Five different methods for the estimation of the binding potential, a measure of Bmax/Kd, of [11C]raclopride in human striatum were compared using data from a dose ranging study of the neuroleptic CP-88,059-01. Binding potential was estimated indirectly, from distribution volumes in striatum and cerebellum, using both single- and two-tissue compartment models with a metabolite-corrected plasma curve as input function. The two-tissue compartment model was also used for a direct estimate of the binding potential. In addition, a direct estimate was obtained from the reference tissue compartment model using the cerebellum as indirect input function. Finally, an estimate of binding potential was calculated from the ratio of striatum over cerebellum counts at late times after injection. The estimates of striatum binding potential from all methods, except the direct determination using a two-tissue compartment model with metabolite-corrected plasma input function, correlated with each other. Use of an average metabolite correction resulted in only a small reduction in accuracy in this series of normal subjects. The reference tissue model provided estimates of the binding potential with the same sensitivity for detecting changes as those methods that required a metabolite-corrected plasma input function. This indicates that for routine analysis of clinical [11C]raclopride studies, no arterial cannulation is required. The range of normal values was significantly less variable with the reference tissue method than when simple striatum-to-cerebellum ratios were used.

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.

Summary: Carbon-l l·labeled flu maze nil combined with positron emission tomography (PET) was used to mea sure the concentration (BmaX> of the benzodiazepine (Bz) receptor in the brain and its equilibrium dissociation con stant (KD) for flumazenil in five normal sUbjects. The steady-state approach was used injecting the tracer as a bolus of high specific activity. In each subject two studies were carried out. The first study was performed at essen tially zero receptor occupancy, the tracer alone study. The second study was performed at a steady-state recep tor occupancy of about 50%, achieved by a prolonged constant infusion of nonlabeled ("cold") flumazenil starting 2 h before the bolus tracer injection and continu ing until the end of the scanning period. In this second study the free concentration of unmetabolized flumazenil in plasma water was measured in mUltiple blood samples. The observed tissue and plasma tracer curves, calibrated in the same units of radioactivity per millimeter, were an alyzed in two ways: (a) by the noncompartmental (stoCarbon-II-labeled flumazenil has been intro duced as a positron emission tomography (PET) ligand for studying central benzodiazepine (Bz) re ceptors in the human brain (Ehrin et aI., 1984; Ma ziere et aI., 1984). Flumazenil is a Bz receptor an tagonist that can be injected at doses that result in a significant degree of occupation of receptor sites with negligible clinical effects in drug-naive sub jects. Flumazenil has the properties of a good PET ligand: (a) fairly rapid metabolism in the liver to a hydrophilic molecule that does not cross the blood- In general, the approach has been to record a dynamic set of tomograms, describing the uptake and subsequent washout of the tracer following bo lus injection of the tracer at high and low specific activities. In the case of a low-specific activity study the changing concentrations of unlabeled flu maze nil will result in a changing receptor occu pancy throughout the investigation. Various ap proaches have been proposed to handle this non steady state, for example, by calculating the bound l free ratio of the tracer during a time interval of assumed near-equilibrium, the so-called pseu doequilibrium approach (Pappata et aI., 1988), or by fitting the nonlinear differential equations resulting from the non-steady state (Blomquist et aI., 1990;