Increased 18F-FDG uptake is predictive of rupture in a novel rat abdominal aortic aneurysm rupture model.

OBJECTIVE: To determine whether F-fluorodeoxyglucose (F-FDG) micro-positron emission tomography (micro-PET) can predict abdominal aortic aneurysm (AAA) rupture. BACKGROUND: An infrarenal AAA model is needed to study inflammatory mechanisms that drive rupture. F-FDG PET can detect vascular inflammation in animal models and patients. METHODS: After exposing Sprague-Dawley rats to intra-aortic porcine pancreatic elastase (PPE) (12 U/mL), AAA rupture was induced by daily, subcutaneous, ß-aminopropionitrile (BAPN, 300 mg/kg, N = 24) administration. Negative control AAA animals (N = 15) underwent daily saline subcutaneous injection after PPE exposure. BAPN-exposed animals that did not rupture served as positive controls [nonruptured AAA (NRAAA) 14d, N = 9]. Rupture was witnessed using radiotelemetry. Maximum standard uptakes for F-FDG micro-PET studies were determined. Aortic wall PAI-1, uPA, and tPA concentrations were determined by western blot analyses. Interleukin (IL)-1ß, IL-6, IL-10, and MIP-2 were determined by Bio-Plex bead array. Neutrophil and macrophage populations per high-power field were quantified. Matrix metalloproteinase (MMP) activities were determined by zymography. RESULTS: When comparing ruptured AAA (RAAA) to NRAAA 14d animals, increased focal F-FDG uptakes were detected at subsequent sites of rupture (P = 0.03). PAI-1 expression was significantly less in RAAA tissue (P = 0.01), with comparable uPA and decreased tPA levels (P = 0.02). IL-1ß (P = 0.04), IL-6 (P = 0.001), IL-10 (P = 0.04), and MIP-2 (P = 0.02) expression, neutrophil (P = 0.02) and macrophage presence (P = 0.002), and MMP9 (P < 0.0001) activity were increased in RAAA tissue. CONCLUSIONS: With this AAA rupture model, increased prerupture F-FDG uptake on micro-PET imaging was associated with increased inflammation in the ruptured AAA wall. F-FDG PET imaging may be used to monitor inflammatory changes before AAA rupture.

Synthesis of 68Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced 68Ga as exemplified by [68Ga]Ga-PSMA-11 for prostate cancer PET imaging.

[68Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [68Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g., [177Lu]Lu-PSMA-617, [225Ac]Ac-PSMA-617) and large prostate cancer patient volumes requiring access are poised to create an unprecedented demand for [68Ga]Ga-PSMA-11 in nuclear medicine clinics around the world. Meeting this global demand is going to require a variety of synthesis methods compatible with 68Ga eluted from a generator or produced on a cyclotron. To address this urgent need in the PET radiochemistry community, herein we report detailed protocols for the synthesis of [68Ga]Ga-PSMA-11, (also known as HBED-CC, Glu-urea-Lys(Ahx)-HBED-CC and PSMA-HBED-CC) using both generator-eluted and cyclotron-produced 68Ga and contrast the pros and cons of each method. The radiosyntheses are automated and have been validated for human use at two sites (University of Michigan (UM), United States; Royal Prince Alfred Hospital (RPA), Australia) and used to produce [68Ga]Ga-PSMA-11 for patient use in good activity yields (single generator, 0.52 GBq (14 mCi); dual generators, 1.04-1.57 GBq (28-42 mCi); cyclotron method (single target), 1.47-1.89 GBq (40-51 mCi); cyclotron method (dual target), 3.63 GBq (98 mCi)) and high radiochemical purity (99%) (UM, n = 645; RPA, n > 600). Both methods are appropriate for clinical production but, in the long term, the method employing cyclotron-produced 68Ga is the most promising for meeting high patient volumes. Quality control testing (visual inspection, pH, radiochemical purity and identity, radionuclidic purity and identity, sterile filter integrity, bacterial endotoxin content, sterility, stability) confirmed doses are suitable for clinical use, and there is no difference in clinical prostate cancer PET imaging using [68Ga]Ga-PSMA-11 prepared using the two production methods.

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target.

PURPOSE: To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module. METHODS: Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2-0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50-75 min) and beam currents (27-40 µA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use. RESULTS: The decay corrected yield of 68Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia (< 2% combined 66/67Ga) for a practical clinical product shelf-life. The activity yield of [68Ga]GaCl3 was typically > 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA). CONCLUSION: Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.

Registration methodology for histological sections and in vivo imaging of human prostate.

RATIONALE AND OBJECTIVES: Registration enables quantitative spatial correlation of features from different imaging modalities. Our objective is to register in vivo imaging with histologic sections of the human prostate so that histologic truth can be correlated with in vivo imaging features. MATERIALS AND METHODS: In vivo imaging of the prostate included T2-weighted anatomic and diffusion weighted 3-T magnetic resonance imaging (MRI) as well as 11C-choline positron emission tomography (PET). In addition, ex vivo 3-T MRI of the prostate specimen, histology, and associated block face photos of the prostate specimen were obtained. A standard registration method based on mutual information (MI) and thin-plate spline (TPS) was applied. Registration among in vivo imaging modalities is well established; however, accurate registration involving histology is difficult. Our approach breaks up the difficult direct registration of histology and in vivo imaging into achievable subregistration tasks involving intermediate ex vivo modalities like block face photography and specimen MRI. Results of subregistration tasks are combined to compute the intended, final registration between in vivo imaging and histology. RESULTS: The methodology was applied to two patients and found to be clinically feasible. Overall registered anatomic MRI, diffusion MRI, and 11C-choline PET aligned well with histology qualitatively for both patients. There is no ground truth of registration accuracy as the scans are real patient scans. An indirect validation of the registration accuracy has been proposed comparing tumor boundary markings found in diffusion MRI and histologic sections. Registration errors for two patients between diffusion MRI and histology were 3.74 and 2.26 mm. CONCLUSION: This proof of concept paper demonstrates a method based on intrinsic image information content for successfully registering in vivo imaging of the human prostate with its post-resection histology, which does not require the use of extrinsic fiducial markers. The methodology successfully mapped histology onto the in vivo imaging space, allowing the observation of how well different in vivo imaging features correspond to histologic truth. The methodology is therefore the basis for a systematic comparison of in vivo imaging for staging of human prostate cancer.

High-Yielding Automated Convergent Synthesis of No-Carrier-Added [11C-Carbonyl]-Labeled Amino Acids Using the Strecker Reaction.

A new variant of the Strecker synthesis using no-carrier-added [11C]cyanide for the synthesis of radiolabeled amino acids is described. The protocol is fully automated using a radiochemistry synthesis module and applied to the production of a number of new PET radiotracers. [11C-Carbonyl]sarcosine, [11C-carbonyl]methionine, [11C-carbonyl]-N-phenylglycine, and [11C-carbonyl]glycine are all synthesized in moderate to good radiochemical yields. The synthesis of [11C-carbonyl]sarcosine has been validated for production of doses for clinical use, and preliminary evaluation of the new radiotracer in PC3 tumor-bearing mice is also reported.

Assessment of the biodistribution of an [(18) F]FDG-loaded perfluorocarbon double emulsion using dynamic micro-PET in rats.

Perfluorocarbon (PFC) double emulsions loaded with a water-soluble, therapeutic agent can be triggered by ultrasound in a process known as acoustic droplet vaporization. Elucidating the stability and biodistribution of these sonosensitive vehicles and encapsulated agents is critical in developing targeted drug delivery strategies using ultrasound. [(18) F]fluorodeoxyglucose (FDG) was encapsulated in a PFC double emulsion and the in vitro diffusion of FDG was assessed using a Franz diffusion cell. Using dynamic micro-positron emission tomography and direct tissue sampling, the biodistribution of FDG administered as a solution (i.e. non-emulsified) or as an emulsion was studied in Fisher 344 rats (n = 6) bearing subcutaneous 9L gliosarcoma. Standardized uptake values (SUVs) and area under the curve of the SUV (AUCSUV ) of FDG were calculated for various tissues. The FDG flux from the emulsion decreased by up to a factor of 6.9 compared with the FDG solution. FDG uptake, calculated from the AUCSUV , decreased by 36% and 44% for brain and tumor, respectively, when comparing FDG solution vs FDG emulsion (p < 0.01). Decreases in AUCSUV in highly metabolic tissues such as brain and tumor demonstrated retention of FDG within the double emulsion. No statistically significant differences in lung AUCSUV were observed, suggesting minimal accumulation of the emulsion in the pulmonary capillary bed. The liver AUCSUV increased by 356% for the FDG emulsion, thus indicating significant hepatic retention of the emulsion.

Imaging of carrageenan-induced local inflammation and adjuvant-induced systemic arthritis with [(11)C]PBR28 PET.

INTRODUCTION: [(11)C] PBR28 binding to translocator protein (TSPO) was evaluated for imaging of acute and chronic inflammation using two established rat models. METHODS: Acute inflammation was induced by local carrageenan injection into the paw of Fisher 344 rats (model A). T-cell mediated adjuvant arthritis was induced by heat-inactivated Mycobacterium butyricum injection in Lewis rats (model B). Micro-PET scan was performed after injection of approximately 35 MBq [(11)C]PBR28. In model A, volumes of interest (VOIs) were defined in the paw of Fisher 344 rats (n=6) with contralateral sham treatment as control. For model B, VOIs were defined in the tail, sacroiliac joints, hips, knees and thigh muscles of M. butyricum treated animals (n=8) and compared with sham-treated controls (n=4). The peak (11)C-PBR28 SUV (SUVpeak) and area under the curve (AUCSUV) of 60-minute time-activity data were calculated. Immunohistochemistry for CD68, a macrophage stain, was performed from paw tissues. In addition, the [(11)C]PBR28 cell uptake was measured in lipopolysaccharide (LPS)-stimulated and non-stimulated macrophage cultures. RESULTS: LPS-stimulated macrophages displayed dose-dependent increased [(11)C]PBR28 uptake, which was blocked by non-labeled PBR28. In both models, radiotracer uptake of treated lesions increased rapidly within minutes and displayed overall accumulative kinetics. The SUVpeak and AUCSUV of carrageenan-treated paws was significantly increased compared to controls. Also, the [(11)C]PBR28 uptake ratio of carrageenan-treated vs. sham-treated paw correlated significantly with CD68 staining ratios of the same animals. In adjuvant arthritis, significantly increased [(11)C]PBR28 SUVpeak and AUCSUV values were identified at the tail, knees, and sacroiliac joints, while no significant differences were identified in the lumbar spine and hips. CONCLUSIONS: Based on our initial data, [(11)C]PBR28 PET appears to have potential for imaging of various inflammatory processes involving macrophage activation.