Philip H Elsinga

Publications (89)388.68 Total impact

• Article: An Update of Radiolabeled Bombesin Analogues for Gastrin-Releasing Peptide Receptor Targeting.

  Zilin Yu, Hildo J K Ananias, Giuseppe Carlucci, Hilde D Hoving, Wijnand Helfrich, Rudi A J O Dierckx, Fan Wang, Igle J de Jong, Philip H Elsinga
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  ABSTRACT: Prostate cancer is a critical public health problem in USA and Europe. New non-invasive imaging methods are urgently needed, due to the low accuracy and specificity of current screen methods and the desire of localizing primary prostate cancer and bone metastasis. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are the non-invasive and sensitive imaging methods which have been widely used for diagnosing diseases in the clinic. Lack of suitable radiotracers is the major issue for nuclear imaging of prostate cancer, although radiolabeled bombesin (BN) peptides targeting the Gastrin-Releasing Peptide Receptor (GRPR) on tumor cells are widely investigated. In this review we discuss the recent trends in the development of GRPR-targeted radiopharmaceuticals based on BN analogues with regard to their potential for imaging and therapy of GRPR-expressing malignancies. Following a brief introduction of GRPR and bombesin peptides, we summarize the properties of prostate cancer specific radiolabeled bombesins. New bombesin tracers published in the last five years are reviewed and compared according to their novelties in biomolecules, radionuclides, labeling methods, bifunctional chelators and linkers. Hot topics such as multimerization, application of agonists and antagonists are highlighted in the review. Lastly, a few clinical trials of cancer nuclear imaging with radiolabeled bombesin are being discussed.
  Current pharmaceutical design 02/2013; · 4.41 Impact Factor
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  Available from: Aren van Waarde

  Dataset: Waarde2008b

  Philip H Elsinga, Aren van Waarde
• Source

  Available from: Aren van Waarde

  Article: Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT.

  Nathalie Matusiak, Aren van Waarde, Rainer Bischoff, Ruth Oltenfreiter, Christophe van de Wiele, Rudi A J O Dierckx, Philip H Elsinga
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  ABSTRACT: 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 characterisation 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 [111In]-DTPA-RP782, [99mTc]-(HYNIC-RP805)(tricine)(TPPTS), or Marimastat-ArB[18F]F3 and the picolyl-benzenesulfonamide [123I]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.
  Current pharmaceutical design 01/2013; · 4.41 Impact Factor
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  Available from: Hidde J Haisma

  Article: Induction of β-Glucuronidase Release by Cytostatic Agents in Small Tumors.

  Inês F Antunes, Hidde J Haisma, Philip H Elsinga, Valentina Di Gialleonardo, Aren van Waarde, Antoon T M Willemsen, Rudi A Dierckx, Erik F J de Vries
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  ABSTRACT: Extracellular β-glucuronidase (β-GUS) in tumors has been investigated as a target enzyme for prodrug therapy. However, despite encouraging preclinical results, animal studies also indicate that the success of prodrug therapy might be limited by the insufficient prodrug-converting enzyme activity, especially in small tumors. We hypothesized that a single dose of a cytostatic drug might induce the release of β-GUS in small tumors, resulting in increased levels of extracellular β-GUS and consequently a higher efficacy of the prodrug treatment. Here we examine the extent of β-GUS release in small C6 glioma tumors after a single treatment of doxorubicin (DOX), carmustine (BCNU) and tumor necrosis factor α (TNF-α) with positron emission tomography (PET) and the tracer 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-d-glucopyronuronate, [(18)F]FEAnGA, which has been proven to be selective for extracellular β-GUS. Induction of β-GUS release was first investigated in cultured C6 glioma cells. In addition, a [(18)F]FEAnGA PET study was performed in C6 tumor-bearing rats 48 h after a single treatment with different cytostatics to evaluate the extent of β-glucuronidase release. The cleavage of [(18)F]FEAnGA by β-GUS was analyzed in tumor homogenates. The induction of tumor necrosis and leukocyte infiltration was confirmed by histochemical analysis and flow cytometry. The in vitro studies indicated that all treatments resulted in a decline of viable cells and an increase of extracellular β-GUS activity. PET studies confirmed that β-GUS was released in vivo and the distribution volume of the PET tracer [(18)F]FEAnGA in C6 gliomas was increased significantly by 15-70%, depending on the treatment. Histochemical analysis of the tumors indicated that carmustine and TNF-α treatment caused a larger necrotic area with the absence of infiltrating immune cells, whereas doxorubicin induced an increase in leukocyte infiltration. These results were confirmed by flow cytometry. In conclusion, the present study demonstrates that a single dose of a cytostatic agent is able to increase the release of β-GUS. The release in β-GUS can be monitored by [(18)F]FEAnGA PET in a noninvasive manner. This study may open the way to a two-step chemotherapy-prodrug approach, in which tumors are treated with a single dose of a cytostatic drug prior to prodrug treatment.
  Molecular Pharmaceutics 09/2012; · 4.78 Impact Factor
• Article: Evaluation of a technetium-99m labeled bombesin homodimer for GRPR imaging in prostate cancer.

  Zilin Yu, Giuseppe Carlucci, Hildo J K Ananias, Rudi A J O Dierckx, Shuang Liu, Wijnand Helfrich, Fan Wang, Igle J de Jong, Philip H Elsinga
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  ABSTRACT: Multimerization of peptides can improve the binding characteristics of the tracer by increasing local ligand concentration and decreasing dissociation kinetics. In this study, a new bombesin homodimer was developed based on an ε-aminocaproic acid-bombesin(7-14) (Aca-bombesin(7-14)) fragment, which has been studied for targeting the gastrin-releasing peptide receptor (GRPR) in prostate cancer. The bombesin homodimer was conjugated to 6-hydrazinopyridine-3-carboxylic acid (HYNIC) and labeled with (99m)Tc for SPECT imaging. The in vitro binding affinity to GRPR, cell uptake, internalization and efflux kinetics of the radiolabeled bombesin dimer were investigated in the GRPR-expressing human prostate cancer cell line PC-3. Biodistribution and the GRPR-targeting potential were evaluated in PC-3 tumor-bearing athymic nude mice. When compared with the bombesin monomer, the binding affinity of the bombesin dimer is about ten times lower. However, the (99m)Tc labeled bombesin dimer showed a three times higher cellular uptake at 4 h after incubation, but similar internalization and efflux characters in vitro. Tumor uptake and in vivo pharmacokinetics in PC-3 tumor-bearing mice were comparable. The tumor was visible on the dynamic images in the first hour and could be clearly distinguished from non-targeted tissues on the static images after 4 h. The GRPR-targeting ability of the (99m)Tc labeled bombesin dimer was proven in vitro and in vivo. This bombesin homodimer provides a good starting point for further studies on enhancing the tumor targeting activity of bombesin multimers.
  Amino Acids 07/2012; · 3.25 Impact Factor
• Article: Multimerization improves targeting of peptide radio-pharmaceuticals.

  Giuseppe Carlucci, Hildo J K Ananias, Zilin Yu, Christophe Van de Wiele, Rudi A Dierckx, Igle J de Jong, Philip H Elsinga
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  ABSTRACT: Multimerization offers unique kinetic and thermodynamic properties to molecules. Multimeric ligands, characterized by multiple similar or different monomeric molecules tethered together, can bind several receptors simultaneously. Multimerization occurs also in nature. This process can be used to develop molecules with high diagnostic and therapeutic value. By altering parameters as linkers` length and flexibility, scaffold and backbones insertion, and ligands-receptors recognition, it is possible to provide high selectivity and binding affinity. The resultant multimeric ligand has a more favorable binding affinity than corresponding monomeric ligands.
  Current pharmaceutical design 04/2012; 18(17):2501-16. · 4.41 Impact Factor
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  Available from: Hidde J Haisma

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

  Inês F Antunes, Hidde J Haisma, Philip H Elsinga, Jurgen W A Sijbesma, Aren van Waarde, Antoon T M Willemsen, Rudi A Dierckx, Erik F J de Vries
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  ABSTRACT: The PET tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-d-glucopyronuronate ([(18)F]FEAnGA), was recently developed for PET imaging of extracellular β-glucuronidase (β-GUS). However, [(18)F]FEAnGA exhibited rapid renal clearance, which resulted in a relatively low tracer uptake in the tumor. To improve the pharmacokinetics of [(18)F]FEAnGA, we developed its more lipophilic methyl ester analog, [(18)F]FEAnGA-Me. [(18)F]FEAnGA-Me was obtained by alkylation of the O-protected glucuronide methyl ester precursor with [(18)F]-fluoroethylamine ([(18)F]FEA), followed by removal of the acetate protecting groups with NaOMe/MeOH. The PET tracer was evaluated by in vitro and in vivo studies. [(18)F]FEAnGA-Me was obtained in 5%-10% overall radiochemical yield. It is 10-fold less hydrophilic than [(18)F]FEAnGA and it is stable in PBS and in the presence of β-GUS for 1 h. However, in the presence of esterase or plasma [(18)F]FEAnGA-Me is converted to [(18)F]FEAnGA, and subsequently converted to [(18)F]FEA by β-GUS. MicroPET studies in Wistar rats bearing a C6 glioma and a sterile inflammation showed similar uptake in tumors after injection of either [(18)F]FEAnGA-Me or [(18)F]FEAnGA. Both tracers had a rapid two-phase clearance of total plasma radioactivity with a half-life of 1 and 8 min. The [(18)F]FEAnGA fraction generated from [(18)F]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 [(18)F]FEAnGA-Me or [(18)F]FEAnGA. The imaging properties of [(18)F]FEAnGA-Me were not significantly better than those of [(18)F]FEAnGA. Therefore, other strategies should be applied in order to improve the kinetics of these tracers.
  Nuclear Medicine and Biology 03/2012; 39(6):854-63. · 3.02 Impact Factor
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  Available from: Hidde J Haisma

  Article: 18F-FEAnGA for PET of β-glucuronidase activity in neuroinflammation.

  Inês F Antunes, Janine Doorduin, Hidde J Haisma, Philip H Elsinga, Aren van Waarde, Antoon T M Willemsen, Rudi A Dierckx, Erik F J de Vries
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  ABSTRACT: Activation of microglia is a hallmark of inflammatory, infectious, and degenerative diseases of the central nervous system. Several studies have indicated that there is an increase in release of β-glucuronidase by activated microglia into the extracellular space at the site of neuroinflammation. β-glucuronidase is involved in the hydrolysis of glycosaminoglycans on the cell surface and the degradation of the extracellular matrix. Therefore, β-glucuronidase might be a biomarker for ongoing neurodegeneration induced by neuroinflammation. In this study, we investigated whether the PET tracer (18)F-FEAnGA was able to detect β-glucuronidase release during neuroinflammation in a rat model of herpes encephalitis. Male Wistar rats were intranasally inoculated with herpes simplex virus 1 (HSV-1) or phosphate-buffered saline as a control. (11)C-(R)-PK11195 and (18)F-FEAnGA small-animal PET scans were acquired for 60 min. Logan graphical analysis was used to calculate (18)F-FEAnGA distribution volumes (DV(Logan)) in various brain areas. After administration of (18)F-FEAnGA, the area under the activity concentration-versus-time curve of the whole brain was 2 times higher in HSV-1-infected rats than in control rats. In addition, the DV(Logan) of (18)F-FEAnGA was most increased in the frontopolar cortex, frontal cortex, bulbus olfactorius, cerebral cortex, cerebellum, and brainstem of HSV-1-infected rats, when compared with control rats. The conversion of (18)F-FEAnGA to 4-hydroxy-3-nitrobenzyl alcohol was found to be 1.6 times higher in HSV-1-infected rats than in control rats and correlated with the DV(Logan) of (18)F-FEAnGA in the same areas of the brain. Furthermore, the DV(Logan) of (18)F-FEAnGA also correlated with β-glucuronidase activity in the same brain regions. In addition, DV(Logan) of (18)F-FEAnGA showed a tendency to correlate with (11)C-(R)-PK11195 uptake (marker for activated microglia) in the same brain regions. Despite relatively low brain uptake, (18)F-FEAnGA was able to detect an increased release of β-glucuronidase during neuroinflammation.
  Journal of Nuclear Medicine 03/2012; 53(3):451-8. · 6.38 Impact Factor
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  Available from: Aren van Waarde

  Article: Evaluation of 4'-[methyl-11C]thiothymidine in a rodent tumor and inflammation model.

  Jun Toyohara, Philip H Elsinga, Kiichi Ishiwata, Jurgen W A Sijbesma, Rudi A J O Dierckx, Aren van Waarde
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  ABSTRACT: 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) is a novel radiopharmaceutical that can be used for tumor imaging because of its rapid incorporation into DNA as a substrate for DNA synthesis. The in vivo stability of (11)C-4DST is much greater than that of natural thymidine, because of the presence of a sulfur atom in the 4'-position. Here, we evaluated the tissue kinetics and biodistribution of (11)C-4DST in a rodent tumor and acute sterile inflammation model in comparison with the previously published biodistribution data of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), (18)F-FDG, (11)C-choline, (11)C-methionine, and 2 σ-receptor ligands in the same animal model. C6 tumor cells were implanted subcutaneously into the right shoulder and turpentine (0.1 mL) was injected intramuscularly into the left hind leg of male Wistar rats 11 d and 24 h, respectively, before the scanning day. The animals were anesthetized with isoflurane, and (11)C-4DST (20-50 MBq) was injected intravenously. A dynamic PET scan was performed for 60 min with either the shoulder or hind leg region in the field of view. The animals were sacrificed, and a biodistribution study was performed. (11)C-4DST showed the highest tumor uptake (standardized uptake value, 4.93) of all radiopharmaceuticals tested. Its tumor-to-muscle concentration ratio (12.7) was similar to that of (18)F-FDG (13.2). The selectivity of (11)C-4DST for tumor as compared with acute inflammation was high (37.7), comparable to that of the σ-ligand (18)F-FE-SA5845 and much higher than that of (18)F-FDG (3.5). Rapidly proliferating tissues (tumor and bone marrow) showed a steadily increasing uptake. In inflamed muscle, (11)C-4DST showed relatively rapid washout, and tracer concentrations in inflamed and noninflamed muscle were not significantly different at intervals greater than 40 min. Competition of endogenous thymidine for (11)C-4DST uptake in target tissues was negligible, in contrast to competition for (18)F-FLT uptake. Thus, pretreatment of animals with thymidine phosphorylase was not required before PET with (11)C-4DST. In our rodent model, (11)C-4DST showed high tumor uptake (sensitivity) and high tumor selectivity. The different kinetics of (11)C-4DST in rapidly proliferating and inflammatory tissue may allow distinction between tumor and acute inflammation in a clinical setting. These promising results for (11)C-4DST warrant further investigation in PET studies in patients with various types of tumors.
  Journal of Nuclear Medicine 03/2012; 53(3):488-94. · 6.38 Impact Factor
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  Available from: Aren van Waarde

  Article: In vivo evaluation of 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-D-glucopyronuronate: a positron emission tomographic tracer for imaging β-glucuronidase activity in a tumor/inflammation rodent model.

  Inês F Antunes, Hidde J Haisma, Philip H Elsinga, Aren van Waarde, Antoon T M Willemsen, Rudi A Dierckx, Erik F J de Vries
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  ABSTRACT: β-Glucuronidase (β-GUS) plays an important role in inflammation and degenerative processes. The enzyme has also been investigated as a target in prodrug therapy for cancer. To investigate the role of β-GUS in pathologies and to optimize β-GUS-based prodrug therapies, we recently developed a positron emission tomographic (PET) tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-D-glucopyronuronate ([18F]FEAnGA), which proved to be selectively cleaved by β-GUS. Here we present the in vivo evaluation of [18F]FEAnGA for imaging of β-GUS in a tumor/inflammation model. Ex vivo biodistribution of [18F]FEAnGA was conducted in healthy rats. PET imaging and pharmacokinetic modeling were performed in Wistar rats bearing C6 tumors of different sizes and sterile inflammation. The biodistribution studies of [18F]FEAnGA indicated low uptake in major organs and rapid excretion through the renal pathway. MicroPET studies revealed three times higher uptake in the viable part of larger C6 gliomas than in smaller C6 gliomas. Uptake in inflamed muscle was significantly higher than in control muscle. The distribution volume of [18F]FEAnGA in the viable part of the tumor correlated well with the cleavage of the tracer to [18F]fluoroethylamine and the spacer 4-hydroxy-3-nitrobenzyl alcohol. [18F]FEAnGA is a PET tracer able to detect increased activity of β-GUS in large solid tumors and in inflamed tissues.
  Molecular Imaging 02/2012; 11(1):77-87, E1. · 3.18 Impact Factor
• Article: Strain-promoted copper-free "click" chemistry for 18F radiolabeling of bombesin.

  Lachlan S Campbell-Verduyn, Leila Mirfeizi, Anne K Schoonen, Rudi A Dierckx, Philip H Elsinga, Ben L Feringa
  Angewandte Chemie International Edition 09/2011; 50(47):11117-20. · 13.45 Impact Factor
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  Available from: Aren van Waarde

  Article: n Vivo Evaluation of 1-O-(4-(2-Fluoroethyl-Carbamoyloxymethyl)-2-Nitrophenyl)-O-β-d-Glucopyronuronate: A Positron Emission Tomographic Tracer for Imaging β-Glucuronidase Activity in a Tumor/Inflammation Rodent Model.

  Inês F Antunes, Hidde J Haisma, Philip H Elsinga, Aren van Waarde, Antoon T M Willemsen, Rudi A Dierckx, Erik F J de Vries
  [show abstract] [hide abstract]
  ABSTRACT: β-Glucuronidase (β-GUS) plays an important role in inflammation and degenerative processes. The enzyme has also been investigated as a target in prodrug therapy for cancer. To investigate the role of β-GUS in pathologies and to optimize β-GUS-based prodrug therapies, we recently developed a positron emission tomographic (PET) tracer, 1-O-(4-(2-fluoroethyl-carbamoyloxymethyl)-2-nitrophenyl)-O-β-d-glucopyronuronate ([(18)F]FEAnGA), which proved to be selectively cleaved by β-GUS. Here we present the in vivo evaluation of [(18)F]FEAnGA for imaging of β-GUS in a tumor/inflammation model. Ex vivo biodistribution of [(18)F]FEAnGA was conducted in healthy rats. PET imaging and pharmacokinetic modeling were performed in Wistar rats bearing C6 tumors of different sizes and sterile inflammation. The biodistribution studies of [(18)F]FEAnGA indicated low uptake in major organs and rapid excretion through the renal pathway. MicroPET studies revealed three times higher uptake in the viable part of larger C6 gliomas than in smaller C6 gliomas. Uptake in inflamed muscle was significantly higher than in control muscle. The distribution volume of [(18)F]FEAnGA in the viable part of the tumor correlated well with the cleavage of the tracer to [(18)F]fluoroethylamine and the spacer 4-hydroxy-3-nitrobenzyl alcohol. [(18)F]FEAnGA is a PET tracer able to detect increased activity of β-GUS in large solid tumors and in inflamed tissues.
  Molecular Imaging 09/2011; · 3.18 Impact Factor
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  Available from: Anna A. Rybczynska

  Article: The cholinergic system, sigma-1 receptors and cognition.

  Aren van Waarde, Nisha K Ramakrishnan, Anna A Rybczynska, Philip H Elsinga, Kiichi Ishiwata, Ingrid M Nijholt, Paul G M Luiten, Rudi A Dierckx
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  ABSTRACT: This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of β-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescent-accelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress.
  Behavioural brain research 08/2011; 221(2):543-54. · 3.22 Impact Factor
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  Available from: Aren van Waarde

  Article: Small-animal PET study of adenosine A(1) receptors in rat brain: blocking receptors and raising extracellular adenosine.

  Soumen Paul, Shivashankar Khanapur, Anna A Rybczynska, Chantal Kwizera, Jurgen W A Sijbesma, Kiichi Ishiwata, Antoon T M Willemsen, Philip H Elsinga, Rudi A J O Dierckx, Aren van Waarde
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  ABSTRACT: Activation of adenosine A(1) receptors (A(1)R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A(1)R can be visualized using 8-dicyclopropylmethyl-1-(11)C-methyl-3-propyl-xanthine ((11)C-MPDX) and PET. This study aims to test whether (11)C-MPDX can be used for quantitative studies of cerebral A(1)R in rodents. (11)C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A(1)R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A(1)R, whereas ethanol and ABT-702 increase extracellular adenosine. In groups 1 and 3, the brain was clearly visualized. High uptake of (11)C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2-tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K(1)/k(2) from the model fit) was not altered under the study conditions. (11)C-MPDX shows a regional distribution in rat brain consistent with binding to A(1)R. Tracer binding is blocked by the selective A(1)R antagonist DPCPX. Pretreatment of animals with ethanol and adenosine kinase inhibitor increases (11)C-MPDX uptake. This increase may reflect an increased availability of A(1)R after acute exposure to ethanol.
  Journal of Nuclear Medicine 08/2011; 52(8):1293-300. · 6.38 Impact Factor
• Article: Tailored imaging of islet cell tumors of the pancreas amidst increasing options.

  Helle-Brit Fiebrich, Sophie J van Asselt, Adrienne H Brouwers, Hendrik M van Dullemen, Milan E J Pijl, Philip H Elsinga, Thera P Links, Elisabeth G E de Vries
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  ABSTRACT: Pancreatic islet cell tumors are neuroendocrine tumors, which can produce hormones and can arise as part of multiple endocrine neoplasia type 1 or von-Hippel-Lindau-disease, two genetically well-defined hereditary cancer syndromes. Currently, technical innovation improves conventional and specific molecular imaging techniques. To organize the heterogeneous results described for the imaging of these tumors, we distinguished three indications (1) imaging of a patient with hormone hypersecretion, (2) search for a pancreatic primary in case of proven neuroendocrine cancer of unknown primary, and (3) screening of asymptomatic mutation carriers. We searched for publications on imaging of islet cell tumors between 1995 and January 2010 and defined a Level of Evidence (LOE) for the applicability of each technique. For each technique, data were analyzed in a Forest plot and arranged per imaging indication and tumor subtype. LOEs are weak for all imaging techniques. Analyses indicate a prominent role for endoscopic ultrasound for all three indications.
  Critical reviews in oncology/hematology 06/2011; 82(2):213-26. · 5.27 Impact Factor
• Article: (99m)technetium-HYNIC(tricine/TPPTS)-Aca-bombesin(7-14) as a targeted imaging agent with microSPECT in a PC-3 prostate cancer xenograft model.

  Hildo J K Ananias, Zilin Yu, Rudi A Dierckx, Christophe van der Wiele, Wijnand Helfrich, Fan Wang, Yongjun Yan, Xiaoyuan Chen, Igle J de Jong, Philip H Elsinga
  [show abstract] [hide abstract]
  ABSTRACT: The peptide bombesin (BN) and derivates thereof show high binding affinity for the gastrin-releasing peptide receptor (GRPR), which is highly expressed in primary and metastasized prostate cancer. We have synthesized a new BN-based radiopharmaceutical (99m)technetium-HYNIC(tricine/TPPTS)-Aca-BN(7-14) ((99m)Tc-HABN) and evaluated its GRPR targeting properties in vitro and in a xenograft tumor model for human prostate cancer in athymic mice. (99m)Tc-HABN was synthesized, and its lipophilicity and stability were investigated. The IC(50), internalization and efflux properties were determined in vitro using the GRPR expressing human prostate cancer cell line PC-3. (99m)Tc-HABN biodistribution and microSPECT imaging were performed in PC-3 tumor-bearing athymic mice. (99m)Tc-HABN was prepared with high labeling yield (>90%), high radiochemical purity (>95%) and a specific activity of ~19.8 MBq/nmol. The partition coefficient log D value was -1.60 ± 0.06. (99m)Tc-HABN proved to be stable in human serum for 6 h. The IC50 of HYNIC-Aca-BN(7-14) was 12.81 ± 0.14 nM. Incubation of PC-3 cells with (99m)Tc-HABN demonstrated rapid cellular internalization and a long intracellular retention time. When mice were injected with (99m)Tc-HABN, the activity was predominantly cleared via the kidneys. Uptake in the tumor was 2.24 ± 0.64% ID/g after 30 min, with a steady decrease during the 4 h study period. In vivo experiments with a blocking agent showed GRPR mediated uptake. (99m)Tc-HABN microSPECT imaging resulted in clear delineation of the tumor. (99m)Tc-HABN is a novel BN-based radiopharmaceutical that proved to be suitable for targeted imaging of prostate cancer with microSPECT using the human prostate cancer cell line PC-3 in a xenograft mouse model.
  Molecular Pharmaceutics 06/2011; 8(4):1165-73. · 4.78 Impact Factor
• Article: In vivo imaging of apoptosis in oncology: an update.

  Christel Vangestel, Marc Peeters, Gilles Mees, Ruth Oltenfreiter, Hendrikus H Boersma, Philip H Elsinga, Chris Reutelingsperger, Nancy Van Damme, Bart De Spiegeleer, Christophe Van de Wiele
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  ABSTRACT: In this review, data on noninvasive imaging of apoptosis in oncology are reviewed. Imaging data available are presented in order of occurrence in time of enzymatic and morphologic events occurring during apoptosis. Available studies suggest that various radiopharmaceutical probes bear great potential for apoptosis imaging by means of positron emission tomography and single-photon emission computed tomography (SPECT). However, for several of these probes, thorough toxicologic studies are required before they can be applied in clinical studies. Both preclinical and clinical studies support the notion that 99mTc-hydrazinonicotinamide-annexin A5 and SPECT allow for noninvasive, repetitive, quantitative apoptosis imaging and for assessing tumor response as early as 24 hours following treatment instigation. Bioluminescence imaging and near-infrared fluorescence imaging have shown great potential in small-animal imaging, but their usefulness for in vivo imaging in humans is limited to structures superficially located in the human body. Although preclinical tumor-based data using high-frequency-ultrasonography (US) are promising, whether or not US will become a routinely clinically useful tool in the assessment of therapy response in oncology remains to be proven. The potential of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) for imaging late apoptotic processes is currently unclear. Neither 31P MRS nor 1H MRS signals seems to be a unique identifier for apoptosis. Although MRI-measured apparent diffusion coefficients are altered in response to therapies that induce apoptosis, they are also altered by nonapoptotic cell death, including necrosis and mitotic catastrophe. In the future, rapid progress in the field of apoptosis imaging in oncology is expected.
  Molecular Imaging 04/2011; 10(5):340-58. · 3.18 Impact Factor
• Article: Effect of radiotherapy and chemotherapy on bone marrow activity: a 18F-FLT-PET study.

  Ali Agool, Riemer H J A Slart, Kristin K Thorp, Andor W J M Glaudemans, David C P Cobben, Lukas B Been, Fred R Burlage, Philip H Elsinga, Rudi A J O Dierckx, Edo Vellenga, Jennifer L Holter
  [show abstract] [hide abstract]
  ABSTRACT: Radiotherapy (RT) and chemotherapy are important treatment modalities for a variety of malignant tumor types. During therapy for malignant diseases, often the limitation for further therapy is determined by the capability of the bone marrow to withstand radiochemotherapeutic effects. Evaluation of hematologic toxicity is commonly performed with peripheral blood counts, and occasionally, sampling of marrow through a bone marrow biopsy. Neither method provides a comprehensive assessment, as bone marrow biopsy is invasive, and both are subject to sampling variability. Fluorine-18-3'-fluoro-3'-deoxy-L-thymidine-PET (18F-FLT-PET) is a noninvasive method and related to the rate of DNA synthesis and visualizes the high cycling activity of hematopoietic cells in the bone marrow compartment. To prove the clinical consistency of marrow function and imaging, we investigated populations of patients typically seen in clinical practice, after radiation and chemotherapy. In this feasibility study, patients were evaluated (i) to prove the ability of visualization and quantification of the activity of the bone marrow compartment with 18F-FLT-PET and (ii) to examine the effect of RT and chemotherapy on bone marrow activity and the correlation with clinical findings. Bone marrow activity in the cervical region of 10 patients with laryngeal carcinoma who received a mean total dose of 68 Gy (range 30-41 fractions) was evaluated with 18F-FLT-PET, before and 1 month after RT. Whole body FLT images were assessed in nine patients with nonseminomatous testicular germ cell tumor, before and 6 months after the last chemotherapy, consisting of four courses of bleomycin, cisplatin, and etoposide. The maximum standardized uptake value (SUVmax) was used to quantify FLT uptake in bone marrow at the standard bone marrow regions. A significant decrease in 18F-FLT-PET uptake was observed in all the studied laryngeal carcinoma patients in the cervical region after RT of the adjacent bone marrow compartment. Tumor stage and additional field-of-view of RT were inversely related to the 18F-FLT uptake in bone marrow. The mean 18F-FLT SUVmax before RT was 3.0+/-1.34 and after RT was 1.94+/-0.60 (P=0.013). The mean 18F-FLT SUVmax of the spine (Th5-Th12) regions outside the field-of-view of RT were stable and reproducible and not significantly different (5.56+/-1.56 vs. 5.16+/-1.35, P=0.16). Chemotherapy did not result in a significant difference of whole body SUVmax value, with a mean SUVmax of 4.99+/-1.15 prechemotherapy, and a mean SUVmax of 5.28+/-1.0 postchemotherapy (P=0.21). Laboratory analysis of the hematologic parameters confirmed repopulation of the bone marrow. 18F-FLT uptake in the bone marrow decreases after RT, but not after chemotherapy. We conclude that 18F-FLT-PET is a potential noninvasive tool that can be used in the assessment of quantification of cellular division in the hematopoietic organ.
  Nuclear Medicine Communications 01/2011; 32(1):17-22. · 1.40 Impact Factor
• Article: Effect of radiotherapy and chemotherapy on bone marrow activity: a 18F–FLT–PET study

  Ali Agool, Riemer H.J.A. Slart, Kristin K. Thorp, Andor W.J.M. Glaudemans, David C.P. Cobben, Lukas B. Been, Fred R. Burlage, Philip H. Elsinga, Rudi A.J.O. Dierckx, Edo Vellenga, Jennifer L. Holter
  [show abstract] [hide abstract]
  ABSTRACT: Background: Radiotherapy (RT) and chemotherapy are important treatment modalities for a variety of malignant tumor types. During therapy for malignant diseases, often the limitation for further therapy is determined by the capability of the bone marrow to withstand radiochemotherapeutic effects. Evaluation of hematologic toxicity is commonly performed with peripheral blood counts, and occasionally, sampling of marrow through a bone marrow biopsy. Neither method provides a comprehensive assessment, as bone marrow biopsy is invasive, and both are subject to sampling variability. Fluorine-18–3′-fluoro-3′-deoxy-L-thymidine–PET (18F–FLT–PET) is a noninvasive method and related to the rate of DNA synthesis and visualizes the high cycling activity of hematopoietic cells in the bone marrow compartment. To prove the clinical consistency of marrow function and imaging, we investigated populations of patients typically seen in clinical practice, after radiation and chemotherapy. In this feasibility study, patients were evaluated (i) to prove the ability of visualization and quantification of the activity of the bone marrow compartment with 18F–FLT–PET and (ii) to examine the effect of RT and chemotherapy on bone marrow activity and the correlation with clinical findings. Methods: Bone marrow activity in the cervical region of 10 patients with laryngeal carcinoma who received a mean total dose of 68 Gy (range 30–41 fractions) was evaluated with 18F–FLT–PET, before and 1 month after RT. Whole body FLT images were assessed in nine patients with nonseminomatous testicular germ cell tumor, before and 6 months after the last chemotherapy, consisting of four courses of bleomycin, cisplatin, and etoposide. The maximum standardized uptake value (SUVmax) was used to quantify FLT uptake in bone marrow at the standard bone marrow regions. Results: A significant decrease in 18F–FLT–PET uptake was observed in all the studied laryngeal carcinoma patients in the cervical region after RT of the adjacent bone marrow compartment. Tumor stage and additional field-of-view of RT were inversely related to the 18F–FLT uptake in bone marrow. The mean 18F–FLT SUVmax before RT was 3.0±1.34 and after RT was 1.94±0.60 (P=0.013). The mean 18F–FLT SUVmax of the spine (Th5–Th12) regions outside the field-of-view of RT were stable and reproducible and not significantly different (5.56±1.56 vs. 5.16±1.35, P=0.16). Chemotherapy did not result in a significant difference of whole body SUVmax value, with a mean SUVmax of 4.99±1.15 prechemotherapy, and a mean SUVmax of 5.28±1.0 postchemotherapy (P=0.21). Laboratory analysis of the hematologic parameters confirmed repopulation of the bone marrow. Conclusion: 18F–FLT uptake in the bone marrow decreases after RT, but not after chemotherapy. We conclude that 18F–FLT–PET is a potential noninvasive tool that can be used in the assessment of quantification of cellular division in the hematopoietic organ.
  Nuclear Medicine Communications 12/2010; 32(1):17–22. · 1.40 Impact Factor
• Article: VEGF-PET imaging is a noninvasive biomarker showing differential changes in the tumor during sunitinib treatment.

  Wouter B Nagengast, Marjolijn N Lub-de Hooge, Sjoukje F Oosting, Wilfred F A den Dunnen, Frank-Jan Warnders, Adrienne H Brouwers, Johan R de Jong, Patricia M Price, Harry Hollema, Geke A P Hospers, Philip H Elsinga, Jan Willem Hesselink, Jourik A Gietema, Elisabeth G E de Vries
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  ABSTRACT: Non-invasive imaging of angiogenesis could ease the optimization of antiangiogenesis treatments for cancer. In this study, we evaluated the role of VEGF-PET as a biomarker of dynamic angiogenic changes in tumors following treatment with the kinase inhibitor sunitinib. The effects of sunitinib treatment and withdrawal on the tumor was investigated using the new VEGF-PET tracer (89)Zr-ranibizumab as well as (18)F-FDG PET, and (15)O-water PET in mouse xenograft models of human cancer. The obtained imaging results were compared with tumor growth, VEGF plasma levels and immunohistologic analyzes. In contrast to (18)F-FDG and (15)O-water PET, VEGF-PET demonstrated dynamic changes during sunitinib treatment within the tumor with a strong decline in signal in the tumor center and only minimal reduction in tumor rim, with a pronounced rebound after sunitinib discontinuation. VEGF-PET results corresponded with tumor growth and immunohistochemical vascular- and tumor- markers. Our findings highlight the strengths of VEGF-PET imaging to allow serial analysis of angiogenic changes in different areas within a tumor.
  Cancer Research 11/2010; 71(1):143-53. · 7.86 Impact Factor