SPECT and PET in Eating Disorders

Medical imaging techniques like PET and SPECT have been applied for investigation of brain function in anorexia and bulimia nervosa. Regional abnormalities have been detected in cerebral blood flow, glucose metabolism, the availability of several neurotransmitter receptors (serotonin 1A and 2A, dopamine D2/D3, histamine H1, mu-opioid, GABA(A)-benzodiazepine, and cannabinoid CB1), stimulant-induced dopamine release, presynaptic FDOPA influx, and the density of serotonin transporters. Different subtypes of eating disorders appear to be associated with specific functional changes. It is hard to judge whether such changes are a consequence of chronic dietary restrictions or are caused by a putative anorexia (or bulimia) nervosa endophenotype. Many abnormalities (particularly those of glucose metabolism) appear to be reversible after restoration of weight or normal patterns of food intake and may represent consequences of purging or starvation. However, some changes of regional flow and neurotransmitter systems persist even after successful therapy which suggests that these reflect traits that are independent of the state of the illness. Changes of the serotonergic system (altered activity of 5-HT1A and 5-HT2A receptors and 5-HT transporters) may contribute to dysregulation of appetite, mood, and impulse control in eating disorders and may represent a trait which predisposes to the development of anxiety, obsessionality, and behavioral inhibition. Assessment of functional changes in the brain with PET or SPECT may have prognostic value and predict neuropsychological status after several years of therapy

Rapid reduction of sigma(1)-Receptor binding and F-18-FDG uptake in rat gliomas after in vivo treatment with doxorubicin

sigma-Receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled sigma(1)-ligand for therapy monitoring, we compared early changes of C-11-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (C-11-SA4503) binding and F-18-FDG uptake in gliomas after in vivo chemotherapy. Methods: C6 cells (2.5 x 10(6)) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 cl, the tumor volume was 0.60 +/- 0.08 cm(3). Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (n = 20) were scanned first with C-11-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by 18F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to sigma-receptor assays. The biodistribution of 18F-FDG was assessed. Results: Tumors appeared 4-5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy (C-11-SA4503: 26.5% +/- 6.5% at 24 h, 26.5% +/- 7.5% at 48 h; 18F-FDG: 22.6% +/- 3.2% at 24 h, 27.4% +/- 3.2% at 48 h; ex vivo F-18-FDG: 22.4% +/- 5.4% at 24 h, 31.7% +/- 12.7% at 48 h). sigma(1)-Receptor density in treated tumors was also reduced (from 172 +/- 35 to 125 +/- 28 fmol/mg of protein). Conclusion: Both C-11-SA4503 binding and 18F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of C-11-SA4503 corresponded to a loss of (sigma(1)-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h

Potential applications for sigma receptor ligands in cancer diagnosis and therapy

AbstractSigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers

[F-18]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats

Statins are 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [F-18]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [F-18]Atorvastatin was synthesized via a previously optimized F-18-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [F-18]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [F-18]atorvastatin was 38 +/- 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [F-18]atorvastatin kinetics in the liver. A strong correlation (R-2 &gt; 0.93) between quantitative Ki (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of Ki for monitoring [F-18]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [F-18]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [F-18]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.</p

Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Advanced melanoma is characterized by a pronounced resistance to therapy leading to a limited patient survival of ~6 - 9 months. Here, we report on a novel bifunctional therapeutic fusion protein, designated anti-MCSP:TRAIL, that is comprised of a melanoma-associated chondroitin sulfate proteoglycan (MCSP)-specific antibody fragment (scFv) fused to soluble human TRAIL. MCSP is a well-established target for melanoma immunotherapy and has recently been shown to provide important tumorigenic signals to melanoma cells. TRAIL is a highly promising tumoricidal cytokine with no or minimal toxicity towards normal cells. Anti-MCSP:TRAIL was designed to <b>1</b>. selectively accrete at the cell surface of MCSP-positive melanoma cells and inhibit MCSP tumorigenic signaling and <b>2</b>. activate apoptotic TRAIL-signaling.</p> <p>Results</p> <p>Treatment of a panel of MCSP-positive melanoma cell lines with anti-MCSP:TRAIL induced TRAIL-mediated apoptotic cell death within 16 h. Of note, treatment with anti-MCSP:sTRAIL was also characterized by a rapid dephosphorylation of key proteins, such as FAK, implicated in MCSP-mediated malignant behavior. Importantly, anti-MCSP:TRAIL treatment already inhibited anchorage-independent growth by 50% at low picomolar concentrations, whereas > 100 fold higher concentrations of non-targeted TRAIL failed to reduce colony formation. Daily i.v. treatment with a low dose of anti-MCSP:TRAIL (0.14 mg/kg) resulted in a significant growth retardation of established A375 M xenografts. Anti-MCSP:TRAIL activity was further synergized by co-treatment with rimcazole, a σ-ligand currently in clinical trials for the treatment of various cancers.</p> <p>Conclusions</p> <p>Anti-MCSP:TRAIL has promising pre-clinical anti-melanoma activity that appears to result from combined inhibition of tumorigenic MCSP-signaling and concordant activation of TRAIL-apoptotic signaling. Anti-MCSP:TRAIL alone, or in combination with rimcazole, may be of potential value for the treatment of malignant melanoma.</p

Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses

Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D-2 receptor (D2R) antagonists or weak partial agonists and may have pro-mnemonic and neuroprotective effects. The mechanism underlying their stimulatory and neuroprotective actions is unknown but could involve sigma-1R binding. The present study examined sigma-1R and D2R occupancy by the dopamine stabilizer pridopidine (ACR16) at behaviorally relevant doses in living rats. Rats were administered 3 or 15 mg/kg pridopidine, or saline, before injection of the radiotracer C-11-SA4503 (sigma-1R) or C-11-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with C-11-raclopride. Cerebral C-11-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V (T)) calculated by Logan graphical analysis. C-11-raclopride binding was quantified using striatum-to-cerebellum ratios and binding potentials calculated with a simplified reference tissue model. Cunningham-Lassen plots indicated sigma-1R occupancies of 57 +/- 2 and 85 +/- 2 % after pretreatment of animals with 3 and 15 mg/kg pridopidine. A significant (44-66 %) reduction of C-11-raclopride binding was only observed at 60 mg/kg pridopidine. At doses shown to elicit neurochemical and behavioral effects, pridopidine occupied a large fraction of sigma-1Rs and a negligible fraction of D(2)Rs. Significant D2R occupancy was only observed at a dose 20-fold higher than was required for sigma-1R occupancy. The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low D2R affinity

In vivo evaluation of [F-18]FEAnGA-Me:a PET tracer for imaging beta-glucuronidase (beta-GUS) activity in a tumor/inflammation rodent model

Introduction: The PET tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-beta-D-glucopyronuronate ([F-18]FEAnGA), was recently developed for PET imaging of extracellularl beta-glucuronidase (beta-GUS). However,[F-18]FEAnGA exhibited rapid renal clearance, which resulted in a relatively low tracer uptake in the tumor. To improve the pharmacokinetics of [F-18]FEAnGA, we developed its more lipophilic methyl ester analog, [F-18]FEAnGA-Me. Methods: [F-18]FEAnGA-Me was obtained by alkylation of the O-protected glucuronide methyl ester precursor with [F-18]-fluoroethylamine ([F-18]FEA), followed by removal of the acetate protecting groups with NaOMe/MeOH. The PET tracer was evaluated by in vitro and in vivo studies. Results: [F-18]FEAnGA-Me was obtained in 5%-10% overall radiochemical yield. It is 10-fold less hydrophilic than [F-18]FEAnGA and it is stable in PBS and in the presence of beta-GUS for 1 h. However, in the presence of esterase or plasma [F-18]FEAnGA-Me is converted to [F-18]FEAnGA, and subsequently converted to [F-18]FEA by beta-GUS. MicroPET studies in Wistar rats bearing a C6 glioma and a sterile inflammation showed similar uptake in tumors after injection of either [F-18]FEAnGA-Me or [F-18]FEAnGA. Both tracers had a rapid two-phase clearance of total plasma radioactivity with a half-life of 1 and 8 min. The [F-18]FEAnGA fraction generated from [F-18]FEAnGA-Me by in vivo hydrolysis had a circulation half-life of 1 and 11 min in plasma. Similar distribution volume in the viable part of the tumor was found after injection of either [F-18]FEAnGA-Me or [F-18]FEAnGA. Conclusion: The imaging properties of [F-18]FEAnGA-Me were not significantly better than those of [F-18]FEAnGA. Therefore, other strategies should be applied in order to improve the kinetics of these tracers. (C) 2012 Elsevier Inc. All rights reserved

Probes for Non-invasive Matrix Metalloproteinase-targeted Imaging with PET and SPECT

Dysregulation of matrix metalloproteinase (MMP) activity can lead to a wide range of disease states such as atherosclerosis, inflammation or cancer. The ability to image MMP activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterization of atherosclerotic plaques, inflammatory lesions or tumors. Here we present an overview of radiolabelled MMP inhibitors (MMPIs) and MMP peptides for positron emission tomography (PET) and single photon emission computed tomography (SPECT) for the detection of proteolytic activity of MMPs. So far, most studies are at a preliminary stage; however, some hydroxamate-based tracers such as the peptidomimetics [In-111]-DTPA-RP782, [Tc-99m]-(HYNIC-RP805)(tricine)(TPPTS), or Marimastat-ArB[F-18]F-3 and the picolyl-benzenesulfonamide [I-123]I-HO-CGS 27023A identified specifically the enzymatic action of MMPs in animal models of various pathologies. The development of new compounds that may lead to novel tracers (e.g. modification of zinc-binding group, variation of substituents attached to the S1', S2' and S3' pockets of the MMP inhibitors) and the use of antibodies and cell penetrating peptides are also discussed. In general, preclinical studies with atherosclerosis models proved to be more successful than those with oncological models

Rapid reduction of σ1-receptor binding and 18F-FDG uptake in rat gliomas after in vivo treatment with doxorubicin

金沢大学疾患モデル総合研究センターσ-Receptors are strongly overexpressed in most rodent and human tumors and are proliferation markers. To evaluate the potential of a radiolabeled σ1-Higand for therapy monitoring, we compared early changes of 11C-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine (11C-SA4503) binding and 18F-FDG uptake in gliomas after in vivo chemotherapy. Methods: C6 cells (2.5 × 10 6) were subcutaneously injected into the right shoulder of male Wistar rats. After 7 d, the tumor volume was 0.60 ± 0.08 cm3. Animals then received either saline or doxorubicin (8 mg/kg, intraperitoneally). One control and 1 treated rat were imaged simultaneously, 24 or 48 h after treatment, under pentobarbital anesthesia. Rodents (n = 20) were scanned first with 11C-SA4503 (25 MBq, intravenously) followed more than 100 min afterward by 18F-FDG (20 MBq, intravenously), using a dedicated small-animal PET camera (60-min protocol, tumors in the field of view). Tumor homogenates were prepared and subjected to σ-receptor assays. The biodistribution of 18F-FDG was assessed. Results: Tumors appeared 4-5 d after inoculation and grew exponentially. No significant reduction of tumor growth was visible within 48 h after doxorubicin treatment. Both PET tracers visualized the tumors and showed reduced uptake after chemotherapy ( 11C-SA4503: 26.5% ± 6.5% at 24 h, 26.5% ± 7.5% at 48 h; 18F-FDG: 22.6% ± 3.2% at 24 h, 27.4% ± 3.2% at 48 h; ex vivo 18F-FDG: 22.4% ± 5.4% at 24 h, 31.7% ± 12.7% at 48 h). σ1-Receptor density in treated tumors was also reduced (from 172 ± 35 to 125 ± 28 fmol/mg of protein). Conclusion: Both 11C-SA4503 binding and 18F-FDG uptake declined in gliomas after chemotherapy. Decreased binding of 11C-SA4503 corresponded to a loss of σ1-receptors from the tumors. Changes in tracer uptake preceded the morphologic changes by at least 48 h. Copyright © 2007 by the Society of Nuclear Medicine, Inc

In Vivo Induction of P‑Glycoprotein Function can be Measured with [18F]MC225 and PET

P-Glycoprotein (P-gp) is an efflux pump located at the blood−brain barrier (BBB) that contributes to the protection of the central nervous system by transporting neurotoxic compounds out of the brain. A decline in P-gp function has been related to the pathogenesis of neurodegenerative diseases. P-gp inducers can increase the P-gp function and are considered as potential candidates for the treatment of such disorders. The P-gp inducer MC111 increased P-gp expression and function in SW480 human colon adenocarcinoma and colo-320 cells, respectively. Our study aims to evaluate the P-gp inducing effect of MC111 in the whole brain in vivo, using the P-gp tracer [18F]MC225 and positron emission tomography (PET). Eighteen Wistar rats were treated with either vehicle solution, 4.5 mg/kg of MC111 (low-dose group), or 6 mg/kg of MC111 (high-dose group). Animals underwent a 60 min dynamic PET scan with arterial-blood sampling, 24 h after treatment with the inducer. Data were analyzed using the 1-tissue-compartment model and metabolite-corrected plasma as the input function. Model parameters such as the influx constant (K1) and volume of distribution (VT) were calculated, which reflectthe in vivo P-gp function. P-gp and pregnane xenobiotic receptor (PXR) expression levels of the whole brain were assessed using western blot. The administration of MC111 decreased K1 and VT of [18F]MC225 in the whole brain and all of the selected brain regions. In the high-dose group, whole-brain K1 was decreased by 34% (K1-high-dose = 0.20 ± 0.02 vs K1-control = 0.30 ± 0.02; p &lt; 0.001) and in the low-dose group by 7% (K1-low-dose = 0.28 ± 0.02 vs K1-control = 0.30 ± 0.02; p = 0.42) compared to controls. Whole-brain VT was decreased by 25% in the high-dose group (VT-high-dose = 5.92 ± 0.41 vs VT-control = 7.82 ± 0.38; p &lt; 0.001) and by 6% in the low-dose group (VT-low-dose = 7.35 ± 0.38 vs VT-control = 7.82 ± 0.37; p = 0.38) compared to controls. k2 values did not vary after treatment. The treatment did not affect the metabolism of [18F]MC225. Western blot studies using the whole brain tissue did not detect changes in the P-gp expression, however, preliminary results using isolated brain capillaries found an increasing trend up to 37% in treated rats. The decrease in K1 and VT values after treatment with the inducer indicates an increase in the P-gp functionality at the BBB of treated rats. Moreover, preliminary results using brain endothelial cells also sustained the increase in the P-gp expression. In conclusion, the results verify that MC111 induces P-gp expression and function at the BBB in rats. An increasing trend regarding the P-gp expression levels is found using western blot and an increased P-gp function is confirmed with [18F]MC225 and PET