Regional cerebral blood flow (CBF), oxygen extraction ratio (OER), oxygen utilization (CMRO2) and blood volume (CBV) were measured in a group of 34 healthy volunteers (age range 22-82 yrs) using the 15O steady-state inhalation method and positron emission tomography. Between subjects CBF correlated positively with CMRO2, although the interindividual variability of the measured values was large. OER was not dependent on CMRO2, but highly negatively correlated with CBF. CBV correlated positively with CBF. When considering the values of all the regions of interest within a single subject, a strict coupling between CMRO2 and CBF, and between CBF and CBV was found, while OER was constant and independent of CBF and CMRO2. In 'pure' grey and white matter regions CMRO2, CBF and CBV decreased with age approximately 0.50% per year. In other regions the decline was less evident, most likely due to partial volume effects. OER did not change or showed a slight increase with age (maximum in the grey matter region 0.35%/yr). The results suggest diminished neuronal firing or decreased dendritic synaptic density with age.

The integrin a v b 3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18 F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. Methods: The biodistribution of 18 F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18 F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. Results: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18 F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18 F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P 5 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. Conclusion: 18 F-AH111585 designed to bind the a v b 3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.

We investigated whether PET/CT angiography using 11 C-(R)-PK11195, a selective ligand for the translocator protein (18 kDa) expressed in activated macrophages, could allow imaging and quantification of arterial wall inflammation in patients with large-vessel vasculitis. Methods: Seven patients with systemic inflammatory disorders (3 symptomatic patients with clinical suspicion of active vasculitis and 4 asymptomatic patients) underwent PET with 11 C-(R)-PK11195 and CT angiography to colocalize arterial wall uptake of 11 C-(R)-PK11195. Tissue regions of interest were defined in bone marrow, lung parenchyma, wall of the ascending aorta, aortic arch, and descending aorta. Blood-derived and image-derived input functions (IFs) were generated. A reversible 1-tissue compartment with 2 kinetic rate constants and a fractional blood volume term were used to fit the time-activity curves to calculate total volume of distribution (V T ). The correlation between V T and standardized uptake values was assessed. Results: V T was significantly higher in symptomatic than in asymptomatic patients using both image-derived total plasma IF (0.55 6 0.15 vs. 0.27 6 0.12, P 5 0.009) and image-derived parent plasma IF (1.40 6 0.50 vs. 0.58 6 0.25, P 5 0.018). A good correlation was observed between V T and standardized uptake value (R 5 0.79; P 5 0.03). Conclusion: 11 C-(R)-PK11195 imaging allows visualization of macrophage infiltration in inflamed arterial walls. Tracer uptake can be quantified with image-derived IF without the need for metabolite corrections and evaluated semiquantitatively with standardized uptake values.

The 'EXACT3D' positron tomograph, which is now in routine clinical research use, was developed with the aim of achieving unprecedented sensitivity, high spatial and temporal resolution and simplicity of design using proven detector technology. It consists of six rings of standard detector blocks (CTI/Siemens EXACT HR+) with 4.39 mm x 4.05 mm x 30 mm elements, giving an axial field of view (FOV) of 23.4 cm. This extended FOV and the absence of interplane septa and retractable transmission rod sources has allowed greatly simplified gantry and detector cassette design. Operation in exclusive 3D mode requires an alternative to the conventional coincidence method for transmission scanning, and a single photon approach using a hydraulically driven 137Cs point source has been implemented. The tomograph has no other moving parts. A single time frame of data without any compression is very large (> 300 Mbyte) and two approaches are employed to overcome this difficulty: (a) adjacent sinograms can be summed automatically into different combinations and (b) listmode (event-by-event) acquisition has been instituted, which is both storage efficient (particularly for acquisition of sparse data sets) and maximizes temporal resolution. The high-speed I/O and computing hardware can maintain a sustained acquisition rate of about 4 million coincidence events per second. A disadvantage of the large axial FOV in 3D is the increased sensitivity to activity outside the coincidence FOV. However, this can be minimized by additional side shielding. The mean spatial resolution is 4.8 +/- 0.2 mm FWHM (transaxial, 1 cm off-axis) and 5.6 +/- 0.5 mm (axial, on-axis). Its absolute efficiency is 5.8% for a line source in air (just spanning the axial FOV) and 10% for a central point source (with thresholds of 350-650 keV). For a uniform 20 cm diameter cylinder, the efficiency is 69 kcps kBq(-1) ml(-1) (after subtraction of a scatter fraction of 42%). Sensitivity relative to the EXACT HR+ (with four rings of blocks) is 2.5 (3D) and 12 (2D) times respectively. The rate of random events in blood flow studies in the brain and body, using 15O-labelled water, can be controlled by limiting the administered dose and inserting additional side shielding.

A small diameter positron emission tomography, designed specifically for small animal studies, was constructed from existing, commercially available, bismuth germanate (BGO) detectors and electronics. The scanner consists of 16 BGO detector blocks arranged to give a tomograph with a diameter of 115 mm and an axial field of view (FOV) of 50 mm. Each block is cut to produce eight (axial) by seven (radial) individual detector elements. The absence of interplane septa enables the acquisition of 3D data sets consisting of 64 sinograms. A 2D data set of 15 sinograms, consisting of eight direct and seven adjacent cross planes, can be extracted from the 3D data set. Images are reconstructed from the 2D sinograms using a conventional filtered backprojection algorithm. Two methods of normalization were investigated, based on either a rotating 68Ge rod source, or a uniform 68Ge plane source, with a uniform cylindrical 18F phantom. Attenuation of the emitted photons was estimated using a rotating 68Ge rod source. The transaxial resolution of the tomograph was measured as 2.3 mm full width at half maximum (FWHM) and 5.6 mm full width at tenth maximum (FWTM) at the centre of the FOV, degrading to 6.6 mm (radial) and 4.4 mm (tangential) FWHM and 10.4 mm (radial) and 14.4 mm (tangential) FWTM at 40.0 mm from the centre of the FOV. The axial slice width was 4.3 mm FWHM, 10.3 mm FWTM at the centre of the transaxial field of view and 4.4 mm FWHM, 10.6 mm FWTM at 20.0 mm from the centre of the FOV. A scatter fraction of 31.0% was measured at 250-850 keV, for an 18F line source centred in a 60 mm diameter, water-filled phantom, reducing to 20.4% and 13.8% as the lower energy discrimination was increased to 380 keV and 450 keV, respectively. The count rate performance was measured using a noise equivalent count rate method, and the linearity of the dead time correction was confirmed over the count rates encountered during routine scanning. In 2D mode, the absolute sensitivity of the tomograph was measured as 9948 counts s-1 MBq-1 at 250-850 keV, 8284 counts s-1 MBq-1 at 380-850 keV and 6280 counts s-1 MBq-1 at 450-850 keV.

We report the safety, biodistribution, and internal radiation dosimetry of a new PET tracer, 18 F-AH111585, a peptide with a high affinity for the a v b 3 integrin receptor involved in angiogenesis. Methods: PET scans of 8 healthy volunteers were acquired at time points up to 4 h after a bolus injection of 18 F-AH111585. 18 F activity in whole blood and plasma and excreted urine were measured up to 4 h after injection. In vivo 18 F activities in up to 12 source regions were determined from quantitative analysis of the images. The cumulated activities subsequently calculated were then used to determine the internal radiation dosimetry, including the effective dose. Results: Injection of 18 F-AH111585 was well tolerated in all subjects, with no serious or drug-related adverse events reported. The main route of 18 F excretion was renal (37%), and the 3 highest initial uptakes were by liver (15%); combined walls of the small, upper large, and lower large intestines (11%); and kidneys (9%). The 3 highest absorbed doses were received by the urinary bladder wall (124 mGy/MBq), kidneys (102 mGy/MBq), and cardiac wall (59 mGy/MBq). The effective dose was 26 mGy/MBq. Conclusion: 18 F-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common 18 F PET tracers. Int egrin receptors are heterodimeric transmembrane proteins, expressed on the surfaces of endothelial cells and by a variety of tumor types, that bind to neighboring cell membrane proteins and the extracellular matrix (1,2). In particular, a v b 3 integrin receptors are associated with the regulation of tumor growth and are expressed on activated endothelial cells. As a v b 3 receptor antagonists are being evaluated for antiangiogenic therapy (3), clear interest in developing means of in vivo monitoring of such therapy is evident. Several molecular imaging agents have been investigated for the provision of in vivo assessment of angiogenesis (4,5).AH111585 is a cyclic peptide containing an arginineglycine-aspartic acid (RGD) motif that binds to integrin receptors such as a v b 3 with high affinity. We are investigating 18 F-labeled AH111585 for the quantitative in vivo monitoring of antiangiogenic therapy using PET. Details of the 18 F-AH111585 agent and its feasibility in detecting primary and metastatic cancer have been described previously (6). The study described here determined the safety of 18 F-AH111585 in healthy adult volunteers, biodistribution of 18 F, and the associated radiation dosimetry calculated after the MIRD schema (7). MATERIALS AND METHODSUnless otherwise specified, numeric data are provided as the mean 6 1 SD. Radiopharmaceutical PreparationSynthesis of the agent has been described previously (6,8). SubjectsApproval for this study was received from the Hammersmith Hospitals NHS Trust Research Ethics Committee, the Administration of Radioactive Substances Advisory Committee, and the Medicines and Healthcare Products Regulatory Agency. Eight healthy volunteers (5 men, 3 women), with an age of 61 6 4 y and body mass index of ...

We present an enhancement of the OSEM (ordered set expectation maximization) algorithm for 3D PET reconstruction, which we call the inter-update Metz filtered OSEM (IMF-OSEM). The IMF-OSEM algorithm incorporates filtering action into the image updating process in order to improve the quality of the reconstruction. With this technique, the multiplicative correction image--ordinarily used to update image estimates in plain OSEM--is applied to a Metz-filtered version of the image estimate at certain intervals. In addition, we present a software implementation that employs several high-speed features to accelerate reconstruction. These features include, firstly, forward and back projection functions which make full use of symmetry as well as a fast incremental computation technique. Secondly, the software has the capability of running in parallel mode on several processors. The parallelization approach employed yields a significant speed-up, which is nearly independent of the amount of data. Together, these features lead to reasonable reconstruction times even when using large image arrays and non-axially compressed projection data. The performance of IMF-OSEM was tested on phantom data acquired on the GE Advance scanner. Our results demonstrate that an appropriate choice of Metz filter parameters can improve the contrast-noise balance of certain regions of interest relative to both plain and post-filtered OSEM, and to the GE commercial reprojection algorithm software.

The future of Zr-based immuno-PET is reliant upon the development of new chelators with improved stability compared to the currently used deferoxamine (DFO). Herein, we report the evaluation of the octadentate molecule DFO-HOPO (3) as a suitable chelator forZr and a more stable alternative to DFO. The molecule showed good potential for the future development of a DFO-HOPO-based bifunctional chelator (BFC) for the radiolabelling of biomolecules with Zr. This work broadens the selection of available chelators forZr in search of improved successors to DFO for clinical Zr-immuno-PET.