitric acid solution of (212)Pb was used to label the immunoconjugate Trastuzumab-TCMC (2-(4-isothiocyanatobenzyl-1,4,7,10-tetraaza-1,4,7,10,tetra-(2-carbamonylmethyl)-cyclododecane) at pH5.5. RESULTS: Elution of (212)Pb from the generator was efficient yielding>90% of available (212)Pb. Trastuzumab-TCMC was efficiently labeled with a radiochemical yield of 94% ± 4% (n=7) by ITLC and an isolated yield of 73% ± 3% (n=7). CONCLUSIONS: The results show the feasibility of generating radioimmunoconjugates and peptide conjugates for use as in vivo α generator systems in the clinic. The technology holds promise in applications involving the treatment of minimal disease such as micrometastases and residual tumor after surgical debulking, hematological cancers, infections, and compartmental cancers, such as ovarian cancer.

Synthesis and characterization of αvß3-targeting peptidomimetic chelate conjugates for PET and SPECT imaging.

There is growing interest in small peptidomimetic α(v)ß(3) integrin antagonists that are readily synthesized and characterized and can be easily handled using physiological conditions. Peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-ß-alanine (IAC) was successfully conjugated to 1-(1-carboxy-3-carbo-t-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODA-GA(tBu)(3)) and 1-(1-carboxy-3-carbotertbutoxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA-GA(tBu)(4)) and radiolabeled with (111)In, (67)Ga and (203)Pb. Results of a radioimmunoassay demonstrated binding to purified α(v)ß(3) integrin when 1-4equiv of integrin were added to the reaction. Based on this promising result, investigations are moving forward to evaluate the NODA-GA-IAC and DOTA-GA-IAC conjugates for targeting tumor associated angiogenesis and α(v)ß(3) integrin positive tumors to define their PET and SPECT imaging qualities as well as their potential for delivery of therapeutic radionuclides.