Cardiac Chemical Exchange Saturation Transfer MR Imaging Tracking of Cell Survival or Rejection in Mouse Models of Cell Therapy

Purpose: To examine whether cardiac chemical exchange saturation transfer (CEST) imaging can be serially and noninvasively used to probe cell survival or rejection after intramyocardial implantation in mice. Materials and Methods: Experiments were compliant with the National Institutes of Health Guidelines on the Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee. One million C2C12 cells labeled with either europium (Eu) 10-(2-hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid (HP-DO3A) or saline via the hypotonic swelling technique were implanted into the anterior-lateral left ventricular wall in C57BL/6J (allogeneic model, n = 17) and C3H (syngeneic model, n = 13) mice. Imaging (frequency offsets of ±15 parts per million) was performed 1, 10, and 20 days after implantation, with the asymmetrical magnetization transfer ratio (MTRasym) calculated from image pairs. Histologic examination was performed at the conclusion of imaging. Changes in MTRasym over time and between mice were assessed by using two-way repeated-measures analysis of variance. Results: MTRasym was significantly higher in C3H and C57BL/6J mice in grafts of Eu-HP-DO3A–labeled cells (40.2% ± 5.0 vs 37.8% ± 7.0, respectively) compared with surrounding tissue (−0.67% ± 1.7 vs −1.8% ± 5.3, respectively; P \u3c .001) and saline-labeled grafts (−0.4% ± 6.0 vs −1.2% ± 3.6, respectively; P \u3c .001) at day 1. In C3H mice, MTRasym remained increased (31.3% ± 9.2 on day 10, 28.7% ± 5.2 on day 20; P \u3c .001 vs septum) in areas of in Eu-HP-DO3A–labeled cell grafts. In C57BL/6J mice, corresponding MTRasym values (11.3% ± 8.1 on day 10, 5.1% ± 9.4 on day 20; P \u3c .001 vs day 1) were similar to surrounding myocardium by day 20 (P = .409). Histologic findings confirmed cell rejection in C57BL/6J mice. Estimation of graft area was similar with cardiac CEST imaging and histologic examination (R2 = 0.89). Conclusion: Cardiac CEST imaging can be used to image cell survival and rejection in preclinical models of cell therapy

Transition Metal-Catalyzed Intramolecular C-H Amination Reactions and Applications in Drug Discovery

This thesis describes the development of methodology towards the formation of complex N-heterocycles via transition metal-mediated C-H amination of aryl azides. These novel reactions lead to the formation of α-, β-, γ-, and δ-carbolinium ions and the corresponding carbolines. These complex heterocylces are then used in the synthesis of new antischistosomal and pulmonary arterial hypertension therapeutic targets. Assay development is also carried out to test the potency of these novel inhibitors

Cardiac Chemical Exchange Saturation Transfer MR Imaging Tracking of Cell Survival or Rejection in Mouse Models of Cell Therapy

PURPOSE: To examine whether cardiac chemical exchange saturation transfer (CEST) imaging can be serially and noninvasively used to probe cell survival or rejection after intramyocardial implantation in mice. MATERIALS AND METHODS: Experiments were compliant with the National Institutes of Health Guidelines on the Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee. One million C2C12 cells labeled with either europium (Eu) 10-(2-hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid (HP-DO3A) or saline via the hypotonic swelling technique were implanted into the anterior-lateral left ventricular wall in C57BL/6J (allogeneic model, n = 17) and C3H (syngeneic model, n = 13) mice. Imaging (frequency offsets of ±15 parts per million) was performed 1, 10, and 20 days after implantation, with the asymmetrical magnetization transfer ratio (MTR(asym)) calculated from image pairs. Histologic examination was performed at the conclusion of imaging. Changes in MTR(asym) over time and between mice were assessed by using two-way repeated-measures analysis of variance. RESULTS: MTR(asym) was significantly higher in C3H and C57BL/6J mice in grafts of Eu-HP-DO3A–labeled cells (40.2% ± 5.0 vs 37.8% ± 7.0, respectively) compared with surrounding tissue (−0.67% ± 1.7 vs −1.8% ± 5.3, respectively; P < .001) and saline-labeled grafts (−0.4% ± 6.0 vs −1.2% ± 3.6, respectively; P < .001) at day 1. In C3H mice, MTR(asym) remained increased (31.3% ± 9.2 on day 10, 28.7% ± 5.2 on day 20; P < .001 vs septum) in areas of in Eu-HP-DO3A–labeled cell grafts. In C57BL/6J mice, corresponding MTR(asym) values (11.3% ± 8.1 on day 10, 5.1% ± 9.4 on day 20; P < .001 vs day 1) were similar to surrounding myocardium by day 20 (P = .409). Histologic findings confirmed cell rejection in C57BL/6J mice. Estimation of graft area was similar with cardiac CEST imaging and histologic examination (R(2) = 0.89). CONCLUSION: Cardiac CEST imaging can be used to image cell survival and rejection in preclinical models of cell therapy. (©) RSNA, 2016 Online supplemental material is available for this article