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Dosimetric studies in normal mice of 177Lu-DOTA-SP and 177Lu-DOTA-His2-MG
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Abstracts / Nuclear Medicine and Biology 37 (2010) 677–726
Dosimetric studies in normal mice of 177Lu-DOTA-SP and 177 Lu-DOTA-His2-MG
Imaging biomarkers for diagnosis and quantification with positron emission tomography: assistance to therapy
Nancy Puerta Yepes, Ana C. López Bularte, Noemí Nevares, Miguel Zapata, Juan Pérez, Ana Rojo Nuclear Regulatory Authority, Argentina
Irina Velikyana,bAnders Sundinc, Barbro Erikssond, Hans Lundqviste, Jens Sörensenf, Mats Bergströmg, Bengt Långströma a Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 599, SE-751 24 Uppsala, Sweden b Uppsala Applied Science Lab, GEMS PET Systems, GE Healthcare, SE-752 28 Uppsala, Sweden c Department of Radiology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden d Department of Endocrine Oncology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden e Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala, Sweden f Department of Medicinal Sciences, Clinical Physiology and Nuclear Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden g Department of Pharmaceutical Biosciences, Uppsala University, Uppsala Biomedical Centre, Uppsala, Sweden
Labelled peptides with beta negative emmiters are used in peptide receptor radionuclide therapy for treatment of various tumor species. Substance P (SP) and minigastrin (His2-MG) are possible targets for malignant glioma and medullar thyroid cancer, respectively. Biodistribution of the both radiopharmaceuticals in normal mice were performed at different times. Absorbed doses for different mice organs (cGy/μCi) and human organs were calculated using two methods, time scaling (A) and direct extrapolation (B). Maximum tolerated doses (MTD) according to critical organs (mCi/Kg) were calculated. Dosimetric calculations showed that kidneys received the highest dose, for both radiopharmeceuticals. The best results were obtained using time scaling method (A). The MTD for 177Lu-DOTA-SP that can be injected without kidney toxicity are 11.2 and 11.4 mCi/kg for adult man and woman, respectively. In the same way, the MTD for 177 Lu-DOTA-His2-MG are 13.2 and 14 mCi/kg for adult man and woman, respectively.
doi:10.1016/j.nucmedbio.2010.04.117 SPECT metalloprobes for monitoring MDR1 P-glycoprotein-mediated transport at the blood-brain barrier Jothilingam Sivapackiam, Scott E. Harpstrite, Julie L. Prior, David Piwnica-Worms, Vijay Sharma Molecular Imaging Center, Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA Emerging models of transporter-mediated efflux pathways at the bloodbrain barrier (BBB) suggest a role for multidrug resistance (MDR1) Pglycoprotein (Pgp) in development of neurodegenerative diseases. To assess Pgp-mediated functional transport at the BBB, we have synthesized novel 67Ga-radiopharmaceuticals. These metalloprobes were obtained by treatment of hexadentate ligands with 67Ga (acetylacetonate)3 and purified using the Radio-HPLC. 67Ga-complexes demonstrated accumulation in human epidermal carcinoma cells, and uptake profiles were found to be inversely proportional to Pgp expression. Additionally, LY335979 (1 μM), a Pgp specific inhibitor, reversed efflux of radiotracers in Pgp expressing KB 8-5 cells, equivalent to levels found in Pgp negative KB 3-1 cells, thus demonstrating the specificity of these agents to probe the transporter-mediated activity. Additionally, 67Ga complexes showed brain uptake and retention in mdr1a/1b(−/−) gene-deleted (dKO) mice compared with facile excretion patterns in their wild-type (WT) counterparts, with insignificant differences in blood pharmacokinetics, thus consistent with their recognition by Pgp, expressed at the capillary BBB. Further evaluation of single photon emission computed tomography (SPECT) probes in cross-bred APP/dKO and APP/WT mice is in progress to evaluate role of the Pgp in Alzheimer’s disease. Upon validation, these agents could offer potential leads for enabling noninvasive SPECT/positron emission tomography monitoring of MDR1 Pgp-mediated functional transport at the BBB.
doi:10.1016/j.nucmedbio.2010.04.165
Positron emission tomography (PET) is a non-invasive imaging technique of high resolution, sensitivity and accurate quantification. The use of 68Ge/68Ga generator produced positron emitting 68Ga (T1/2=68 min) might make PET examinations possible at centres lacking accelerators. 68Ga radionuclide has the potential for labelling of tracer molecules to be used for diagnosis, dosimetry, planning and following up the response to chemo- and radiotherapy. These applications may require accurate quantification of tracer concentration in vivo, which may in turn be dependent on the specific radioactivity of a tracer. The feasibility of in vivo quantification of somatostatin receptor density/expression for adequate planning and monitoring of corresponding treatment strategies has been demonstrated. Our results suggest that there are great differences in tumour receptor expression between patients, indicating the importance to individually determine the receptor expression pattern in each patient before therapy. In our opinion, the quantification option by PET has not yet been fully explored or sufficiently utilised. The availability of the methodology for the labelling of tracers with high specific radioactivity as well as technological platforms for automated production might be of great benefit for clinical practice and promote personalized medicine. doi:10.1016/j.nucmedbio.2010.04.052 Monitoring AAV mediated somatostatin receptor gene transfer by PET with Ga68-DOTATATE Luigi Aloja, Michela Aurilioa, Valentina Rinaldia, Armida Faellab, Patrizia Annunziatab,c, Anita Capalbob,c, Gabriella Cotugnob,c, Alberto Auricchiob,c a COSTBM0607-WG2, AF Medicina Nucleare, Fondazione “G.Pascale”, Napoli, Italy b Telethon Institute of Genetics and Medicine (TIGEM) c Department of Pediatrics, Medical Genetics, “Federico II” University, Napoli We are using positron emission tomography (PET) with 68Ga-DOTA-Tyr(3)Thr(8)-octreotate (68Ga-DOTATATE) to monitor somatostatin receptor 2 (SSTR2) gene transfer. Adeno associated virus (AAV) vectors encoding the human SSTR2 gene under the cytomegalovirus (CMV) or the thyroxin-binding globulin (TBG) promoters were constructed. Different sets of C57/BL6 mice received intravenous (IV) AAV-TBG-SSTR2 or intramuscular (IM) AAVCMV-SSTR2. PET imaging was carried out over a 6-month period following the AAV administration in treated and control animals with 1–5 MBq of 68GaDOTATATE. IV AAV-TBG-SSTR2 transduced animals showed several-fold increased uptake in the liver compared to control animals. IM AAV-CMV-
Abstracts / Nuclear Medicine and Biology 37 (2010) 677–726
Dosimetric studies in normal mice of 177Lu-DOTA-SP and 177 Lu-DOTA-His2-MG
Imaging biomarkers for diagnosis and quantification with positron emission tomography: assistance to therapy
Nancy Puerta Yepes, Ana C. López Bularte, Noemí Nevares, Miguel Zapata, Juan Pérez, Ana Rojo Nuclear Regulatory Authority, Argentina
Irina Velikyana,bAnders Sundinc, Barbro Erikssond, Hans Lundqviste, Jens Sörensenf, Mats Bergströmg, Bengt Långströma a Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 599, SE-751 24 Uppsala, Sweden b Uppsala Applied Science Lab, GEMS PET Systems, GE Healthcare, SE-752 28 Uppsala, Sweden c Department of Radiology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden d Department of Endocrine Oncology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden e Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala, Sweden f Department of Medicinal Sciences, Clinical Physiology and Nuclear Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden g Department of Pharmaceutical Biosciences, Uppsala University, Uppsala Biomedical Centre, Uppsala, Sweden
Labelled peptides with beta negative emmiters are used in peptide receptor radionuclide therapy for treatment of various tumor species. Substance P (SP) and minigastrin (His2-MG) are possible targets for malignant glioma and medullar thyroid cancer, respectively. Biodistribution of the both radiopharmaceuticals in normal mice were performed at different times. Absorbed doses for different mice organs (cGy/μCi) and human organs were calculated using two methods, time scaling (A) and direct extrapolation (B). Maximum tolerated doses (MTD) according to critical organs (mCi/Kg) were calculated. Dosimetric calculations showed that kidneys received the highest dose, for both radiopharmeceuticals. The best results were obtained using time scaling method (A). The MTD for 177Lu-DOTA-SP that can be injected without kidney toxicity are 11.2 and 11.4 mCi/kg for adult man and woman, respectively. In the same way, the MTD for 177 Lu-DOTA-His2-MG are 13.2 and 14 mCi/kg for adult man and woman, respectively.
doi:10.1016/j.nucmedbio.2010.04.117 SPECT metalloprobes for monitoring MDR1 P-glycoprotein-mediated transport at the blood-brain barrier Jothilingam Sivapackiam, Scott E. Harpstrite, Julie L. Prior, David Piwnica-Worms, Vijay Sharma Molecular Imaging Center, Mallinckrodt Institute of Radiology, School of Medicine, Washington University, St. Louis, MO 63110, USA Emerging models of transporter-mediated efflux pathways at the bloodbrain barrier (BBB) suggest a role for multidrug resistance (MDR1) Pglycoprotein (Pgp) in development of neurodegenerative diseases. To assess Pgp-mediated functional transport at the BBB, we have synthesized novel 67Ga-radiopharmaceuticals. These metalloprobes were obtained by treatment of hexadentate ligands with 67Ga (acetylacetonate)3 and purified using the Radio-HPLC. 67Ga-complexes demonstrated accumulation in human epidermal carcinoma cells, and uptake profiles were found to be inversely proportional to Pgp expression. Additionally, LY335979 (1 μM), a Pgp specific inhibitor, reversed efflux of radiotracers in Pgp expressing KB 8-5 cells, equivalent to levels found in Pgp negative KB 3-1 cells, thus demonstrating the specificity of these agents to probe the transporter-mediated activity. Additionally, 67Ga complexes showed brain uptake and retention in mdr1a/1b(−/−) gene-deleted (dKO) mice compared with facile excretion patterns in their wild-type (WT) counterparts, with insignificant differences in blood pharmacokinetics, thus consistent with their recognition by Pgp, expressed at the capillary BBB. Further evaluation of single photon emission computed tomography (SPECT) probes in cross-bred APP/dKO and APP/WT mice is in progress to evaluate role of the Pgp in Alzheimer’s disease. Upon validation, these agents could offer potential leads for enabling noninvasive SPECT/positron emission tomography monitoring of MDR1 Pgp-mediated functional transport at the BBB.
doi:10.1016/j.nucmedbio.2010.04.165
Positron emission tomography (PET) is a non-invasive imaging technique of high resolution, sensitivity and accurate quantification. The use of 68Ge/68Ga generator produced positron emitting 68Ga (T1/2=68 min) might make PET examinations possible at centres lacking accelerators. 68Ga radionuclide has the potential for labelling of tracer molecules to be used for diagnosis, dosimetry, planning and following up the response to chemo- and radiotherapy. These applications may require accurate quantification of tracer concentration in vivo, which may in turn be dependent on the specific radioactivity of a tracer. The feasibility of in vivo quantification of somatostatin receptor density/expression for adequate planning and monitoring of corresponding treatment strategies has been demonstrated. Our results suggest that there are great differences in tumour receptor expression between patients, indicating the importance to individually determine the receptor expression pattern in each patient before therapy. In our opinion, the quantification option by PET has not yet been fully explored or sufficiently utilised. The availability of the methodology for the labelling of tracers with high specific radioactivity as well as technological platforms for automated production might be of great benefit for clinical practice and promote personalized medicine. doi:10.1016/j.nucmedbio.2010.04.052 Monitoring AAV mediated somatostatin receptor gene transfer by PET with Ga68-DOTATATE Luigi Aloja, Michela Aurilioa, Valentina Rinaldia, Armida Faellab, Patrizia Annunziatab,c, Anita Capalbob,c, Gabriella Cotugnob,c, Alberto Auricchiob,c a COSTBM0607-WG2, AF Medicina Nucleare, Fondazione “G.Pascale”, Napoli, Italy b Telethon Institute of Genetics and Medicine (TIGEM) c Department of Pediatrics, Medical Genetics, “Federico II” University, Napoli We are using positron emission tomography (PET) with 68Ga-DOTA-Tyr(3)Thr(8)-octreotate (68Ga-DOTATATE) to monitor somatostatin receptor 2 (SSTR2) gene transfer. Adeno associated virus (AAV) vectors encoding the human SSTR2 gene under the cytomegalovirus (CMV) or the thyroxin-binding globulin (TBG) promoters were constructed. Different sets of C57/BL6 mice received intravenous (IV) AAV-TBG-SSTR2 or intramuscular (IM) AAVCMV-SSTR2. PET imaging was carried out over a 6-month period following the AAV administration in treated and control animals with 1–5 MBq of 68GaDOTATATE. IV AAV-TBG-SSTR2 transduced animals showed several-fold increased uptake in the liver compared to control animals. IM AAV-CMV-