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51. In vivo detection of antigen-specific CD8+T cells by immuno-positron emission tomography

Author

Woodham, Andrew W., Zeigler, Stad H., Zeyang, Ella L., Kolifrath, Stephen C., Cheloha, Ross W., Rashidian, Mohammad, Chaparro, Rodolfo J., Seidel, Ronald D., Garforth, Scott J., Dearling, Jason L., Mesyngier, Maia, Duddempudi, Phaneendra K., Packard, Alan B., Almo, Steven C., and Ploegh, Hidde L.

Abstract

The immune system’s ability to recognize peptides on major histocompatibility molecules contributes to the eradication of cancers and pathogens. Tracking these responses in vivo could help evaluate the efficacy of immune interventions and improve mechanistic understanding of immune responses. For this purpose, we employ synTacs, which are dimeric major histocompatibility molecule scaffolds of defined composition. SynTacs, when labeled with positron-emitting isotopes, can noninvasively image antigen-specific CD8+T cells in vivo. Using radiolabeled synTacs loaded with the appropriate peptides, we imaged human papillomavirus-specific CD8+T cells by positron emission tomography in mice bearing human papillomavirus-positive tumors, as well as influenza A virus–specific CD8+T cells in the lungs of influenza A virus–infected mice. It is thus possible to visualize antigen-specific CD8+T-cell populations in vivo, which may serve prognostic and diagnostic roles.

Published
2020
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52. Cyclotron production of 68Ga via the 68Zn(p,n)68Ga reaction in aqueous solution

Author

Pandey, Mukesh K, Byrne, John F, Jiang, Huailei, Packard, Alan B, and DeGrado, Timothy R

Subjects
Original Article
Abstract

The objective of the present work is to extend the applicability of the solution target approach to the production of (68)Ga using a low energy cyclotron. Since the developed method does not require solid target infrastructure, it offers a convenient alternative to (68)Ge/(68)Ga generators for the routine production of (68)Ga. A new solution target with enhanced heat exchange capacity was designed and utilized with dual foils of Al (0.20 mm) and Havar (0.038 mm) separated by helium cooling to degrade the proton energy to ~14 MeV. The water-cooled solution target insert was made of Ta and its solution holding capacity (1.6 mL) was reduced to enhance heat transfer. An isotopically enriched (99.23%) 1.7 M solution of (68)Zn nitrate in 0.2 N nitric acid was utilized in a closed target system. After a 30 min irradiation at 20 μA, the target solution was unloaded to a receiving vessel and the target was rinsed with 1.6 mL water, which was combined with the target solution. An automated module was used to pass the solution through a cation-exchange column (AG-50W-X8, 200-400 mesh, hydrogen form) which efficiently trapped zinc and gallium isotopes. (68)Zn was subsequently eluted with 30 mL of 0.5 N HBr formulated in 80% acetone without any measurable loss of (68)Ga. (68)Ga was eluted with 7 mL of 3 N HCl solution with 92-96% elution efficiency. The radionuclidic purity was determined using an HPGe detector. Additionally, ICP-MS was employed to analyze for non-radioactive metal contaminants. The product yield was 192.5 ± 11.0 MBq/μ·h decay-corrected to EOB with a total processing time of 60-80 min. The radionuclidic purity of (68)Ga was found to be99.9%, with the predominant contaminant being 67Ga. The ICP-MS analysis showed small quantities of Ga, Fe, Cu, Ni and Zn in the final product, with (68)Ga specific activity of 5.20-6.27 GBq/μg. Depending upon the user requirements, (68)Ga production yield can be further enhanced by increasing the (68)Zn concentration in the target solution and extending the irradiation time. In summary, a simple and efficient method of (68)Ga production was developed using low energy cyclotron and a solution target. The developed methodology offers a cost-effective alternative to the (68)Ge/(68)Ga generators for the production of (68)Ga.

Published
2014

53. Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection

Author

Cowan, Douglas B., primary, Yao, Rouan, additional, Akurathi, Vamsidhar, additional, Snay, Erin R., additional, Thedsanamoorthy, Jerusha K., additional, Zurakowski, David, additional, Ericsson, Maria, additional, Friehs, Ingeborg, additional, Wu, Yaotang, additional, Levitsky, Sidney, additional, del Nido, Pedro J., additional, Packard, Alan B., additional, and McCully, James D., additional

Published
2016
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54. Colitis ImmunoPET

Author

Dearling, Jason L. J., primary, Daka, Ala, additional, Veiga, Nuphar, additional, Peer, Dan, additional, and Packard, Alan B., additional

Published
2016
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56. The Effect of the Prosthetic Group on the Pharmacologic Properties of 18F-labeled Rhodamine B, a Potential Myocardial Perfusion Agent for PET

Author

Bartholomä, Mark D., Gottumukkala, Vijay, Zhang, Shaohui, Baker, Amanda, Dunning, Patricia, Fahey, Frederic H., Treves, S. Ted, and Packard, Alan B.

Subjects
Fluorine Radioisotopes, Rhodamines, Myocardium, Myocardial Perfusion Imaging, Esters, Heart, Article, Rats, Glycols, Mice, Structure-Activity Relationship, Positron-Emission Tomography, Animals, Humans, Tissue Distribution, Radiopharmaceuticals
Abstract

We recently reported the development of the 2-[(18)F]fluoroethyl ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging. This compound, which was prepared using a [(18)F]fluoroethyl prosthetic group, has significant uptake in the myocardium in rats but also demonstrates relatively high liver uptake and is rapidly hydrolyzed in vivo in mice. We have now prepared (18)F-labeled rhodamine B using three additional prosthetic groups (propyl, diethylene glycol, and triethylene glycol) and found that the prosthetic group has a significant effect on the in vitro and in vivo properties of these compounds. Of the esters prepared to date, the diethylene glycol ester is superior in terms of in vitro stability and pharmacokinetics. These observations suggest that the prosthetic group plays a significant role in determining the pharmacological properties of (18)F-labeled compounds. They also support the value of continued investigation of (18)F-labeled rhodamines as PET radiopharmaceuticals for myocardial perfusion imaging.

Published
2012

57. Mitochondrial Transplantation by Intra-Arterial Injection for Acute Kidney Injury

Author

Doulamis, Ilias P, Guariento, Alvise, Duignan, Thomas, Kido, Takashi, Orfany, Arzoo, Saeed, Mossab Y, Weixler, Viktoria H, Blitzer, David, Shin, Borami, Snay, Erin R, Inkster, James A.H., Packard, Alan B, Zurakowski, David, Rousselle, Thomas, Bajwa, Amandeep, Parikh, Samir M, Stillman, Isaac E, del Nido, Pedro J., and McCully, James D

Abstract

Acute kidney injury (AKI) is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury (IRI) was investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon-catheters. Following 60 minutes ischemia, the balloon catheters were deflated and the animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries. The injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of cortex and medulla. There were no safety related issues detected with mitochondrial transplantation. Following 24 hours of reperfusion, estimated glomerular filtration rate and urine output were significantly increased while serum creatinine and blood urea nitrogen were significantly decreased in swine receiving mitochondria as compared to those receiving vehicle. Gross anatomy, histopathological analysis, acute tubular necrosis scoring and transmission electron microscopy showed that the renal cortex of vehicle group had extensive coagulative necrosis of primarily proximal tubules, while the mitochondrial transplanted kidney showed only patchy mild acute tubular injury. Renal cortex IL-6 expression was significantly increased in Vehicle kidneys as compared to the kidneys receiving mitochondrial transplantation. These results demonstrate that mitochondrial transplantation by intra-arterial injection provides renal protection from IRI, significantly enhancing renal function and reducing renal damage.

Published
2024
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60. The Ionic Charge of Copper-64 Complexes Conjugated to an Engineered Antibody Affects Biodistribution

Author

Dearling, Jason L. J., primary, Paterson, Brett M., additional, Akurathi, Vamsidhar, additional, Betanzos-Lara, Soledad, additional, Treves, S. Ted, additional, Voss, Stephan D., additional, White, Jonathan M., additional, Huston, James S., additional, Smith, Suzanne V., additional, Donnelly, Paul S., additional, and Packard, Alan B., additional

Published
2015
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61. American College of Radiology and Society of Nuclear Medicine and Molecular Imaging Joint Credentialing Statement for PET/MR Imaging: Brain

Author

Jadvar, Hossein, primary, Subramaniam, Rathan M., additional, Berman, Claudia G., additional, Boada, Fernando, additional, Colletti, Patrick M., additional, Guimaraes, Alexander R., additional, McConathy, Jonathan, additional, Meltzer, Carolyn C., additional, Noto, Richard B., additional, Packard, Alan B., additional, Rohren, Eric M., additional, and Oates, M. Elizabeth, additional

Published
2015
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63. Kidneys

Author

Treves, S. T., primary, Harmon, William E., additional, Packard, Alan B., additional, and Kuruc, Alvin, additional

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68. Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64 Cu-SarAr immunoconjugates

Author

Voss, Stephan D, Smith, Suzanne, DiBartolo, Nadine, McIntosh, Lacey J, Cyr, Erika M, Bonab, Ali A, Dearling, Jason L J, Carter, Edward A, Fischman, Alan J, Treves, S Ted, Gillies, Stephen D, Sargeson, Alan, Huston, James S, Packard, Alan B, Voss, Stephan D, Smith, Suzanne, DiBartolo, Nadine, McIntosh, Lacey J, Cyr, Erika M, Bonab, Ali A, Dearling, Jason L J, Carter, Edward A, Fischman, Alan J, Treves, S Ted, Gillies, Stephen D, Sargeson, Alan, Huston, James S, and Packard, Alan B

Abstract

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18F-FDG. Copper-64 (64Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability

Published
2007

72. A Sensitive Method for the Measurement of Copper at Trace Levels Using an HPLC-Based Assay

Author

Packard, Alan B. and Dearling, Jason L.J.

Abstract

Background: Measurement of trace metal contamination is critical in the production of radiometals, such as 64Cu, for protein labeling. ICP-MS provides these data with high sensitivity and high specificity, but at high (instrument) cost. TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11- tetraacetic acid) titration provides high sensitivity at low cost but with low specificity. A method that allowed the measurement of trace metals with high sensitivity but also at relatively low cost would, therefore, be very useful in the development of new radiometal production methods. Objective: The goal of this project was to develop an analytical method for copper that uses readily available laboratory equipment while minimally achieving low ppm sensitivity. Method: The metal-chelating macrocycle 2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA) was coupled to fluorescein to produce a molecule that combines high UV absorbance and high quantum yield with the ability to chelate a wide range of transition metals. The fluorescein-DOTA was mixed with Cu(II) samples at low ppm concentrations, and the samples were analyzed by reversed-phase HPLC. Results: Copper chelation by the DOTA moiety decreased its overall charge, leading to a delayed elution from a C18 HPLC column. The absorbance signal of the fluorescein-DOTA-Cu(II) peak (453 nm) linearly correlated with the copper concentration allowing measurement of Cu(II) down to 1.25 ppm. Furthermore, using fluorescence detection (521 nm) the detection limit was reduced by almost three orders of magnitude, to 2.5 ppb (p<0.05). Conclusion: Using a fluorescent dye (fluorescein) coupled to a macrocyclic chelator (DOTA) and an HPLC equipped with a standard UV detector is it possible to measure Cu at ppm concentrations, the Cu concentration observed in typical samples of 64Cu.

Published
2017

73. Functional Imaging of Multidrug Resistance in Breast Cancer With PET

Author

CHILDREN'S HOSPITAL CORP BOSTON MA, Packard, Alan B., CHILDREN'S HOSPITAL CORP BOSTON MA, and Packard, Alan B.

Abstract

The object of this project is the development of a PET radiopharmaceutical for measuring multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer. Single-photon myocardial perfusion agents such as 99mTc-MIBI are substrates for Pgp, the protein implicated in mdr, and are now being studied for evaluation of mdr. A PET mdr tracer would provide significant advantages over 99mTc- MIBI, and the half-life of 64Cu (12.7 h) is better matched to the apparent biological half-life of the mdr process in breast cancer (-24O min.) than are other PET radionuclides (e.g., 11C, T1/2= 11 min). We are carrying out in vivo and in vitro studies of lipophilic cationic 64Cu-based PET radiopharmaceuticals as potential PET mdr radiopharmaceuticals using murine (MAT-B) and human (MCF-7) breast cancer models. In vitro studies of prototype 64Cu-based complexes reveal a pattern of uptake similar to that observed for 99mTc-MIBI. Studies are currently underway to determine that optimal chemical properties of this agent. The development of a radiopharmaceuticals for the measurement of the mdr status of breast cancer lesions will facilitate optimization of treatment protocols, monitoring of the development of acquired resistance, and real-time evaluation of mdr modulators.

Published
2003

75. Functional Imaging of Multidrug Resistance in Breast Cancer with PET

Author

CHILDREN'S HOSPITAL CORP BOSTON MA, Packard, Alan B., CHILDREN'S HOSPITAL CORP BOSTON MA, and Packard, Alan B.

Abstract

The objective of this project is the development of a PET radiopharmaceutical for measuring multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer. Single-photon myocardial perfusion agents such as Tc-MIBI are substrates for Pgp, the protein implicated in mdr, and are now being studied for evaluation of mdr. A PET mdr tracer would provide significant advantages over Tc-MIBI, and the half-life of 64Cu (12.7 h) is better matched to the apparent biological half-life of the mdr process in breast cancer (^24O min.) than are other PET radionuclides 11 (e.g., C, T1/2= 11 min). We are carrying out in vivo and in vitro studies of lipophilic cationic 64Cu-based PET radiopharmaceuticals as potential PET mdr radiopharmaceuticals using murine (MAT-B) and human (MCF-7) breast cancer models. In vitro studies of prototype 64Cu complexes reveal a pattern of uptake similar to that observed for 99mTc-MIBI. Studies are currently underway to determine the optimal chemical properties of this agent. The development of a radiopharmaceutical for the measurement of the mdr status of breast cancer lesions will facilitate optimization of treatment protocols, monitoring of the development of acquired resistance, and real-time evaluation of mdr modulators.

Published
2002

76. Functional Imaging of Multidrug Resistance in Breast Cancer with PET

Author

CHILDREN'S HOSPITAL CORP BOSTON MA, Packard, Alan B., CHILDREN'S HOSPITAL CORP BOSTON MA, and Packard, Alan B.

Abstract

The objective of this project is the development of a PET radiopharmaceutical for measuring multidrug resistance (mdr) in breast cancer. Multidrug resistance is resistance of a lesion to a specific class of drugs that includes many of the chemotherapeutics that are most effective against breast cancer. Single-photon myocardial perfusion agents such as 99mmTc-MIBI are substrates for Pgp, the protein implicated in mdr, and are now being studied for evaluation of mdr. A PET mdr tracer would provide significant advantages over 99mmTc-MIBI, and the half-life of 64Cu (12.7 h) is better matched to the apparent biological half-life of the mdr process in breast cancer (-240 min.) than are other PET radionuclides (e.g., 64C, T1/2= 11 min). We are carrying out in vivo and in vitro studies of lipophilic cat ionic 64Cu-based PET radiopharmaceuticals as potential PET mdr radiopharmaceuticals using murine (MAT-13) and human (MCF-7) breast cancer models. In vitro studies of prototype 64Cu complexes reveal a pattern of uptake similar to that observed for 99mmTc-MIBI. Studies are currently underway to determine the optimal chemical properties of this agent. The development of a radiopharmaceutical for the measurement of the mdr status of breast cancer lesions will facilitate optimization of treatment protocols, monitoring of the development of acquired resistance, and real-time evaluation of mdr modulators.

Published
2001

77. Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64 Cu-SarAr immunoconjugates

Author

Voss, Stephan D., primary, Smith, Suzanne V., additional, DiBartolo, Nadine, additional, McIntosh, Lacey J., additional, Cyr, Erika M., additional, Bonab, Ali A., additional, Dearling, Jason L. J., additional, Carter, Edward A., additional, Fischman, Alan J., additional, Treves, S. Ted, additional, Gillies, Stephen D., additional, Sargeson, Alan M., additional, Huston, James S., additional, and Packard, Alan B., additional

Published
2007
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84. Convenient synthesis of 18F-radiolabeled R-(−)-N- n-propyl-2-(3-fluoropropanoxy-11-hydroxynoraporphine.

Author

Sromek, Anna W., Zhang, Shaohui, Akurathi, Vamsidhar, Packard, Alan B., Li, Wei, Alagille, David, Morley, Thomas J., Baldwin, Ronald, Tamagnan, Gilles, and Neumeyer, John L.

Subjects
APORPHINE, DOPAMINE agonists, NEUROLOGICAL disorders, POSITRON emission tomography, FLUORINE isotopes
Abstract

Aporphines are attractive candidates for imaging D2 receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D2 antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D2 dysregulation, such as schizophrenia and Parkinson's disease. Accordingly, MCL-536 (R-(−)-N-n-propyl-2-(3-[18F]fluoropropanoxy-11-hydroxynoraporphine) was selected for labeling with 18F based on in vitro data obtained for the non-radioactive (19F) compound. Fluorine-18-labeled MCL-536 was synthesized in 70% radiochemical yield, >99% radiochemical purity, and specific activity of 167 GBq/µmol (4.5 Ci/µmol) using p-toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination. [ABSTRACT FROM AUTHOR]

Published
2014
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97. Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64Cu-SarAr immunoconjugates.

Author

Voss, Stephan D., Smith, Suzanne V., Dibartolo, Nadine, Mclntosh, Lacey J., Cyr, Erika M., Bonab, Ali A., Dearling, Jason L. J., Carter, Edward A., Fischman, Alan J., Treves, S. Ted, Gillies, Stephen D., Sargeson, Alan M., Huston, James S., and Packard, Alan B.

Subjects
POSITRON emission tomography, RADIOACTIVE tracers, DIAGNOSTIC imaging, POSITRON emission, ANTIBODY-toxin conjugates, NEUROBLASTOMA
Abstract

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18F-FDG. Copper-64 (64Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,1 9-hexaazabicyclo[6.6.6]- eicosane-1,8-diamine) for use in developing a new class of tumor- specific 64Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, chl4.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiola- beling with 64Cu resulted in >95% of the 64Cu being chelated by the immunoconjugate. Specific activities of at least 10 μCi/μg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after 64Cu labeling. Solid-phase radioimmuno- assays and intact cell-binding assays confirmed retention of bio- activity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15–20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5–10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xeno- graft was significantly lower (<5% injected dose per gram). Mi- croPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The 64Cu-SarAr-mAb system described here is potentially applicable to 64Cu-PET imaging with a broad range of antibody or peptide-based imaging agents. [ABSTRACT FROM AUTHOR]

Published
2007
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98. Fat fractions and spectral T2 values in vertebral bone marrow in HIV- and non-HIV-infected men: A 1H spectroscopic imaging study.

Author

Mulkern, Robert V., Huang, Jeannie, Vajapeyam, Sridhar, Packard, Alan B., Oshio, Koichi, and Grinspoon, Steven

Abstract

Fat fractions and spectral T2 values of fat and water within the vertebral marrow of non-HIV- and HIV-infected men were measured with the use of a Carr-Purcell-Meiboom-Gill (CPMG) line scan spectroscopic imaging sequence. The fat fraction for the HIV-infected men (0.29 ± 0.08) was significantly lower ( P < 0.05, Student's unpaired t-test) than the fat fraction found in non-HIV-infected men (0.40 ± 0.12). The mean water and fat T2 values did not differ between the two groups, and did not show any systematic dependence on fat fraction over the wide range of fat fractions encountered in this study. The marrow water and fat T2 values measured with the CPMG approach were markedly longer than the spectral T2 values reported by other groups using the more common point-resolved spectroscopy (PRESS) and stimulated-echo acquisition mode (STEAM) acquisitions. Proton spectroscopic studies of vertebral marrow revealed differences between non-HIV- and HIV-infected men that may prove useful for studying the effects of this disease and/or antiretroviral agents on body composition. Magn Reson Med 52:552-558, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Published
2004
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