Synthesis and evaluation of [67Ga]-AMD3100; A novel imaging agent for targeting chemokine receptor...
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other hand, molecular imaging investigations using [RGD-Glu-[ 64 Cu- NO2A]-6-Ahx-RM2] produced high-quality, high contrast images in PC- 3 tumor-bearing mice at the 4 h time-point. Conclusions: This study describes dual GRPR/PSMA- and GRPR/α v β 3 - targeting radioligands and indicates [RGD-Glu-[ 64 Cu-NO2A]-6-Ahx- RM2] to be a potential candidate for translation into human patients. http://dx.doi.org/10.1016/j.nucmedbio.2014.05.006 99 89 Zr labeling and preliminary evaluation of a trimeric RGD peptide based on a novel siderophore derived chelating scaffold Chuangyan Zhai a , Peter Knetsch a , Dominik Summer a , Christine Rangger a , Hubertus Haas b , Roland Haubner a , Clemens Decristoforo a a Department of Nuclear Medicine, Innsbruck Medical University, Innsbruck, Austria b Division of Molecular Biology/Biocenter, Innsbruck Medical University, Innsbruck, Austria Within the last years 89 Zr has attracted increasing attention as long lived PET radionuclide. So far the bifunctional chelating system employed for 89 Zr-applications is desferrioxamine B (DFO). Fusarinine C (FSC), a cyclic peptide siderophore, could be an alternative with potentially higher stability due to its cyclic structure, having complexing properties comparable to DFO. As proof of principle in this study 89 Zr-labelling of RGD-derivatised FSC, the optimization of analytical procedures and preliminary evaluation of this compound are reported. High radiochemical yield (N 96%) for 89 Zr-FSC-(RGD) 3 could be achieved at high SA. HPLC was used for characterization of 89 Zr-FSC(RGD) 3 , but was not suitable for determination of RCP. Using TLC best separation properties were achieved using ITLC-SG and CH 3 COOH/H 2 O (1:9) as a mobile phase. In vitro characterization of [ 89 Zr]FSC-(RGD) 3 showed comparable properties to the 68 Ga-coun- terpart with a hydrophilic character (logD value of -2.9) and low serum protein-bound activity. [ 89 Zr]FSC-(RGD) 3 was stable in PBS (pH 7.4), in FeCl 3 -solution as well as in fresh human serum, in DTPA- solution at 37 °C at 24 hours a slight degradation of the 89 Zr-peptide was found. Cell internalized activity was 2.07% cpm/mg protein for α v β 3 positive M21 cells which could be reduced to 0.23% cpm/mg protein via addition of c(RGDyV) revealing specific receptor binding. These results indicate very promising properties of the fusarinine C scaffold as basis for multimeric targeting constructs for labelling with 89 Zr. Biodistribution experiments are currently ongoing. http://dx.doi.org/10.1016/j.nucmedbio.2014.05.075 100 Enabling simultaneous imaging and treatment with the theragnostic radionuclide Tin-117 m Suresh C. Srivastava Brookhaven National Laboratory The high-LET conversion electron (C.E.) emitter Sn-117 m (t ½ 14 d, γ 159 keV, 86%) shows considerable promise for the non-invasive molecular imaging and treatment of inflammatory diseases including cancer, and of atherosclerosis caused by vulnerable plaques (VP) in the coronary and carotid arteries that when ruptured cause significant cardiac events (~70%) leading to MI and sudden death. The C.E. from Sn- 117 m is ideal for treating VPs, as their discrete range in tissue (~300 μm) is approximately the same as the VP thickness in human carotid and coronary arteries. We have developed and used (i) Sn-117 m electro- plated coronary stents (Sn-117 m stents), and (ii) Sn-117 m-DOTA– Annexin V [TA] for evaluating the possibility of simultaneous imaging and therapy of VP with this dual-purpose (theragnostic) radionuclide. Histochemical analysis of proliferating macrophages and smooth muscle cells in a hyper-lipidemic rabbit model, 3 d after Sn-117 m- stent implantation [4 doses: 0 (cold tin), 30, 60, and 150 μCi Sn- 117 m per stent] showed that inflammatory cells in the Sn-117 m- stented segments were dramatically reduced in a dose-dependent manner. Recent studies in an Apo-E mouse VP model with systemically administered TA have also showed a significant therapeutic effect. A phase I/II clinical trial with TA, in which human carotid endarterectomy patients were dosed and imaged for VP, with histology as the comparison, has demonstrated promising results. http://dx.doi.org/10.1016/j.nucmedbio.2014.05.065 101 Targeting Gastrin-Releasing Peptide Receptor-Positive Tumors using Yttrium-86 labeled DOTA-Bombesin(7-14) Analogs N. Bandara, K. Cherukuri, S. Krieger, J. Parry, S.E. Lapi, B.E. Rogers Washington University School of Medicine, St. Louis, MO The gastrin-releasing peptide receptor (GRPR) is overexpressed on a variety of human cancers including breast and prostate. Bombesin (BN) is a fourteen amino acid neuropeptide that binds with high affinity to GRPR. Our laboratory was amongst the first to evaluate BN analogues radiolabelled with positron-emitting radionuclides for imaging by positron-emission tomography (PET). The goal of this study was to evaluate DOTA-linker-BN(7–14) analogues radiolabelled with 86 Y (t 1/2 = 14.7 h, β + = 33%, E avg = 664 keV) to determine the effect of using 86 Y in place of 64 Cu on tumor and normal tissue uptake. We hypothesize that imaging using the 86 Y analogs would give better dosimetry estimates for their 90 Y therapeutic counterparts as compared to 64 Cu and may also reduce background signal in non-target tissues. In this study BN(7–14) analogues comprising two unique amino acid linkers (gly-ser-gly and gly-ser-ser) have been radiolabelled with 86 Y and evaluated for internalisation into PC-3 cells. These results show a rapid and specific uptake of both analogues over 24 h. Studies to evaluate these compounds in mice bearing PC-3 tumor xenografts by biodistribution and small animal PET imaging are ongoing. http://dx.doi.org/10.1016/j.nucmedbio.2014.05.144 102 Synthesis and evaluation of [ 67 Ga]-AMD3100; A novel imaging agent for targeting chemokine receptor CXCR4 Ayoub Aghanejad a,c , Amir R. Jalilian b , Yousef Fazaeli b , Behrouz Alirezapoor b , Mehraban Pouladi b , Davoud Beiki c , Stephan Maus d , Ali Khalaj c a Department of Nuclear Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran b Nuclear Science and Technology Research Institute, Tehran, 11365–3486, Iran c Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran d Clinic of Nuclear Medicine, University Medical Centre Mainz, Langenbeckstr, 1, D-55131 Mainz, Germany In order to develop a possible CXCR4 imaging agent for oncological scintigraphy, [ 67 Ga]labeled 1,1′-[1,4-phenylenebis(meth- ylene)] bis-1,4,8,11-tetraazacyclo-tetradecane ([ 67 Ga]-AMD3100) Abstracts 640
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other hand, molecular imaging investigations using [RGD-Glu-[64Cu-NO2A]-6-Ahx-RM2] produced high-quality, high contrast images in PC-3 tumor-bearing mice at the 4 h time-point.Conclusions: This study describes dual GRPR/PSMA- and GRPR/αvβ3-targeting radioligands and indicates [RGD-Glu-[64Cu-NO2A]-6-Ahx-RM2] to be a potential candidate for translation into human patients.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.006
9989Zr labeling and preliminary evaluation of a trimeric RGDpeptide based on a novel siderophore derived chelating scaffoldChuangyan Zhaia, Peter Knetscha, Dominik Summera,Christine Ranggera, Hubertus Haasb,Roland Haubnera, Clemens Decristoforoa
aDepartment of Nuclear Medicine, Innsbruck Medical University,Innsbruck, AustriabDivision of Molecular Biology/Biocenter, Innsbruck Medical University,Innsbruck, Austria
Within the last years 89Zr has attracted increasing attention as longlived PET radionuclide. So far the bifunctional chelating systememployed for 89Zr-applications is desferrioxamine B (DFO). FusarinineC (FSC), a cyclic peptide siderophore, could be an alternative withpotentially higher stability due to its cyclic structure, havingcomplexing properties comparable to DFO. As proof of principle inthis study 89Zr-labelling of RGD-derivatised FSC, the optimization ofanalytical procedures and preliminary evaluation of this compoundare reported. High radiochemical yield (N96%) for 89Zr-FSC-(RGD)3could be achieved at high SA. HPLC was used for characterization of89Zr-FSC(RGD)3, but was not suitable for determination of RCP. UsingTLC best separation properties were achieved using ITLC-SG andCH3COOH/H2O (1:9) as a mobile phase. In vitro characterization of[89Zr]FSC-(RGD)3 showed comparable properties to the 68Ga-coun-terpart with a hydrophilic character (logD value of −2.9) and lowserum protein-bound activity. [89Zr]FSC-(RGD)3 was stable in PBS(pH 7.4), in FeCl3-solution as well as in fresh human serum, in DTPA-solution at 37 °C at 24 hours a slight degradation of the 89Zr-peptidewas found. Cell internalized activity was 2.07% cpm/mg protein forαvβ3 positive M21 cells which could be reduced to 0.23% cpm/mgprotein via addition of c(RGDyV) revealing specific receptor binding.These results indicate very promising properties of the fusarinine Cscaffold as basis for multimeric targeting constructs for labelling with89Zr. Biodistribution experiments are currently ongoing.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.075
100Enabling simultaneous imaging and treatment with thetheragnostic radionuclide Tin-117 mSuresh C. Srivastava
Brookhaven National Laboratory
The high-LET conversion electron (C.E.) emitter Sn-117 m (t½ 14 d, γ159 keV, 86%) shows considerable promise for the non-invasivemolecular imaging and treatment of inflammatory diseases includingcancer, and of atherosclerosis caused by vulnerable plaques (VP) in thecoronary and carotid arteries that when ruptured cause significantcardiac events (~70%) leading toMI and sudden death. The C.E. from Sn-117 m is ideal for treatingVPs, as their discrete range in tissue (~300 μm)is approximately the same as the VP thickness in human carotid and
coronary arteries. We have developed and used (i) Sn-117 m electro-plated coronary stents (Sn-117 m stents), and (ii) Sn-117 m-DOTA–Annexin V [TA] for evaluating the possibility of simultaneous imagingand therapy of VP with this dual-purpose (theragnostic) radionuclide.
Histochemical analysis of proliferating macrophages and smoothmuscle cells in a hyper-lipidemic rabbit model, 3 d after Sn-117 m-stent implantation [4 doses: 0 (cold tin), 30, 60, and 150 μCi Sn-117 m per stent] showed that inflammatory cells in the Sn-117 m-stented segments were dramatically reduced in a dose-dependentmanner. Recent studies in an Apo-E mouse VP model withsystemically administered TA have also showed a significanttherapeutic effect. A phase I/II clinical trial with TA, in which humancarotid endarterectomy patients were dosed and imaged for VP, withhistology as the comparison, has demonstrated promising results.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.065
101Targeting Gastrin-Releasing Peptide Receptor-Positive Tumorsusing Yttrium-86 labeled DOTA-Bombesin(7-14) AnalogsN. Bandara, K. Cherukuri, S. Krieger, J. Parry, S.E. Lapi, B.E. Rogers
Washington University School of Medicine, St. Louis, MO
The gastrin-releasing peptide receptor (GRPR) is overexpressed on avariety of human cancers including breast and prostate. Bombesin (BN)is a fourteen amino acid neuropeptide that binds with high affinity toGRPR. Our laboratory was amongst the first to evaluate BN analoguesradiolabelled with positron-emitting radionuclides for imaging bypositron-emission tomography (PET). The goal of this study wasto evaluate DOTA-linker-BN(7–14) analogues radiolabelled with86Y (t1/2 = 14.7 h, β+ = 33%, Eavg = 664 keV) to determine the effectof using 86Y in place of 64Cu on tumor and normal tissue uptake. Wehypothesize that imaging using the 86Y analogs would give betterdosimetry estimates for their 90Y therapeutic counterparts as comparedto 64Cu and may also reduce background signal in non-target tissues. Inthis study BN(7–14) analogues comprising two unique amino acidlinkers (gly-ser-gly and gly-ser-ser) have been radiolabelled with86Y and evaluated for internalisation into PC-3 cells. These results showa rapid and specific uptake of both analogues over 24 h. Studies toevaluate these compounds in mice bearing PC-3 tumor xenografts bybiodistribution and small animal PET imaging are ongoing.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.144
102Synthesis and evaluation of [67Ga]-AMD3100; A novel imagingagent for targeting chemokine receptor CXCR4Ayoub Aghanejada,c, Amir R. Jalilianb, Yousef Fazaelib,Behrouz Alirezapoorb, Mehraban Pouladib, Davoud Beikic,Stephan Mausd, Ali Khalajc
aDepartment of Nuclear Pharmacy, Faculty of Pharmacy, TehranUniversity of Medical Sciences, Tehran, IranbNuclear Science and Technology Research Institute, Tehran, 11365–3486, IrancResearch Center for Nuclear Medicine, Tehran University of Medical Sciences,Tehran, IrandClinic of NuclearMedicine, UniversityMedical CentreMainz, Langenbeckstr, 1,D-55131 Mainz, Germany
In order to develop a possible CXCR4 imaging agent foroncological scintigraphy, [67Ga]labeled 1,1′-[1,4-phenylenebis(meth-ylene)] bis-1,4,8,11-tetraazacyclo-tetradecane ([67Ga]-AMD3100)
Abstracts640
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was prepared using [67Ga]GaCl3 and AMD-3100 for 2 h at 50 °C(radiochemical purity: N95% ITLC, N99% HPLC, specific activity:1800–2000 TBq/mmol) in acetate buffer. Stability of the complexwas checked in presence of human serum (37 °C) and in finalformulation for 4 days. The biodistribution of the labeled compoundin vital organs of wild-type Sprague–Dawley rats were determinedand compared with that of free Ga3+ cation up to 48 h. Consideringspleen as the target organ, the best target:non target ratios wereobtained 48 h post injection (spleen:blood ratio; 14.5 and spleen:muscle ratio; 88.4). Initial SPECT images and biodistribution resultsin wild type rats matched each other and demonstrate rapid washout of the tracer from urinal tract. SPECT images in human breastcarcinoma-bearing mice demonstrated detectable tumor uptake in48 h post injection.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.108
10368Ga-labelled curcuminoids complexes: Characterization of potentialradiotracers for imaging of Alzheimer's diseaseMattia Astia, Erika Ferrarib, Stefania Crocic, Giulia Attia,Sara Rubagottia, Michele Ioria, Pier C. Capponia, Alessandro Zerbinic,Monica Saladinib, Annibale Versaria
aNuclear Medicine Unit, IRCCS-Arcispedale Santa Maria Nuova,Reggio Emilia, ItalybDepartment of Chemical and Geological Sciences, University ofModena, Modena, ItalycClinical Immunology, Allergy, and Advanced Biotechnologies Unit,IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
Introduction: Curcumin and curcuminoids complexes labelled with18F or 99mTc have recently shown their potential as diagnostic toolsfor Alzheimer's disease. Herein, 68Ga-labelled complexes withcurcumin (CUR) and two curcuminoids, namely diacetyl-curcumin(DAC) and bis-dehydroxy-curcumin (bDHC), were synthesizedand characterized.Materials and methods: The radiotracers were prepared by reacting68Ga3+ obtained from a 68Ge/68Ga generator with 1 mg/ml curcu-minoids solutions. Reaction parameters (precursor amount, reactiontemperature, and pH) were optimized in order to obtain high andreproducible radiochemical yield and purity. Stoichiometry andformation of the curcuminoids complexes were investigated byMALDI-TOF-MS, UV–vis, and fluorescence spectroscopy on theequivalent natGa–curcuminoids complexes. Moreover, a first evalua-tion of their affinity to synthetic β-amyloid fibrils was performed.Results: The analyses evidenced that curcumin, DAC, and bDHC werepredominantly in the keto-enol form and attested Ga(L)2+ speciesformation. Identity of the 68Ga(L)2+ complexes was confirmed by co-elution with the equivalent natGa(L)2+ complexes in UHPLC analysis. All
the complexes were synthesized at high yield and purity (RCY N95%,RCP N98%) when the optimal reaction conditions were used (pH= 5,100 °C, 10 min., 60 nmol of precursor). 68Ga(CUR)2+, 68Ga(DAC)2+, and68Ga(bDHC)2+were highly (87 ± 4, 90 ± 1%) andmoderately (48 ± 2%),respectively, retained by synthetic β-amyloid fibrils in vitro.Conclusions: These results confirmed the potential application ofthese 68Ga-labelled curcuminoids as Alzheimer's disease detectingradiotracers.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.016
104Influence of different chelators on the radiochemical properties andimaging capabilities of a 68-gallium labelled bombesin analogueMattia Astia, René Martinb, Ralf Bergmannc, Michele Ioria,Pier C. Capponia, Giulia Attia, Sara Rubagottia, Albert Brennauerb,Marco Müllerb, Paola A. Erbad, Annibale Versaria
aNuclear Medicine Unit, IRCCS-Arcispedale Santa Maria Nuova, ReggioEmilia, ItalybABX GmbH, Radeberg, GermanycRadiopharmaceutical Chemical Biology Department, Helmholtz-ZentrumDresden-Rossendorf, Dresden, GermanydNuclear Medicine Unit, University of Pisa, Pisa, Italy
The radiolabelled bombesin analogue AMBA shows high potentialfor diagnosis and treatment of prostate and breast cancer but theinfluence of different chelators has not been explored so far. In thisstudy, we synthesized AMBA analogues linked to the most commonused chelators DOTA, NOTA and NODAGA and compared theirreactivity and in vivo biodistribution after labelling with 68-gallium.Methods: DO3A-, NO2A-, and NODAGA-AMBA were labelled with 68-gallium by using an IGG 100 68Ge/68Ga generator and commonfractionatingmethod. Biodistribution and imaging capability of the labelledcompoundswere assessed onWistar rats and in PC3 tumour bearingNMRInu/nu mice.Results: Radiochemical yield andpurity of all the 68Ga-labelled analogueswere elevated at the optimal reaction conditions. The highest perfor-mances were observed for NODAGA-AMBA (24 nmol of precursor,3.4 pH and 100 °C, RCY N65%). The uptakes in normal pancreas,expressing high GRPR levels, were 3.96, 4.49, and 5.61 (SUV) for 68Ga-DO3A-, 68Ga-NO2A-, and 68Ga-NODAGA-AMBA, respectively. The tu-mours were clearly visible for all the 68Ga-AMBA-chelators and thetumour-to-muscle ratio continuously increased up to a value ofapproximately 10 for 68Ga-DO3A-AMBA and 15 for 68Ga-NO2A- and68Ga-NODAGA-AMBA.Conclusion: All three precursors can be labelled in high yields and aresuitable for the imaging of prostate cancer. NODAGA-AMBA showedthe most favoured features either when labelled with 68-gallium andin terms of biodistribution and imaging capability.
http://dx.doi.org/10.1016/j.nucmedbio.2014.05.080
105Albumin-based nanoformulation for prostate-specific membraneantigen (PSMA)Sangeeta R. Banerjee, Baiqi Wang, Mrudula Pullambhatla,Catherine A. Foss, Martin G. Pomper, Russell H. Morgan
Department of Radiology and Radiological Science, Johns HopkinsMedical Institutions, Baltimore, MD, USA
Fig. 1 Biodistribution of [67Ga]-AMD3100 in wild-type rats (left) and SPECT images of[67Ga]-AMD3100 in human breast carcinoma-bearing bearing mice (right).
Abstracts 641
