Is [11c]cumi-101 binding to 5-ht1a receptors susceptible to intravenous citalopram challenge in humans?
IS [11C]CUMI-101 BINDING TO 5-HT1A RECEPTORS SUSCEPTIBLE TO INTRAVENOUS CITALOPRAM CHALLENGE IN HUMANS? L.H. Pinborg1,2,3, L. Feng1, M. Haahr1, N. Gillings4, A. Ettrup1, H.D. Hansen1, S. Yndgaard5, C. Svarer1, G.M. Knudsen1,3 1Neurobiology Research Unit, N9201, 2Epilepsy Clinic, N8501, 3The Lundbeck Centre for Integrated Molecular Brain Imaging, 4The PET & Cyclotron Unit, 5Department of Thoratic Anaesthesiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkIntroduction and hypothesis: We previously failed to demonstrate a translation of intravenous citalopram challenge into a change in 5-HT2A binding of [18F]altanserin binding(1). Whether we consider changes in radioligand binding following pharmacological challenges to be the result of simple competition between radioligand and 5-HT or the result of agonist-mediated receptor internalization, the fact that most of the 5-HT2A receptors are located intracellularly and [18F]altanserin is an antagonist radioligand are likely to be the most important explanations. Here we present our preliminary results in three healthy subjects using citalopram challenge and the new 5-HT1A agonist radioligand [11C]CUMI-101. Our hypothesis is that [11C]CUMI-101 binding to 5-HT1A receptors is reduced following acute citalopram challenge. Methods: [11C]CUMI-101was synthesized as previously described(2). [11C]CUMI-101was injected as a bolus and PET (high-resolution research tomography scanner, Siemens AG) data were subsequently collected for 120 minutes. Arterial blood samples were obtained during PET scanning and metabolite corrected using HPLC as previously described(3). Thirty minutes after ending the first PET experiment one hour of constant Citalopram (H. Lundbeck A/S, 0.15 mg kg- 1) infusion started. Thirty minutes after Citalopram infusion started a second [11C]CUMI-101-PET experiment was conducted similar to the first experiment. MRI was conducted on a Siemens Magnetom Trio 3 T MR scanner (Invivo, FL, USA) and co-registred to the PET image. VOIs were automatically delineated on each individual's MRI in a strictly user-independent fashion(4). Kinetic modeling (unconstrained 2-tissue compartment modeling and simplified tissue reference modeling) was done in PMOD (version 3.0). Results:
[table] In subject 3 the final analysis of blood data in the baseline situation is to be completed. Conclusion: Our preliminary results do not imply a decrease in [11C]CUMI-101 binding to 5- HT1A receptors following intravenous citalopram challenge. The literature suggests a decrease in regional cerebral blood flow following intravenous administration of citalopram. Our K1 and R1 values do not imply a quantitatively important reduction in tracer delivery following citalopram challenge. Our results do not imply that the use of cerebellum as a reference region is hampered by the increase in extracellular 5-HT following citalopram infusion. Recent unpublished data (Hendry-N et al.) suggest that [11C]CUMI-101 behaves as an antagonist on rodent cortical 5-HT1A receptors. Sensitivity of [11C]CUMI-101to acute pharmacological challenge in monkeys has been demonstrated but at much larger doses of citalopram (2-4 mg kg-1)(5). Thus, the challenge paradigm and the radiotracer may not be optimal for measuring acute changes in extracellular 5-HT. Further studies are needed to draw more firm conclusions using this experimental set-up. References: (1) Pinborg et al. (2004) J Cereb Blood Flow Metab 24:1037-45
(2) Kumar et al. (2007) Eur J Nucl Med Mol Imaging 34:1050-60 (3) Gillings-N (2009) Nucl Med Biol 36:961-65 (4) Svarer et al. (2005) Neuroimage 24:969-79 (5) Milak et al. (2010) J Cereb Blood Flow Metab: Epub ahead of print
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Judges’ Comments: Theme-based sections 2013 (NB. Most issues mentioned in past years’ comments are still relevant) This year’s theme “Australian Science Through The Ages” has been very popular with teachers as it allowed integration of science outcomes (especially Science As A Human Endeavour) and history outcomes, as well as literacy, art and IT skills. I doubt whether this degr