A systematic comparative evaluation of 90Y‐labeled bifunctional chelators for their use in targeted therapy

This paper describes a systematic comparative evaluation of five commonly used bifunctional chelators, namely, p‐isothiocyanato benzyl derivatives of diethylenetriaminepentacetic acid (DTPA‐NCS), trans‐cyclohexyl diethylenetriaminepentacetic acid (CHX‐A″‐DTPA‐NCS), 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA‐NCS), 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid (NOTA‐NCS), and 3,6,9,15‐tetraazabicyclo [9.3.1]pentadeca‐1(15),11,13‐triene‐3,6,9‐triacetic acid (PCTA‐NCS), on the basis of their ability to complex ⁹⁰Y at room temperature, in vitro and in vivo stability and clearance pattern in biological system. The results of the experiments carried out revealed that CHX‐A″‐DTPA‐NCS was the most promising option as it could be radiolabeled with ⁹⁰Y at room temperature with highest specific activity and demonstrated high in vitro stability in human serum and in presence of challenging metal ions commonly present in human plasma. The clearance pattern in Swiss mice revealed that ⁹⁰Y‐CHX‐ A″‐DTPA‐NCS cleared through the kidneys with minimum retention in any other major organ. Thus, the use of cyclohexyl‐DTPA based bifunctional chelators would increase the scope of making ⁹⁰Y‐labeled agents suitable for targeted therapy.     

草莓状毛细血管瘤两种90Sr-90Y敷贴治疗方法的比较

目的：比较少次大剂量和多次小剂量放射敷贴治疗草莓状毛细血管瘤的疗效及皮肤晚期反应,评价其优劣。方法：2008年8月～2010年4月将本院收治的80例草莓状毛细血管瘤患儿随机等分成少次大剂量组和多次小剂量组进行90Sr-90Y敷贴治疗。结果：①少次大剂量组和多次小剂量组的有效率分别为90.0%、92.5%,复发率分别为10.0%、12.5%,两者比较差异均无统计学意义（P〉0.05）。②单次大剂量和多次小剂量放射组的皮肤晚期反应发生率分别为15.0%、17.5%,两者比较差异无统计学意义（P〉0.05）。结论：少次大剂量和多次小剂量敷贴治疗草莓状毛细血管瘤的疗效及皮肤晚期反应差异均无统计学意义,少次大剂量90Sr-90Y敷贴治疗具有费用低、操作简便、患者就诊次数少等优点,值得在临床上推广。     

Preclinical evaluation of potential infection‐imaging probe [68Ga]Ga‐DOTA‐K‐A9 in sterile and infectious inflammation

The development of bacteria‐specific infection radiotracers is of considerable interest to improve diagnostic accuracy and enabling therapy monitoring. The aim of this study was to determine if the previously reported radiolabelled 1,4,7,10‐tetraazacyclododecane‐N,N′,N″,N?‐tetraacetic acid (DOTA) conjugated peptide [⁶⁸Ga]Ga‐DOTA‐K‐A9 could detect a staphylococcal infection in vivo and distinguish it from aseptic inflammation. An optimized [⁶⁸Ga]Ga‐DOTA‐K‐A9 synthesis omitting the use of acetone was developed, yielding 93 ± 0.9% radiochemical purity. The in vivo infection binding specificity of [⁶⁸Ga]Ga‐DOTA‐K‐A9 was evaluated by micro positron emission tomography/magnetic resonance imaging of 15 mice with either subcutaneous Staphylococcus aureus infection or turpentine‐induced inflammation and compared with 2‐deoxy‐2‐[¹⁸F]fluoro‐D‐glucose ([¹⁸F]FDG). The scans showed that [⁶⁸Ga]Ga‐DOTA‐K‐A9 accumulated in all the infected mice at injected doses ≥3.6 MBq. However, the tracer was not found to be selective towards infection, since the [⁶⁸Ga]Ga‐DOTA‐K‐A9 also accumulated in mice with inflammation. In a concurrent in vitro binding evaluation performed with a 5‐carboxytetramethylrhodamine (TAMRA) fluorescence analogue of the peptide, TAMRA‐K‐A9, the microscopy results suggested that TAMRA‐K‐A9 bound to an intracellular epitope and therefore preferentially targeted dead bacteria. Thus, the [⁶⁸Ga]Ga‐DOTA‐K‐A9 uptake observed in vivo is presumably a combination of local hyperemia, vascular leakiness and/or binding to an epitope present in dead bacteria.     

Exploring the radiosynthesis and in vitro characteristics of [68Ga]Ga‐DOTA‐Siglec‐9

Vascular adhesion protein 1 is a leukocyte homing‐associated glycoprotein, which upon inflammation rapidly translocates from intracellular sources to the endothelial cell surface. It has been discovered that the cyclic peptide residues 283–297 of sialic acid‐binding IgG‐like lectin 9 (Siglec‐9) “CARLSLSWRGLTLCPSK” bind to vascular adhesion protein 1 and hence makes the radioactive analogues of this compound ([⁶⁸Ga]Ga‐DOTA‐Siglec‐9) interesting as a noninvasive visualizing marker of inflammation. Three different approaches to the radiosynthesis of [⁶⁸Ga]Ga‐DOTA‐Siglec‐9 are presented and compared with previously published methods. A simple, robust radiosynthesis of [⁶⁸Ga]Ga‐DOTA‐Siglec‐9 with a yield of 62% (non decay‐corrected) was identified, and it had a radiochemical purity >98% and a specific radioactivity of 35 MBq/nmol. Furthermore, the protein binding and stability of [⁶⁸Ga]Ga‐DOTA‐Siglec‐9 were analyzed in vitro in mouse, rat, rabbit, pig, and human plasma and compared with in vivo pig results. The plasma in vitro protein binding of [⁶⁸Ga]Ga‐DOTA‐Siglec‐9 was the lowest in the pig followed by rabbit, human, rat, and mouse. It was considerably higher in the in vivo pig experiments. The in vivo stability in pigs was lower than the in vitro stability. Despite considerable species differences, the observed characteristics of [⁶⁸Ga]Ga‐DOTA‐Siglec‐9 are suitable as a positron emission tomography tracer.     

Synthesis,structure, and biological evaluation of a platinum‐carbazole conjugate

Cisplatin resistance is caused, in part, by the efficient removal of the helix‐distorting cisplatin 1,2‐intrastrand cross‐links by nucleotide excision repair (NER) machinery. To make a platinum‐DNA adduct that causes less helical distortion than the cisplatin 1,2‐intrastrand adduct, we designed and synthesized a monofunctional platinum‐carbazole conjugate (carbazoplatin). The 2.5 Å crystal structure of carbazoplatin‐DNA adduct revealed both the monoplatination of the N7 of a guanine (G) base and the intercalation into two G:C base pairs, while causing a minor distortion of the DNA helix. A 50‐mer dsDNA containing a single carbazoplatin lesion was poorly processed by UvrABC endonuclease, the prokaryotic NER machinery that detects helical distortion and performs dual incision around the lesion. Our cell viability assay indicated that the cytotoxic pathways of carbazoplatin might be different from those of cisplatin; carbazoplatin was 5–8 times more cytotoxic than cisplatin against PANC‐1 and MDA‐MB‐231 cancer cell lines.     

111In‐ and 203Pb‐labeled cyclic arginine‐glycine‐aspartic acid peptide conjugate as an αvβ3 integrin‐binding radiotracer

Methodology for site‐specific modification and chelate conjugation of a cyclic arginine‐glycine‐aspartic acid (cRGD) peptide for the preparation of a radiotracer molecular imaging agent suitable for detecting α_vβ₃ integrin is described. The method involves functionalizing the peptide with an aldehyde moiety and conjugation to a 1,4,7,10‐tetraazacyclododecane‐N,N′,N″,N?‐tetraacetic acid derivative that possesses an aldehyde reactive aminooxy group. The binding assay of the ¹¹¹In‐labeled peptide conjugate with α_vβ₃ integrin showed 60% bound when four equivalents of the integrin was added, a reasonable binding affinity for a monovalent modified RGD peptide.     

Synthesis and biodistribution studiesof 177Lu‐trastuzumab as a therapeutic agent in the breast cancer mice model

Trastuzumab is a humanized monoclonal antibody against the HER2 that has the potential to be used as radioimmunotherapy (RIT) agent in treatment of breast cancer. Lutetium‐177 has beta energy suitable for therapy and gamma photons for imaging. We labeled trastuzumab with lutetium‐177 via DOTA as chelator and performed some necessary tests for the first stage in using complex as a RIT agent. Radiochemical purity, immunoreactivity and stability of complex were determined. The biodistribution and imaging studies were determined in mice bearing breast tumor. The radiochemical purity was 94±0.9%. Lutetium‐Trastuzumab showed a good stability at biological condition. The tumor to blood ratio was calculated 3.29(±0.09) after 7 days. The good tumor uptake in biodistribution studies was agreed with gamma camera images after 7 days. The results showed that the new complex could be considered for further evaluation in animals and possibly in humans as a new radiopharmaceutical for use in RIT against breast cancer. Copyright © 2010 John Wiley & Sons, Ltd.     

Spotlight on 17‐AAG as an Hsp90 inhibitor for molecular targeted cancer treatment

Hsp90 is a ubiquitous chaperone with important roles in the organization and maturation of client proteins that are involved in the progression and survival of cancer cells. Multiple oncogenic pathways can be affected by inhibition of Hsp90 function through degradation of its client proteins. That makes Hsp90 a therapeutic target for cancer treatment. 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG) is a potent Hsp90 inhibitor that binds to Hsp90 and inhibits its chaperoning function, which results in the degradation of Hsp90's client proteins. There have been several preclinical studies of 17‐AAG as a single agent or in combination with other anticancer agents for a wide range of human cancers. Data from various phases of clinical trials show that 17‐AAG can be given safely at biologically active dosages with mild toxicity. Even though 17‐AAG has suitable pharmacological potency, its low water solubility and high hepatotoxicity could significantly restrict its clinical use. Nanomaterials‐based drug delivery carriers may overcome these drawbacks. In this paper, we review preclinical and clinical research on 17‐AAG as a single agent and in combination with other anticancer agents. In addition, we highlight the potential of using nanocarriers and nanocombination therapy to improve therapeutic effects of 17‐AAG.     

In vitro evaluation of 225Ac‐DOTA‐substance P for targeted alpha therapy of glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with dismal prognosis despite treatment by surgery combined with radiotherapy and chemotherapy. The neuropeptide Substance P (SP) is the physiological ligand of the neurokinin‐1 receptor, which is highly expressed in glioblastoma cells. Thus, SP represents a potential ligand for targeted alpha therapy. In this study, a protocol for the synthesis of SP labeled with the alpha emitter ²²⁵Ac was developed and binding affinity properties were determined. The effects of ²²⁵Ac‐DOTA‐SP were investigated on human glioblastoma cell lines (T98G, U87MG, U138MG) as well as GBM stem cells. A significant dose‐dependent reduction in cell viability was detected up to 6 days after treatment. Also, colony‐forming capacity was inhibited at the lower doses tested. In comparison, treatment with the conventional agent temozolomide showed higher cell viability and colony‐forming capacity. ²²⁵Ac‐DOTA‐SP treatment caused induction of late apoptosis pathways. Cells were arrested to G2/M‐phase upon treatment. Increasing doses and treatment time caused additional S‐phase arrest. Similar results were obtained using human glioblastoma stem cells, known to show radioresistance. Our data suggest that ²²⁵Ac‐DOTA‐SP is a promising compound for treatment of GBM.     

[64Cu]‐labelled trastuzumab: optimisation of labelling by DOTA and NODAGA conjugation and initial evaluation in mice

The human epidermal growth factor receptor‐2 (HER2) is overexpressed in 20–30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2‐positive breast cancer. Trastuzumab has previously been labelled with copper‐64 by conjugation of a 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) chelator. The aim of this study was to optimise the ⁶⁴Cu‐labelling of DOTA‐trastuzumab and as the first to produce and compare with its 1,4,7‐triazacyclononane, 1‐glutaric acid‐5,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono‐N‐hydroxysuccinimide (NHS) and NODAGA‐NHS. ⁶⁴Cu‐labelling of DOTA‐trastuzumab was studied by varying the amount of DOTA‐trastuzumab used, reaction temperature and time. Full ⁶⁴Cu incorporation could be achieved using a minimum of 10‐µg DOTA‐trastuzumab, but the fastest labelling was obtained after 15 min at room temperature using 25 µg of DOTA‐trastuzumab. In comparison, 80% incorporation was achieved for ⁶⁴Cu‐labelling of NODAGA‐trastuzumab. Both [⁶⁴Cu]DOTA‐trastuzumab and [⁶⁴Cu]NODAGA‐trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3–9% ID/g for both tracers.     

Potent Triazolothione Inhibitor of Heat‐Shock Protein‐90

Heat‐shock protein‐90 is an attractive target for anticancer drugs, as heat‐shock protein‐90 blockers such as the ansamycin 17‐(allylamino)‐17‐demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17‐(allylamino)‐17‐demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template‐related drawbacks. In this paper, we describe a new, potent non‐ansamycin small‐molecule inhibitor of heat‐shock protein‐90, BX‐2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX‐2819 to the ADP/ATP‐binding pocket of heat‐shock protein‐90. The compound blocked expression of heat‐shock protein‐90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17‐(allylamino)‐17‐demethoxygeldanamycin. In a panel of four cancer cell lines, BX‐2819 blocked growth with an average IC₅₀ value of 32 nm (range of 7–72 nm ). Efficacy studies demonstrated that treatment with BX‐2819 significantly inhibited the growth of NCI‐N87 and HT‐29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat‐shock protein‐90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX‐2819 and related analogs for the treatment of cancer.     

Cerenkov luminescence imaging of αvβ6 integrin expressing tumors using 90Y‐labeled peptides

Cerenkov luminescence imaging (CLI) is an emerging preclinical molecular imaging modality that tracks the radiation emitted in the visible spectrum by fast moving charged decay products of radionuclides. The aim of this study was in vitro and in vivo evaluation of the two radiotracers, ⁹⁰Y‐DOTA‐PEG₂₈‐A20FMDV2 (⁹⁰Y‐1) and ⁹⁰Y‐DOTA‐Ahx‐A20FMDV2 (⁹⁰Y‐2) (>99% radiochemical purity, 3.7 GBq/µmol specific activity) for noninvasive assessment of tumors expressing the integrin α_vβ₆ and their future use in tumor targeted radiotherapy. Cell binding and internalization in α_vβ₆‐positive cells was ⁹⁰Y‐1: 10.1 ± 0.8%, 50.3 ± 2.1%; ⁹⁰Y‐2: 22.4 ± 1.7%, 44.7 ± 1.5% with <5% binding to α_vβ₆‐negative control cells. Biodistribution studies showed maximum α_vβ₆‐positive tumor uptake of the radiotracers at 1‐h post injection (p.i.) (⁹⁰Y‐1: 0.64 ± 0.15% ID/g; ⁹⁰Y‐2: 0.34 ± 0.11% ID/g) with high renal uptake (>25% ID/g at 24 h). Because of the lower tumor uptake and high radioactivity accumulation in kidneys (that could not be reduced by pre‐administration of either lysine or furosemide), the luminescence signal from the α_vβ₆‐positive tumor was not clearly detectable in CLI images. The studies suggest that CLI is useful for indicating major organ uptake for both radiotracers; however, it reaches its limitation when there is low signal‐to‐noise ratio.     

Synthesis of 5,6‐dihydro‐4H‐benzo[d]isoxazol‐7‐one and 5,6‐dihydro‐4H‐isoxazolo[5,4‐c]pyridin‐7‐one Derivatives as Potential Hsp90 Inhibitors

A novel class of 5,6‐dihydro‐4H‐benzo[d]isoxazol‐7‐ones and 5,6‐dihydro‐4H‐isoxazolo[5,4‐c]pyridin‐7‐ones was designed, synthesized, and assayed to investigate the affinity toward Hsp90 protein. The synthetic route was based on a 1,3‐dipolar cycloaddition of nitriloxides, generated in situ from suitable benzaldoximes, with 2‐bromocyclohex‐2‐enones or 3‐bromo‐5,6‐dihydro‐1H‐pyridin‐2‐ones. Whereas all the compounds bearing a benzamide group on the bicyclic scaffold were devoid of activity, the derivatives carrying a resorcinol‐like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme.     

Effect of Colchicine on Drug Absorption from the Rat Small Intestine in Situ and in Vitro

Abstract The effect of colchicine (1 mg/kg intraperitoneally on two successive days) on the absorption of isoniazid, quinidine and sulphafurazole (sulfisoxazole) from the rat small intestine was studied in situ and in vitro. Colchicine produced two different types of histological damage in the small intestine, one with degenerative and the other with regenerative changes predominating. The small intestinal surface area was variably reduced. The colchicine-treated rats were lethargic and hypothermic as compared to controls. Colchicine retarded the disappearance of fluid and all three drugs from the small intestinal lumen in situ 2 days after the first colchicine injection. In vitro the total amounts of fluid and drugs passed through the intestinal wall were not significantly changed by colchicine, although there was a slight tendency towards an increased absorption of quinidine. Hence, colchicine as an antimitotic drug decreases drug absorption from the rat small intestine in situ, apparently due to the decreased surface area of the small intestine, the decreased water flux through the intestinal wall, the retarded intestinal motility and hypothermia of the rats. In vitro the changes are small, which makes the in vitro tests less suitable for studying the effect of colchicine on absorption.     

Synthesis and evaluation of a 99mTc‐labeled tubulin‐binding agent for tumor imaging

Cholchicine and its derivatives are very potent tubulin‐binding compounds and can be used as a potential tumor targeting agents. In this study, colchicine was labeled with ^99mTc via hydrazinonicotinic acid (HYNIC) and was investigated further. HYNIC/cholchicine was synthesized and labeling with ^99mTc was performed at 95 °C for 15 min and radiochemical analysis included HPLC method. The stability of radiconjugate was checked in the presence of human serum at 37 °C up to 24 h. Biodistribution was studied in breast tumor‐bearing mice. Labeling yield of 95.8 ± 0.54% was obtained corresponding to a specific activity of 54 MBq/µmol. Radioconjugate showed good stability in the presence of human serum. Biodistribution studies in tumor‐bearing mice showed that ^99mTc/HYNIC/colchicine conjugate accumulated in tumor with good uptake (3.17 ± 0.14% g/g at 1 h post‐injection). The radioconjugate was cleared fast from normal organs and showed clearance through urinary and hepatobiliary systems with accumulation of activity in kidneys and intestine. This radioconjugate may be useful to assess the presence of tumor by imaging.     

Synthesis and evaluation of Tc‐99m and fluorescence‐labeled elastin‐derived peptide,VAPG for multimodal tumor imaging in murine tumor model

We developed a Tc‐99m and fluorescence‐labeled peptide, Tc‐99m TAMRA‐GHEG‐ECG‐VAPG to target tumor cells and evaluated the diagnostic performance as a dual‐modality imaging agent for tumor in a murine model. TAMRA‐GHEG‐ECG‐VAPG was synthesized by using Fmoc solid‐phase peptide synthesis. Radiolabeling of TAMRA‐GHEG‐ECG‐VAPG with Tc‐99m was done by using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with SW620 tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry by using confocal microscopy. After radiolabeling procedures with Tc‐99m, Tc‐99m TAMRA‐GHEG‐ECG‐VAPG complexes were prepared in high yield (>96%). The K_d of Tc‐99m TAMRA‐GHEG‐ECG‐VAPG determined by saturation binding was 16.8 ± 3.6 nM. Confocal microscopy images of SW620 cells incubated with TAMRA‐GHEG‐ECG‐VAPG showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc‐99m TAMRA‐GHEG‐ECG‐VAPG in tumors. Tumor uptake was effectively blocked by the coinjection of an excess concentration of VAPG. Specific uptake of Tc‐99m TAMRA‐GHEG‐ECG‐VAPG was confirmed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. In vivo and in vitro studies revealed substantial uptake of Tc‐99m TAMRA‐GHEG‐ECG‐VAPG in tumor cells. Tc‐99m TAMRA‐GHEG‐ECG‐VAPG has potential as a dual‐modality tumor imaging agent.     

Synthesis of isotope‐labeled HSP90 inhibitor: [13CD3] and [14C]‐TAK‐459

[¹³CD₃]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD₃]‐2‐methoxy‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridine was synthesized in two steps from 2,6‐dibromopyridine and stable isotope‐labeled sodium methoxide. [¹⁴C]‐TAK‐459 (1B) was synthesized from [¹⁴C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [¹⁴C]‐(R)‐2‐amino‐7‐(2‐bromo‐4‐fluorophenyl)‐4‐methyl‐7,8‐dihydropyrido[4,3‐d]pyrimidin‐5(6H)‐one, was prepared by microwave‐assisted condensation.     

Rho Kinase Inhibitor Y‐27632 Down‐Regulates Norepinephrine Synthesis and Release in PC12 Cells

Abstract: Rho kinase inhibition is beneficial for neurite outgrowth and nerve disorders, and the Rho kinase inhibitors have been regarded as promising agents to treat neural diseases. The main aim of the study was to elucidate how Rho kinase inhibitor Y‐27632 regulates neurotransmitter norepinephrine synthesis and release in PC12 cells when neurite outgrowth was induced. PC12 cells were treated with Y‐27632 for 6 days. The amount of norepinephrine synthesized in PC12 cells and the amount released evoked by acetylcholine or by KCl were determined by norepinephrine enzyme‐linked immunosorbent assay kits. The results showed that the amount of norepinephrine both synthesized and released was down‐regulated with a concentration‐dependent relationship. Further results of Western blotting found that the protein expression of tyrosine hydroxylase and synapsin I (especially its active form, synapsin I phosphoSer603) was also down‐regulated, which were directly related to synthesis and release of norepinephrine, respectively. All the results suggest that Y‐27632 is able to down‐regulate norepinephrine synthesis and release, the direct mechanism of which may be associated with down‐regulation on expression of some proteins, including tyrosine hydroxylase and synapsin I.     

Synthesis, 99mTc‐labeling,and preliminary biological evaluation of DTPA‐melphalan conjugates

Melphalan (MFL) is a typical nitrogen mustard for the treatment of many types of cancer. For the purpose to develop novel ^99mTc‐labeled tumor imaging agents with SPECT, MFL was directly labeled by ^99mTc using diethylene triamine pentacetate acid (DTPA) as bifunctional chelating agent. The novel ligands were successfully synthesized by conjugation of DTPA to MFL to get monosubstituted DTPA‐MFL and bis‐substituted DTPA‐2MFL. Radiolabeling was performed in high yield to get ^99mTc‐DTPA‐MFL and ^99mTc‐DTPA‐2MFL, respectively, which were hydrophilic and stable at room temperature. The high initial tumor uptake with retention, good tumor/muscle ratios, and satisfactory scintigraphic images suggested the potential of ^99mTc‐DTPA‐MFL and ^99mTc‐DTPA‐2MFL for tumor imaging. However, the slow normal tissue clearance would be a great obstacle. Further modification on the linker and/or ^99mTc‐chelate to improve the tumor targeting efficacy and in vivo kinetic profiles is currently in progress.     

Synthesis and evaluation of a water‐soluble polymer to reduce Ac‐225 daughter migration

The actinium decay chain has been promoted as an in vivo alpha generator for therapy, but migration of daughters from the primary conjugate has lead to increased toxicity away from the target organ. To reduce daughter migration, polyethylenimine (PEI) was used with a primary chelator and secondary chelators. The primary chelator, DOTA, was used to coordinate ²²⁵Actinium and secondary chelators‐acetate and DTPA, were added to the polymer for coordination of daughters formed by decay. The ²²⁵Actinium polymer derivatives containing secondary chelators were found to retain radioactive daughters better than the ²²⁵Actinium bond to the primary alone. The retention of ²¹³Bismuth and ²⁰⁹Thallium had the following order from highest retained to lowest DOTA‐PEI‐DTPA≈DOTA‐PEI‐CH₂OO‐ > DOTA‐PEI. The data suggests this polymer approach could be used to reduce daughter migration and has potential for development of actinium labeled radiopharmaceuticals. Copyright © 2007 John Wiley & Sons, Ltd.