Article: Towards prediction of efficacy of chemotherapy: a proof of concept study in lung cancer patients using [11C]docetaxel and positron emission tomography.Astrid A van der Veldt, Mark Lubberink, Ron Hj Mathijssen, Walter Loos, Gerarda J Herder, Henri N Greuter, Emile F Comans, Hugo Rutten, Jonas Eriksson, Albert D Windhorst, Harry Hendrikse, Pieter E Postmus, Egbert F Smit, Adriaan A Lammertsma[show abstract] [hide abstract]
ABSTRACT: PURPOSE: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([11C]docetaxel). The objective of this study was to investigate whether a [11C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel. EXPERIMENTAL DESIGN: Docetaxel-naïve lung cancer patients underwent two [11C]docetaxel PET scans; one after bolus injection of [11C]docetaxel and another during combined infusion of [11C]docetaxel and a therapeutic dose of docetaxel (75 mg•m-2). Compartmental and spectral analyses were used to quantify [11C]docetaxel tumor kinetics. [11C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans. RESULTS: Net rates of influx (Ki) of [11C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [11C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [11C]docetaxel during the therapeutic scan. At 90 min, the accumulated amount of docetaxel in tumors was <1% of the total infused dose of docetaxel. [11C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman's ρ= 0.715; P= 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman's ρ= -0.800; P= 0.010). CONCLUSIONS: Microdosing data of [11C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.Clinical Cancer Research 04/2013; · 7.74 Impact Factor
Article: Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-HT4 receptor.Hans Jc Buiter, Albert D Windhorst, Marc C Huisman, Joris H De Maeyer, Jan Aj Schuurkes, Adriaan A Lammertsma, Josée E Leysen[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Serotonin 5-HT4 receptor (5-HT4-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-HT4-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-HT4-R agonist, was selected. METHODS: [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its LogDoct,pH7.4 was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. RESULTS: [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% +/- 4% (decay corrected) and a radiochemical purity (>99%), its LogDoct,pH7.4 was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID.g-1) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. CONCLUSION: [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-HT4-R is worthwhile, in view of the therapeutic applications of 5-HT4 agonists for treatment of gastrointestinal motility disorders.EJNMMI research. 04/2013; 3(1):24.
Expert Review of Anti-infective Therapy 04/2013; 13(4):377-9. · 2.65 Impact Factor
Article: Positron emission tomography measured cerebral blood flow and glucose metabolism are decreased in human type 1 diabetes.Larissa W van Golen, Marc C Huisman, Richard G Ijzerman, Nikie J Hoetjes, Lothar A Schwarte, Adriaan A Lammertsma, Michaela Diamant[show abstract] [hide abstract]
ABSTRACT: Subclinical systemic microvascular dysfunction exists already in asymptomatic patients with type 1 diabetes. We hypothesized that microangiopathy, resulting from long-standing systemic hyperglycemia and hyperinsulinemia, may be generalized to the brain, resulting in changes in cerebral blood flow and metabolism in these patients. We performed dynamic [(15)O]H2O and [(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]FDG) brain positron emission tomography (PET) scans to measure cerebral blood flow (CBF) and cerebral glucose metabolism (CMRglu), respectively, in 30 type 1 diabetic patients and 12 age-matched healthy controls after an overnight fast. Regions of interest were automatically delineated on co-registered MRI images and full kinetic analysis was performed. Plasma glucose and insulin levels were higher in patients versus controls. Total grey matter CBF was 9%, whereas CMRglu was 21% lower in type 1 diabetic versus control subjects. We conclude that at real-life fasting glucose and insulin levels, type 1 diabetes is associated with decreased resting cerebral glucose metabolism, that is only partially explained by the decreased CBF. These findings suggest that other mechanisms than generalized microangiopathy account for the altered CMRglu observed in well-controlled type 1 diabetes. (NCT00626080).Diabetes 03/2013; · 8.29 Impact Factor
Hans Jc Buiter, Albert D Windhorst, Marc C Huisman, Maqsood Yaqub, Dirk L Knol, Abraham Fisher, Adriaan A Lammertsma, Josée E Leysen[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: The M1 muscarinic acetylcholine receptor (M1ACh-R) is a G protein-coupled receptor that can occur in interconvertible coupled and uncoupled states. It is enriched in the basal ganglia, hippocampus, olfactory bulb, and cortical areas, and plays a role in motor and cognitive functions. Muscarinic M1 agonists are potential therapeutic agents for cognitive disorders. The aim of this study was to evaluate [11C]AF150(S) as a putative M1ACh-R agonist PET ligand, which, owing to its agonist properties, could provide a tool to explore the active G protein-coupled receptor. METHODS: Regional kinetics of [11C]AF150(S) in rat brain were measured using a high-resolution research tomograph, both under baseline conditions and following pre-treatment with various compounds or co-administration of non-radioactive AF150(S). Data were analysed by calculating standard uptake values and by applying the simplified reference tissue model (SRTM). RESULTS: [11C]AF150(S) was rapidly taken up in the brain, followed by a rapid clearance from all brain regions. Analysis of PET data using SRTM revealed a binding potential (BPND) of 0.25 for the striatum, 0.20 for the hippocampus, 0.16 for the frontal cortical area and 0.15 for the posterior cortical area, all regions rich in M1ACh-R. BPND values were significantly reduced following pre-treatment with M1ACh-R antagonists. BPND values were not affected by pre-treatment with a M3ACh-R antagonist. Moreover, BPND was significantly reduced after pre-treatment with haloperidol, a dopamine D2 receptor blocker that causes an increase in extracellular acetylcholine. The latter may compete with [11C]AF150(S) for binding to the M1ACh-R; further pharmacological agents were applied to investigate this possibility. Upon injection of the highest dose (49.1 nmol kg-1) of [11C]AF150(S) diluted with non-radioactive AF150(S), brain concentration of AF150(S) reached 100 nmol L-1 at peak level. At this concentration, no sign of saturation in binding to M1ACh-R was observed. CONCLUSIONS: The agonist PET ligand [11C]AF150(S) was rapidly taken up in the brain and showed an apparent specific M1ACh-R-related signal in brain areas that are rich in M1ACh-R. Moreover, binding of the agonist PET ligand [11C]AF150(S) appears to be sensitive to changes in extracellular ACh levels. Further studies are needed to evaluate the full potential of [11C]AF150(S) for imaging the active pool of M1ACh-R in vivo.EJNMMI research. 03/2013; 3(1):19.