Development of a 99mTc-labelled RGD peptide as an angiogenesis imaging agent

Abstracts / Nuclear Medicine and Biology 37 (2010) 677–726 Patients presenting cancers that overexpress EGFR or HER2, two members of the ErbB family of growth factor receptors, have poorer prognoses, with higher risks of disease recurrence and metastatic events. Despite regulatory approval of small molecule tyrosine kinase inhibitors as therapies for these cancers, their widespread use has been hampered by an inability to identify subpopulations sensitive to anti-EGFR/HER2 therapy. This project addresses this issue through the design and synthesis of single photon emission computed tomography imaging agents specific to these cancers. This is accomplished by attachment of a characteristic 4-anilinoquinazoline inhibitor scaffold to a linker labeled with 99mTc. The modular synthetic approach employed produces a more readily optimized series of molecular probes, while strategic placement of the radionuclide in solvent-accessible space minimizes the negative effect of its presence on radiotracer binding in the active sites of the receptors. doi:10.1016/j.nucmedbio.2010.04.121 188 Re for targeting intracellular antigens in virus-induced cancers and melanoma

Ekaterina Dadachova, Lynn Francesconi Albert Einstein College of Medicine, NY, NY, USA 188

188-Rhenium ( Re) is a powerful beta-emitting radionuclide with multiple applications in therapy of cancer. Our laboratory is interested in targeting intracellular antigens for treatment of metastatic cancers. Targeting intracellular antigens increases specificity and safety of treatment as intracellular antigens are accessible to antibodies only in fast growing tumors as a result of a cellular turnover and not in the healthy tissues as viable cells are impenetrable for the antibodies. When intracellular antigens are targeted with the radiolabeled antibody, the radionuclides with a long therapeutic range in tissue such as 188Re need to be utilized for the viable tumor cells to be killed via “cross-fire” effect. We have pioneered targeting intracellular viral oncogenic proteins E6 and E7 in human papilloma virus (HPV)-related experimental cervical and head and neck cancers, and melanin pigment, in metastatic melanoma. Cervical and head and neck tumor-bearing mice treated with 188Re-labeled antibody to HPV-16 E6 oncogene demonstrated significant decrease in tumor progression in comparison with untreated controls. The 188Relabeled antibody 6D2 to melanin has been used in recently completed Phase I/II human trial in patients with metastatic melanoma and demonstrated its safety and efficacy. Thus, 188Re seems to be a very promising radionuclide for targeting intracellular antigens in radioimmunotherapy of cancer. doi:10.1016/j.nucmedbio.2010.04.179

Poster Communications (Oral)

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possibility to extend the clinical applications of this class of complexes to tumor imaging and non invasive multidrug resistance studies. Standing on this ground, the kinetic of uptake at 4°C and 37°C of 99mTc(N)DBODC(5) was evaluated in vitro in suitable human cancer cell lines, and in the corresponding sublines, before and after MDR modulator treatment, using 99mTc-sestamibi as reference. Results from this study clearly indicated that (i) the uptake of both 99mTc(N)DBODC(5) and 99mTc-Sestamibi was correlated to metabolic activity of the cells. In fact, low temperature inhibited the cellular uptake of both 99mTctracers, indicating that there was no binding to the cell membranes or to hydrophobic regions of the cell membrane protein. (ii) The cellular accumulation is correlated to the level of Pgp/MRP expression; in fact, an enhancement of uptake in resistant cells was observed after treatment with a MDR inhibitor/modulator, indicating the selective blockade of Pgp/MPR prevent efflux of the tracers. This study gave a preliminary indications on the applicability of 99mTc(N)DBODC(5) in tumour imaging and for detecting MDR-mediated drug resistance in human cancer. doi:10.1016/j.nucmedbio.2010.04.002 Development of a imaging agent

99m

Tc-labelled RGD peptide as an angiogenesis

Peter Iveson, Matthew Morrison, Jon Barnett GE Healthcare, MDx Discovery, The Grove Centre, Amersham, HP79LL Bucks, UK The objective of this work was to develop a RDG peptide-based imaging agent with high affinity to the αvβ3/β5 integrins, a cell adhesion receptor that is highly expressed on tumour neovasculature. The agent could have utility in tumour diagnosis and therapy monitoring. Here we describe how 99m Tc-maraciclatide (formerly 99mTc-NC100692), an integrin imaging agent, with 3.1±1.6 nM affinity for the αvβ3/β5 integrin, was developed. Modifications of the studied RGD peptides, including pegylation, addition of sulfo napthalene or sulfonic acid groups, were shown to have significant effects on the in vivo biodistribution in a tumour-bearing mouse model. Maraciclatide was subsequently chosen as the lead candidate because of its acceptable pharmacokinetics and in vivo efficacy. A tumour uptake of 1.8% ID/g was obtained after 120 min, together with tumour:blood and tumour: muscle ratios of 4.0 and 5.3. Development of a kit formulation is described, together with the radiolabelling and QC of the 99mTc-maraciclatide. Maraciclatide contains an amine oxime chelate which can be labelled in high yield (N90%) at room temperature. Clinical studies involving 46 patients show that scintigraphy with 99mTc-maraciclatide is feasible for the detection of cancer, including lung and brain metastases from breast and lung cancer. doi:10.1016/j.nucmedbio.2010.04.155

99m

Tc(N)–DBODC(5) from cardiology to oncology: preliminary in vitro study Cristina Bolzati a, Davide Carta b, Valentina Gandini b, Cristina Marzano b Nicola Salvarese b, Nicola A. Colabufo c, F. Berardi c, Roberto Perronec, Giuliano Bandoli b a ICIS-CNR, Padua, Italy b Department Pharm. Sci. Padua University, Italy c Dip. Farmacochimico, Bari University, Italy 99m Tc(N)–DBODC(5) is a lipophilic cationic mixed-compound currently under clinical investigation as potential myocardial imaging agent. The findings that this complex accumulates in mitochondrial structures through a mechanism mediated by the negative mitochondrial membrane potential, and that the rapid efflux of 99mTc(N)-DBODC(5) from non-target tissues seems correlated to the Pgp/MDR-Pgp transport function opens the

Chitosan-based 99mTc agent for folate-receptor-mediated targeting Wenyan Guo, Wenjiang Yang, Xianzhong Zhang* Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China Introduction: The aim of this study is to evaluate the feasibility of chitosan as a backbone for the design of 99mTc labeled receptor targeting agent. Methods: Chitosan-folate conjugate (CSFA) was synthesized as a model compound for folate-receptor targeting and characterized by IR, UV and elemental analysis. The bioevaluation of 99mTc-CSFA was performed in normal mice. Results: The coupling ratio of CSFA was calculated as 0.44. Both of 99mTcCSFA and 99mTc-CS were prepared with high radiochemical purity. Biodistribution of 99mTc-CSFA showed that the folate receptor-abundant kidney had the highest radioactivity accumulation (115.68±15.44%ID/g