Introduction The goal of this work is to advance the production and use of 52Mn (t½ = 5.6 d, β+: 242 keV, 29.6%) as a radioisotope for in vivo preclinical nuclear imaging. More specifically, the aims of this study were: (1) to measure the excitation function for the natCr(p,n)52Mn reaction at low energies to verify past results [1–4]; (2) to measure binding constants of Mn(II) to aid the design of a method for isolation of Mn from an irradiated Cr target via ion-exchange chromatography, building upon previously published methods [1,2,5–7]; and (3) to perform phantom imaging by positron emission tomography/magnetic resonance (PET/MR) imaging with 52Mn and non-radioactive Mn(II), since Mn has potential dual-modality benefits that are beginning to be investigated [8]. Material and Methods Thin foils of Cr metal are not available commercially, so we fabricated these in a manner similar to that reported by Tanaka and Furukawa [9]. natCr was electroplated onto Cu discs in an industrial-scale electroplating bath, and then the Cu backing was digested by nitric acid (HNO3). The remaining thin Cr discs (~1 cm diameter) were weighed to determine their thickness (~ 75–85 μm) and arranged into stacked foil targets, along with ~25 μm thick Cu monitor foils. These targets were bombarded with ~15 MeV protons for 1–2 min at ~1–2 μA from a CS-15 cyclotron (The Cyclotron Corporation, Berkeley, CA, USA). The beamline was perpendicular to the foils, which were held in a machined 6061-T6 aluminum alloy target holder. The target holder was mounted in a solid target station with front cooling by a jet of He gas and rear cooling by circulating chilled water (T ≈ 2–5 °C). Following bombardment, these targets were disassembled and the radioisotope products in each foil were counted using a high-purity Ge (HPGe) detector. Cross-sections were calculated for the natCr(p,n)52Mn reaction. Binding constants of Mn(II) were measured by incubating 54Mn(II) (t½ = 312 d) dichloride with anion- or cation-exchange resin (AG 1-X8 (Cl− form) or AG 50W-X8 (H+ form), respectively; both: 200–400 mesh; Bio-Rad, Hercules, CA) in hydrochloric acid (HCl) ranging from 10 mM-8 M (anion-exchange) and from 1 mM-1 M (cation-exchange) or in sulfuric acid (H2SO4) ranging from 10 mM-8 M on cation-exchange resin only. The amount of unbound 54Mn(II) was measured using a gamma counter, and binding constants (KD) were calculated for the various concentrations on both types of ion-exchange resin. We have used the unseparated product for preliminary PET and PET/MR imaging. natCr metal was bombarded and then digested in HCl, resulting in a solution of Cr(III)Cl3 and 52Mn(II)Cl2. This solution was diluted and imaged in a glass scintillation vial using a microPET (Siemens, Munich, Germany) small animal PET scanner. The signal was corrected for abundant cascade gamma-radiation from 52Mn that could cause random false coincidence events to be detected, and then the image was reconstructed by filtered back-projection. Additionally, we have used the digested target to spike non-radioactive Mn(II)Cl2 solutions for simultaneous PET/MR phantom imaging using a Biograph mMR (Siemens) clinical scanner. The phantom consisted of a 4×4 matrix of 15 mL conical tubes containing 10 mL each of 0, 0.5, 1.0, and 2.0 mM concentrations of non-radioactive Mn(II)Cl2 with 0, 7, 14, and 27 μCi (at start of PET acquisition) of 52Mn(II)Cl2 from the digested target added. The concentrations were based on previous MR studies that measured spin-lattice relaxation time (T1) versus concentration of Mn(II), and the activities were based on calculations for predicted count rate in the scanner. The PET/MR imaging consisted of a series of two-dimensional inversion-recovery turbo spin echo (2D-IR-TSE) MR sequences (TE = 12 ms; TR = 3,000 ms) with a wide range of inversion times (TI) from 23–2,930 ms with real-component acquisition, as well as a 30 min. list-mode PET acquisition that was reconstructed as one static frame by 3-D ordered subset expectation maximization (3D-OSEM). Attenuation correction was performed based on a two-point Dixon (2PD) MR sequence. The DICOM image files were loaded, co-registered, and windowed using the Inveon Research Workplace software (Siemens).

No description available.

Introduction Two current major research topics in nuclear medicine are in the development of long-lived positron-emitting nuclides for imaging tracers with long biological half-lives and in theranostics, imaging nuclides which have a chemically analogous therapy isotope. As shown in TABLE 1, the radioisotopes of arsenic (As) are well suited for both of these tasks with several imaging and therapy isotopes of a variety of biologically relevant half-lives accessible through the use of small medical cyclotrons. The five naturally abundant isotopes of germanium are both a boon and challenge for the medical nuclear chemist. They are beneficial in that they facilitate a wide array of producible radioarsenic isotopes. They are a challenge as monoisotopic radioarsenic production requires isotopically-enriched targets that are expensive and of limited availability. This makes it highly desirable that the germanium target material is reclaimed from arsenic isolation chemistry. One major factor which has limited the development of radioarsenic has been difficulties in its incorporation into biologically relevant targeting vectors. Previous studies have labeled antibodies and polymers through covalent bonding of arsenite (As(III)) with the sulfydryl group1,2,3. Recent work in our group has shown the facile synthesis and utility of superparamagnetic iron oxide nanoparticle- (SPION-)bound radioarsenic as a dual modality positron emission tomography (PET)/magnetic resonance imaging (MRI) agent4. Presently, we have built upon previous studies producing, isolating, and labeling untargeted SPION with radioarsenic4,5. We have incorp-rated the use of isotopically-enriched 72GeO2 for the production of radioisotopically pure 72As. The bulk of the 72GeO2 target material was re-claimed from the arsenic isolation chemical procedure for reuse in future irradiations. The 72As was used for ongoing development toward the synthesis of targeted, As-SPION-based, dual-modality PET/MRI agents. Material and Methods Targets of ~100 mg of isotopically-enriched 72GeO2 (96.6% 72Ge, 2.86% 73Ge, 0.35% 70Ge, 0.2% 74Ge, 0.01% 76Ge, Isoflex USA) were pressed into a niobium beam stop at 225 MPa, covered with a 25 µm HAVAR containment foil, attached to a water-cooling target port, and irradiated with 3 µA of 16.1 MeV protons for 2–3 hours using a GE PETtrace cyclotron. After irradiation, the target and beam stop were assembled into a PTFE dissolution apparatus, where the 72GeO2 target material was dissolved with the addition of 2 mL of 4 M NaOH and subsequent stirring. After dissolution was completed, the clear, colorless solution was transferred to a fritted glass column and the bulk 72GeO2 was reprecipitated by neutralizing the solution with the addition of 630 µL [HCl]conc, filtered, and rinsed with 1 mL [HCl]conc. To the combined 72As-containing filtrates, 100 µL 30% H2O2 was added to ensure that 72As was in the nonvolatile As(V) oxidation state. The ~3 mL solution was then evaporated at 115 ˚C while the vessel was purged with argon, followed by a second addition of 100 µL H2O2 after the volume was reduced to 1 mL. When the filtrate volume was ~0.3 mL, the vessel was removed from heat, allowed to cool with argon flow, and the arsenic reconstituted in 1 mL [HCl]conc and loaded onto a 1.5 mL bed volume Bio-Rad AG 1×8, 200–400 mesh anion exchange column preconditioned with 10 M HCl. The radioarsenic was eluted in 10 M HCl in the next ~10 mL, with 90% of the activity eluting in a 4 mL fraction. The column was then eluted with 5 mL 1 M HCl. The 72As-rich 10 M HCl fraction was reduced to As(III) with the addition of ~100 mg CuCl, and heating to 60 ˚C for 1 hour. The resulting AsCl3 was then extracted twice into 4 mL cyclohexane, which were combined and back extracted into 500 µL of water as As(OH)3. This solution of 72As in H2O was then used directly to label SPION and for subsequent experiments conjugating 72As-SPION with TRC105, an angiogenesis-marking monoclonal antibody (MAb) targeting endoglin/CD105. Several methods were initially attempted involving directly conjugating the surface-modified SPION to the MAb through a polyethylene glycol (PEG) linker. More recent studies have investigated the radioarsenic labeling of SPION encapsulated in hollow mesoporous silica nanoparticles (SPION@HMSN) and its subsequent conjugation to TRC105. Results and Conclusion Irradiation of pressed, isotopically-enriched 72GeO2 resulted in a production yield for 72As of 17 ± 2 mCi/(µA·hr·g) and for 71As of 0.37 ± 0.04 mCi/(µA·hr·g), which are 64 % and 33 %, of those predicted from literature6, respectively. However, these production yields are in agreement with those scaled from observed production yields using analagous natGeO2 targets. The end-of-bombardment 72As radionuclidic purity can be improved by minimizing the 72Ge(p,2n)71As reaction by degrading the beam energy. A 125 µm Nb containment foil would degrade impinging protons to 14.1 MeV and is predicted to reduce 71As yield by a factor of three, while only reducing 72As yield by 1 %6, improving end-of-bombardment radionuclidic purity from 98 % to greater than 99 %. Overall decay-corrected radiochemical yield of the 72As isolation procedure from 72GeO2 were 51 ± 2 % (n = 3) in agreement with those observed with natGeO2 57 ± 7 % (n = 14). The beam current was limited to 3 µA as higher cur-rents 4–5 µA exhibited inconsistent dissolution and reprecipitation steps, resulting in an overall yield of 44 ± 21 % (n = 6). Dissolution time also played an important role in overall yield with at least one hour necessary to minimize losses in these first two steps. The separation procedure effectively removed all radiochemical contaminants and resulted in 72As(OH)3 isolated in a small volume, pH~4.5 water solution. Over the course of minutes to hours after back extraction, rapid auto-oxidation to 72AsO4H3 was observed. The bulk 72GeO2 target material, which was reclaimed from the isolation procedure, is being collected for future use. The synthesis of a targeted PET/MRI agent based on the functionalization of 72As-SPION has proved to be a difficult task. Experiments conjugating 72As-SPION to TRC105 through a PEG linker were unsuccessful, despite the investigation of a variety bioconjugation procedures. Current work is investigating the use of SPION@HMSN, which have a similar affinity for 72As as unencapsulated SPION. This new class of 72As-labeled SPION@HMSN has a hollow cavity for potential anti-cancer drug loading, as well as the mesoporous silica surface, which may facilitate the efficient conjugation of TRC105 using a well-developed bioconjugation technique. In summary, radioarsenic holds potential in the field of diagnostic and therapeutic nuclear medicine. However, this potential remains locked behind challenges related to its production and useful in vivo targeting. The present work strives to address several of these challenges through the use of enriched 72GeO2 target material, a chemical isolation procedure that reclaims the bulk of the target material, and the investigation of new targeted nanoparticle-based PET/MRI agents.

Introduction The goal of this work is to advance the production and use of 52Mn (t½ = 5.6 d, β+: 242 keV, 29.6%) as a radioisotope for in vivo preclinical nuclear imaging. More specifically, the aims of this study were: (1) to measure the excitation function for the natCr(p,n)52Mn reaction at low energies to verify past results [1–4]; (2) to measure binding constants of Mn(II) to aid the design of a method for isolation of Mn from an irradiated Cr target via ion-exchange chromatography, building upon previously published methods [1,2,5–7]; and (3) to perform phantom imaging by positron emission tomography/magnetic resonance (PET/MR) imaging with 52Mn and non-radioactive Mn(II), since Mn has potential dual-modality benefits that are beginning to be investigated [8]. Material and Methods Thin foils of Cr metal are not available commercially, so we fabricated these in a manner similar to that reported by Tanaka and Furukawa [9]. natCr was electroplated onto Cu discs in an industrial-scale electroplating bath, and then the Cu backing was digested by nitric acid (HNO3). The remaining thin Cr discs (~1 cm diameter) were weighed to determine their thickness (~ 75–85 μm) and arranged into stacked foil targets, along with ~25 μm thick Cu monitor foils. These targets were bombarded with ~15 MeV protons for 1–2 min at ~1–2 μA from a CS-15 cyclotron (The Cyclotron Corporation, Berkeley, CA, USA). The beamline was perpendicular to the foils, which were held in a machined 6061-T6 aluminum alloy target holder. The target holder was mounted in a solid target station with front cooling by a jet of He gas and rear cooling by circulating chilled water (T ≈ 2–5 °C). Following bombardment, these targets were disassembled and the radioisotope products in each foil were counted using a high-purity Ge (HPGe) detector. Cross-sections were calculated for the natCr(p,n)52Mn reaction. Binding constants of Mn(II) were measured by incubating 54Mn(II) (t½ = 312 d) dichloride with anion- or cation-exchange resin (AG 1-X8 (Cl− form) or AG 50W-X8 (H+ form), respectively; both: 200–400 mesh; Bio-Rad, Hercules, CA) in hydrochloric acid (HCl) ranging from 10 mM-8 M (anion-exchange) and from 1 mM-1 M (cation-exchange) or in sulfuric acid (H2SO4) ranging from 10 mM-8 M on cation-exchange resin only. The amount of unbound 54Mn(II) was measured using a gamma counter, and binding constants (KD) were calculated for the various concentrations on both types of ion-exchange resin. We have used the unseparated product for preliminary PET and PET/MR imaging. natCr metal was bombarded and then digested in HCl, resulting in a solution of Cr(III)Cl3 and 52Mn(II)Cl2. This solution was diluted and imaged in a glass scintillation vial using a microPET (Siemens, Munich, Germany) small animal PET scanner. The signal was corrected for abundant cascade gamma-radiation from 52Mn that could cause random false coincidence events to be detected, and then the image was reconstructed by filtered back-projection. Additionally, we have used the digested target to spike non-radioactive Mn(II)Cl2 solutions for simultaneous PET/MR phantom imaging using a Biograph mMR (Siemens) clinical scanner. The phantom consisted of a 4×4 matrix of 15 mL conical tubes containing 10 mL each of 0, 0.5, 1.0, and 2.0 mM concentrations of non-radioactive Mn(II)Cl2 with 0, 7, 14, and 27 μCi (at start of PET acquisition) of 52Mn(II)Cl2 from the digested target added. The concentrations were based on previous MR studies that measured spin-lattice relaxation time (T1) versus concentration of Mn(II), and the activities were based on calculations for predicted count rate in the scanner. The PET/MR imaging consisted of a series of two-dimensional inversion-recovery turbo spin echo (2D-IR-TSE) MR sequences (TE = 12 ms; TR = 3,000 ms) with a wide range of inversion times (TI) from 23–2,930 ms with real-component acquisition, as well as a 30 min. list-mode PET acquisition that was reconstructed as one static frame by 3-D ordered subset expectation maximization (3D-OSEM). Attenuation correction was performed based on a two-point Dixon (2PD) MR sequence. The DICOM image files were loaded, co-registered, and windowed using the Inveon Research Workplace software (Siemens).

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20981号 / 医博第4327号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 増永 慎一郎, 教授 辻川 明孝, 教授 溝脇 尚志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction Two current major research topics in nuclear medicine are in the development of long-lived positron-emitting nuclides for imaging tracers with long biological half-lives and in theranostics, imaging nuclides which have a chemically analogous therapy isotope. As shown in TABLE 1, the radioisotopes of arsenic (As) are well suited for both of these tasks with several imaging and therapy isotopes of a variety of biologically relevant half-lives accessible through the use of small medical cyclotrons. The five naturally abundant isotopes of germanium are both a boon and challenge for the medical nuclear chemist. They are beneficial in that they facilitate a wide array of producible radioarsenic isotopes. They are a challenge as monoisotopic radioarsenic production requires isotopically-enriched targets that are expensive and of limited availability. This makes it highly desirable that the germanium target material is reclaimed from arsenic isolation chemistry. One major factor which has limited the development of radioarsenic has been difficulties in its incorporation into biologically relevant targeting vectors. Previous studies have labeled antibodies and polymers through covalent bonding of arsenite (As(III)) with the sulfydryl group1,2,3. Recent work in our group has shown the facile synthesis and utility of superparamagnetic iron oxide nanoparticle- (SPION-)bound radioarsenic as a dual modality positron emission tomography (PET)/magnetic resonance imaging (MRI) agent4. Presently, we have built upon previous studies producing, isolating, and labeling untargeted SPION with radioarsenic4,5. We have incorp-rated the use of isotopically-enriched 72GeO2 for the production of radioisotopically pure 72As. The bulk of the 72GeO2 target material was re-claimed from the arsenic isolation chemical procedure for reuse in future irradiations. The 72As was used for ongoing development toward the synthesis of targeted, As-SPION-based, dual-modality PET/MRI agents. Material and Methods Targets of ~100 mg of isotopically-enriched 72GeO2 (96.6% 72Ge, 2.86% 73Ge, 0.35% 70Ge, 0.2% 74Ge, 0.01% 76Ge, Isoflex USA) were pressed into a niobium beam stop at 225 MPa, covered with a 25 µm HAVAR containment foil, attached to a water-cooling target port, and irradiated with 3 µA of 16.1 MeV protons for 2–3 hours using a GE PETtrace cyclotron. After irradiation, the target and beam stop were assembled into a PTFE dissolution apparatus, where the 72GeO2 target material was dissolved with the addition of 2 mL of 4 M NaOH and subsequent stirring. After dissolution was completed, the clear, colorless solution was transferred to a fritted glass column and the bulk 72GeO2 was reprecipitated by neutralizing the solution with the addition of 630 µL [HCl]conc, filtered, and rinsed with 1 mL [HCl]conc. To the combined 72As-containing filtrates, 100 µL 30% H2O2 was added to ensure that 72As was in the nonvolatile As(V) oxidation state. The ~3 mL solution was then evaporated at 115 ˚C while the vessel was purged with argon, followed by a second addition of 100 µL H2O2 after the volume was reduced to 1 mL. When the filtrate volume was ~0.3 mL, the vessel was removed from heat, allowed to cool with argon flow, and the arsenic reconstituted in 1 mL [HCl]conc and loaded onto a 1.5 mL bed volume Bio-Rad AG 1×8, 200–400 mesh anion exchange column preconditioned with 10 M HCl. The radioarsenic was eluted in 10 M HCl in the next ~10 mL, with 90% of the activity eluting in a 4 mL fraction. The column was then eluted with 5 mL 1 M HCl. The 72As-rich 10 M HCl fraction was reduced to As(III) with the addition of ~100 mg CuCl, and heating to 60 ˚C for 1 hour. The resulting AsCl3 was then extracted twice into 4 mL cyclohexane, which were combined and back extracted into 500 µL of water as As(OH)3. This solution of 72As in H2O was then used directly to label SPION and for subsequent experiments conjugating 72As-SPION with TRC105, an angiogenesis-marking monoclonal antibody (MAb) targeting endoglin/CD105. Several methods were initially attempted involving directly conjugating the surface-modified SPION to the MAb through a polyethylene glycol (PEG) linker. More recent studies have investigated the radioarsenic labeling of SPION encapsulated in hollow mesoporous silica nanoparticles (SPION@HMSN) and its subsequent conjugation to TRC105. Results and Conclusion Irradiation of pressed, isotopically-enriched 72GeO2 resulted in a production yield for 72As of 17 ± 2 mCi/(µA·hr·g) and for 71As of 0.37 ± 0.04 mCi/(µA·hr·g), which are 64 % and 33 %, of those predicted from literature6, respectively. However, these production yields are in agreement with those scaled from observed production yields using analagous natGeO2 targets. The end-of-bombardment 72As radionuclidic purity can be improved by minimizing the 72Ge(p,2n)71As reaction by degrading the beam energy. A 125 µm Nb containment foil would degrade impinging protons to 14.1 MeV and is predicted to reduce 71As yield by a factor of three, while only reducing 72As yield by 1 %6, improving end-of-bombardment radionuclidic purity from 98 % to greater than 99 %. Overall decay-corrected radiochemical yield of the 72As isolation procedure from 72GeO2 were 51 ± 2 % (n = 3) in agreement with those observed with natGeO2 57 ± 7 % (n = 14). The beam current was limited to 3 µA as higher cur-rents 4–5 µA exhibited inconsistent dissolution and reprecipitation steps, resulting in an overall yield of 44 ± 21 % (n = 6). Dissolution time also played an important role in overall yield with at least one hour necessary to minimize losses in these first two steps. The separation procedure effectively removed all radiochemical contaminants and resulted in 72As(OH)3 isolated in a small volume, pH~4.5 water solution. Over the course of minutes to hours after back extraction, rapid auto-oxidation to 72AsO4H3 was observed. The bulk 72GeO2 target material, which was reclaimed from the isolation procedure, is being collected for future use. The synthesis of a targeted PET/MRI agent based on the functionalization of 72As-SPION has proved to be a difficult task. Experiments conjugating 72As-SPION to TRC105 through a PEG linker were unsuccessful, despite the investigation of a variety bioconjugation procedures. Current work is investigating the use of SPION@HMSN, which have a similar affinity for 72As as unencapsulated SPION. This new class of 72As-labeled SPION@HMSN has a hollow cavity for potential anti-cancer drug loading, as well as the mesoporous silica surface, which may facilitate the efficient conjugation of TRC105 using a well-developed bioconjugation technique. In summary, radioarsenic holds potential in the field of diagnostic and therapeutic nuclear medicine. However, this potential remains locked behind challenges related to its production and useful in vivo targeting. The present work strives to address several of these challenges through the use of enriched 72GeO2 target material, a chemical isolation procedure that reclaims the bulk of the target material, and the investigation of new targeted nanoparticle-based PET/MRI agents.

Background: The combination of positron emission tomography (PET) and magnetic resonance imaging (MRI) (PET-MRI) is a unique hybrid imaging modality mainly used in oncology and neurology. The MRI-based attenuation correction (MRAC) is crucial for correct quantification of PET data. A suitable phantom to validate quantitative results in PET-MRI is currently missing. In particular, the correction of attenuation due to bone is usually not verified by commonly available phantoms. The aim of this work was, thus, the development of such a phantom and to explore whether such a phantom might be used to validate MRACs. Method: Various materials were investigated for their attenuation and MR properties. For the substitution of bone, water-saturated gypsum plaster was used. The attenuation of 511 keV annihilation photons was regulated by addition of iodine. Adipose tissue was imitated by silicone and brain tissue by agarose gel, respectively. The practicability with respect to the comparison of MRACs was checked as follows: A small flask inserted into the phantom and a large spherical phantom (serving as a reference with negligible error in MRAC) were filled with the very same activity concentration. The activity concentration was measured and compared using clinical protocols on PET-MRI and different built-in and offline MRACs. The same measurements were carried out using PET-CT for comparison. Results: The phantom imitates the human head in sufficient detail. All tissue types including bone were detected as such so that the phantom-based comparison of the quantification accuracy of PET-MRI was possible. Quantitatively, the activity concentration in the brain, which was determined using different MRACs, showed a deviation of about 5% on average and a maximum deviation of 11% compared to the spherical phantom. For PET-CT, the deviation was 5%. Conclusions: The comparatively small error in quantification indicates that it is possible to construct a brain PET-MRI phantom that leads to MR-based attenuation-corrected images with reasonable accuracy.

Introduction: Cholinergic network modulation is carried out through the neurotransmitter acetylcholine (ACh) and expression of α4β2 nicotinic acetylcholine recetors (nAChRs) in central brain regions responsible for the detection of external sensory stimuli through thalamic and basal forebrain circuits but also within mesolimbic reward signaling. Alterations in α4β2 availability could therefore contribute to pathologically increased eating behavior leading to obesity. Investigations of task-related cholinergic neurotransmission in vivo in human obesity comparing baseline versus stimulus conditions have yet to be established. Objective: Aim of this exploratory study was to investigate the neurobiological mechanisms of cholinergic signaling and its ramifications on eating behavior to possibly identify α4β2 as a pharmacological target in obesity therapy approaches. Primary outcome measure was the distribution volume calculated from PET data by VOI-based analyses. We compared α4β2 nAChR availability in OB (participants with obesity) with NW (normal weight participants) under baseline and stimulus conditions. Secondary, we explored whether changes in eating behavior measured by VAS (visual analogue scores) are correlated with changes in α4β2 nAChR availability. We also hypothesized that this relationship differs between resting state and stimulus conditions in both NW as well as OB. Materials and Methods: Study population consisted of 16 study participants with OB (N=16; mean BMI 37.8±3.18 kg/m2; 10 females; mean age 40.6±14.0; range from 20-62 years) and 14 NW (N=14; mean BMI 21.8±1.90 kg/m2; 11 females; mean age 28.1±7.58; range from 19-45 years), all mentally healthy and non-smokers. Every participant underwent simultaneous PET-MR imaging (mMR Siemens) under baseline and stimulus conditions, applying a standard set of salient food items. Calculations of VT was based on the bolus-infusion protocol. This includes investigation of VT as the ratio between mean (-)-[18F]flubatine in brain tissue and mean plasma (-)-[18F]flubatine in venous blood samples at 120 until 165 minutes post injection. During each visit VAS data were obtained. Results: No significant group differences in VT between NW and OB under baseline conditions were found, while OB showed a trend towards lower VT in the Nucleus basalis of Meynert (NBM; NW: mean VT= 11.6; OB: mean VT=10.2; mean difference= 1.35; p= 0.119). Under stimulus conditions, OB demonstrate higher thalamic VT (Thalamus; NW: mean VT= 25.1; OB: mean VT= 28.8; mean difference: -3.63; p= 0.028). Additionally, OB showed a tendency to greater VT mean differences between resting state and stimulus conditions compared with NW. Correlational analyses revealed statistically significant positive correlation (r= 0.61) between HPT and VAS “satiety” in NW and a significant negative correlation (r= -0.59) between NAc and VAS “disinhibition” in OB. Conclusion: These first in-human data suggest substantial changes in cholinergic signaling in brain circuits that process external sensory stimuli with high-incentive properties such as visual food cues in obesity. If confirmed in an extended population with larger sample size and including seed-based fMR imaging investigations, the α4β2 nAChR represent a promising target for pharmacological intervention as a non-invasive alternative to surgical procedures to combat the obesity epidemic.:2. Table of Contents 2. TABLE OF CONTENTS 2 3. ABBREVIATIONS 2 LIST OF FIGURES 4 LIST OF TABLES 6 4. INTRODUCTION 6 4.1 OBESITY AND THE CENTRAL CHOLINERGIC SYSTEM 7 4.2 CHOLINERGIC NEUROTRANSMISSION 9 4.3 STRUCTURE AND RECEPTOR KINETICS OF NACHR 11 4.4 TOPOGRAPHY OF CENTRAL NACHR 13 4.5 CHOLINERGIC NEUROMODULATION 15 4.5.1 Cholinergic Neuromodulation and Cognitive Processes 16 4.5.2 Cholinergic Neuromodulation and Reward 19 4.5.3 Cholinergic Neuromodulation and Eating Behavior 21 4.6. POSITRON EMISSION TOMOGRAPHY (PET) AS A MOLECULAR IMAGING TECHNIQUE FOR MEASURING NACHR IN VIVO 23 4.6.1 PET Imaging 23 4.6.2 Imaging of α4β2 Nicotinic Acetylcholine Receptors 23 4.6.3 (-)-[18F]flubatine: a specific α4β2 nAChR radiotracer 25 4.7 VOLUMES OF INTEREST (VOI) 33 5. OBJECTIVE 34 6. MATERIALS AND METHODS 35 6.1 ETHICS STATEMENT 35 6.2 STUDY DESIGN 35 6.3 STUDY PARTICIPANTS 36 6.4 VISUAL ANALOGUE SCALE (VAS) 38 6.5 PET/MR IMAGING 39 6.6 IMAGING DATA AND BLOOD PLASMA ANALYSIS 43 6.7 STATISTICAL ANALYSIS 45 7. RESULTS 46 7.1 EPIDEMIOLOGICAL DATA 46 7.2 BASELINE AND STIMULUS VT CALCULATIONS 47 7.3 INTRA-INDIVIDUAL VT ASSESSMENT BETWEEN BASELINE AND STIMULUS CONDITIONS 53 7.4 CORRELATIONAL ANALYSES OF VAS VERSUS VT 57 8. DISCUSSION 63 9. SUMMARY 70 10. REFERENCES 72 11. ANLAGEN 81

Erst seit 2010 sind kombinierte Positronenemissionstomographie- Magnetresonanztomographie-Geräte (PET/MRT) zur hybriden Bildgebung verfügbar. Die mit der Entwicklung der Geräte verbundenen Hoffnungen bezüglich der onkologischen Diagnostik lagen zunächst auf einer verbesserten Genauigkeit in der Tumordetektion im Vergleich zur PET/CT. Rasch wurde jedoch deutlich, dass insbesondere die Möglichkeit der non-invasiven, multiparametrischen Charakterisierung von Tumorerkrankungen einen wesentlichen Vorteil der PET/MRT gegenüber der PET/CT darstellt. Der im Universitätsklinikum Leipzig AöR 2011 installierte PET/MRT-Scanner war einer der ersten weltweit und in dieser Habilitationsschrift sind die ersten Erfahrungen mit dieser Methode auf dem Gebiet der onkologischen Diagnostik zusammengefasst. Schwerpunkt ist dabei die Diagnostik von Kopf-Hals-Tumoren, da in diesem Bereich die CT aufgrund des im Vergleich zur MRT schlechteren Weichteilkontrastes Einschränkungen aufweist. In dieser Schrift werden zunächst die unterschiedlichen Konzepte im Gerätedesign der PET/MRT und die Besonderheiten der PET/MRT im Vergleich zur PET/CT erläutert. Auch die kritischen Punkte, die bei der Implementierung eines PET/MRT-Scanners zu beachten sind, werden detailliert dargestellt. Hierbei werden besonders die baulichen und organisatorischen Aspekte berücksichtigt, es werden aber auch Hinweise zur Qualitätskontrolle und zur Entwicklung von Untersuchungsprotokollen gegeben. In der ersten klinischen Studie zur Anwendung der PET/MRT mit 18F-Fluorodesoxyglucose (18F-FDG) bei Patienten mit Kopf-Hals-Tumoren konnten wir hinsichtlich Sensitivität und Spezifität noch keine Unterschiede zur PET/CT nachweisen. Allerdings war hier die untersuchte Patientengruppe heterogen und enthielt sowohl Primär- als auch Rezidivtumore. Aktuell konzentriert sich die onkologische Forschung am PET/MRT auf die Möglichkeiten der multiparametrischen Bildgebung zur Detektion und vor allem Charakterisierung von Tumorerkrankungen. Hier konnten wir signifikante Korrelationen von Glukosestoffwechsel und verschiedenen Perfusionsparametern bei Patienten mit Kopf-Hals-Tumoren nachweisen. Bei Patientinnen mit Zervixkarzinom konnte ein inverser Zusammenhang zwischen Glukosestoffwechsel und Diffusionsrestriktion nachgewiesen werden. Die letzte aufgeführte Arbeit zeigt die Korrelationen zwischen der bildgebenden Tumorcharakterisierung und histopathologischen Ergebnissen bei Kopf-Hals-Tumoren, wo wir Zusammenhänge von Kernfläche und dem Proliferationsmarker Ki-67 mit Diffusionseigenschaften bzw. Glukosestoffwechsel im Tumorgewebe nachweisen konnten.:Inhalt 1. Einführung in die Thematik 1.1. Entwicklung der hybriden Bildgebung 1.2. Technische Konzepte zur Kombination von PET und MRT 1.2.1. Separate Geräte – räumlich getrennt 1.2.2. Separate Geräte - in einem Raum kombiniert 1.2.3. Integrierte Geräte 1.3. Schwächungskorrektur 1.4. Einsatzgebiete 1.5. Untersuchungsprotokoll am PET/MRT 1.5.1. Allgemeine Überlegungen zum Untersuchungsablauf 1.5.2. MRT-Sequenzen 1.5.3. PET-Tracer 1.6. Eigene Studien 2. Originalarbeiten 2.1. Physikalische und organisatorische Maßnahmen für Installation, regulatorische Anforderungen und Implementierung eines simultanen hybriden PET/MR-Bildgebungssystems in Forschung und klinischer Versorgung 2.2. Ergebnisse der simultanen 18F-FDG PET/MRT im Vergleich zur 18F-FDG PET/CT bei Patienten mit Kopf-Hals-Tumoren 2.3. In vivo Korrelation von Glukosemetabolismus, Zelldichte und mikrozirkulatorischen Parametern bei Patienten mit Kopf-Hals-Tumoren: erste Ergebnisse von Untersuchungen mittels simultaner PET/MRT 2.4. Simultane 18F-FDG PET/MRT: Korrelation von scheinbarem Diffusionskoeffizient (ADC) und standardisiertem Aufnahmewert (SUV) beim primären und rezidivierten Zervixkarzinom 2.5. Simultane 18F-FDG PET/MRT: Assoziationen zwischen Diffusion, Glukosemetabolismus und histopathologischen Parametern bei Patienten mit Plattenepithelkarzinomen der Kopf-Hals- Region 3. Ausblick mit Übersichtsartikel „Molekulare Bildgebung bei Kopf-Hals-Tumoren“ 4. Literaturverzeichnis 5. Erklärung über die eigenständige Anfertigung der Arbeit und Kenntlichmachung der benutzten Hilfsmittel bzw. Hilfen 6. Lebenslauf 7. Danksagung

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