Preparation of classical Re/ 99m Tc(CO) 3 + and novel 99m Tc(CO) 2 (NO) 2+ cores complexed with flavonol derivatives and their binding characteristics for Ab (1–40) aggregates Yang Yang, Lin Zhu, Mengchao Cui , Ruikun Tang, Huabei Zhang * Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China article info Article history: Received 26 November 2009 Revised 28 January 2010 Accepted 9 April 2010 Available online 31 July 2010 Keywords: Ab (1–40) aggregates Re/ 99m Tc(CO) 3 + -3-OH-flavone 99m Tc(CO) 2 (NO) 2+ Autoradiography K d Fluorescence UV-spectra Biodistribution abstract Classical 99m Tc(CO) 3 + and novel 99m Tc(CO) 2 (NO) 2+ cores complexed with flavonol derivatives were pre- pared. Autoradiography of postmortem AD transgenic mice (Tg C57, APP, PS1 12-month-old) brain sec- tion confirmed the binding property of [ 99m Tc(CO) 3 + -3-OH-flavone] 0 to Ab (1–40) aggregates, while the novel 99m Tc(CO) 2 (NO) 2+ labeled compounds showed no binding sites in AD transgenic mice sections. Intravenous administration of [ 99m Tc(CO) 3 + -3-OH-flavone] 0 resulted in moderate brain uptake (0.48 ± 0.05%ID/g) at 5 min post-injection and slow clearance from the brain issues in 2 h post-injection (120 min: 0.39 ± 0.08%ID/g). Then an Ab (1–40) -receptor-targeted Re(CO) 3 + -3-OH-flavone, was prepared to identify the structure of the technetium complex. UV–vis absorption and fluorescence emission proper- ties have been studied at room temperature in order to determine the natures of the lowest electronically excited states of Re(CO) 3 + -3-OH-flavone and the ligand. The fluorescent rhenium complex Re(CO) 3 + -3- OH-flavone showed high affinity for Ab (1–40) aggregates in vitro by fluorescence spectra (dissociation con- stant (K d ) = 11.16 nM). In conclusion, the results suggested that 99m Tc(CO) 3 + -3-OH-flavone should be a suitable candidate as Ab plaque SPECT imaging agent for AD. Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved. Alzheimer’s disease (AD) caused 50–60% of all the dementia cases, and it is a brain disorder associated with progressive mem- ory loss and decrease of cognitive function. 1 In the development and progression of AD, the formation of the senile plaques are crit- ical factors, and the senile plaques are extracellular deposits of amyloid fibrils of b-amyloid (Ab) (Ab (1–40) and Ab (1–42) ), 2 the char- acteristic of which was a typical b-sheet form. 3,4 However, early diagnosis of AD is often unreliable and the only definitive confir- mation of AD is by postmortem histopathological examination of amyloid deposits in the brain. 5 Thus, the direct mapping of Ab aggregates in the living brain by PET and SPECT Ab aggregates-spe- cific imaging agents is an active research area. Many agents has been attempted and several of them might be selected as the can- didates for targeting Ab aggregates, such as 18 F-FDDNP, 6 11 C-PIB, 7 and 11 C-SB-13. 8 Currently, novel radioiodinated flavone derivatives for imaging of b-amyloid plaques were reported by Masahiro Ono, 9,10 and the binding affinities of radioiodinated flavones were from 13 to 77 nM. In addition, these compounds displayed high brain uptakes at 2 min post-injection and rapid wash-out from the brain at 30 min in normal mice. The reports suggested that these flavone derivatives might be candidates for b-amyloid aggre- gates imaging. However, the development of 99m Tc-labeled radioactive probes for SPECT was lagging far behind. Technetium-99m labeled com- pounds would be particularly useful in view of the favorable phys- ical properties (t 1/2 = 6 h, E c = 140 keV), easy and widespread availability, and low cost of the 99m Tc nuclide as well. 11 Since there is no stable isotope of Tc available, the use of rhenium, as a VIIB congener of technetium, may facilitate the development of techne- tium-99m labeled complexes, because of the similar physical, chemical and biodistribution properties of the two nuclides. More- over, the methodologies developed to generate Re complexes are generally applicable to generate their corresponding Tc analogs, so rhenium complexes were often used as a non-radioactive alter- native for the structural characterization of technetium complexes and the determination of binding affinities of the Tc-radiotracers. 12 Here to fore, no 99m Tc-labeled compound has been successfully applied for Ab aggregates imaging due to the low penetration into blood–brain barrier (BBB), in spite of their high binding affinities for Ab aggregates. 13–16 However, the classical 99m Tc(CO) 3 + and no- vel 99m Tc(CO) 2 (NO) 2+ cores were helpful to design new radiophar- maceuticals, and in our previous report, we have successfully converted the 99m Tc(CO) 3 + core into 99m Tc(CO) 2 (NO) 2+ with [NO][BF 4 ] in water and acetonitrile. 17 Thus, in order to develop 99m Tc labeled Ab plaques imaging agents, we prepared novel Re/ 99m Tc(CO) 3 + -complexed 3- OH-flavone and 99m Tc(CO) 2 (NO) 2+ core labeled 6-OH-flavone 0960-894X/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.04.026 * Corresponding author. Tel.: +86 10 58802961. E-mail address: hbzhang@bnu.edu.cn (H. Zhang). Bioorganic & Medicinal Chemistry Letters 20 (2010) 5337–5344 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl