Synthesis and in Vitro Evaluation of Novel Nortropane Derivatives As Potential Radiotracers for Muscarinic M(2) Receptors

Overview

Journal Int J Mol Imaging

Date 2011 Jul 15

PMID 21755053

Authors

Remco J J Knol

Jan C van den Bos

Anton G M Janssen

Kora de Bruin

Berthe L F van Eck-Smit

Jan Booij

Affiliations

Soon will be listed here.

Abstract

Disturbances of the cerebral cholinergic neurotransmitter system are present in neurodegenerative disorders. SPECT or PET imaging, using radiotracers that selectively target muscarinic receptor subtypes, may be of value for in vivo evaluation of such conditions. 6β-acetoxynortropane, a potent muscarinic M(2) receptor agonist, has previously demonstrated nanomolar affinity and high selectivity for this receptor. Based on this compound we synthesized four nortropane derivatives that are potentially suitable for SPECT imaging of the M(2) receptor. 6β-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M(1-3) receptors. The original 6β-acetoxynortropane displayed high affinity (K(i) = 70-90 nM) to M(2) receptors and showed good selectivity ratios to the M(1) (65-fold ratio) and the M(3) (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M(2) subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M(2) receptors.

References

Bosboom J, Stoffers D, Wolters E . Cognitive dysfunction and dementia in Parkinson's disease. J Neural Transm (Vienna). 2004; 111(10-11):1303-15. DOI: 10.1007/s00702-004-0168-1. View

Booij J, Andringa G, Rijks L, Vermeulen R, De Bruin K, Boer G . [123I]FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP-lesioned monkeys. Synapse. 1997; 27(3):183-90. DOI: 10.1002/(SICI)1098-2396(199711)27:3<183::AID-SYN4>3.0.CO;2-9. View

Lassen N . A reappraisal of the relative merits of SPET and PET in the quantitation of neuroreceptors: the advantage of a longer half-life!. Eur J Nucl Med. 1996; 23(1):1-4. DOI: 10.1007/BF01736982. View

Perry E, Curtis M, Dick D, Candy J, Atack J, Bloxham C . Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1985; 48(5):413-21. PMC: 1028327. DOI: 10.1136/jnnp.48.5.413. View

Cannon D, Klaver J, Gandhi S, Solorio G, Peck S, Erickson K . Genetic variation in cholinergic muscarinic-2 receptor gene modulates M2 receptor binding in vivo and accounts for reduced binding in bipolar disorder. Mol Psychiatry. 2010; 16(4):407-18. PMC: 2895691. DOI: 10.1038/mp.2010.24. View

Knol R, Doornbos T, van den Bos J, de Bruin K, Pfaffendorf M, Aanhaanen W . Synthesis and evaluation of iodinated TZTP-derivatives as potential radioligands for imaging of muscarinic M2 receptors with SPET. Nucl Med Biol. 2004; 31(1):111-23. DOI: 10.1016/s0969-8051(03)00095-7. View

Ravasi L, Kiesewetter D, Shimoji K, Lucignani G, Eckelman W . Why does the agonist [(18)F]FP-TZTP bind preferentially to the M(2) muscarinic receptor?. Eur J Nucl Med Mol Imaging. 2005; 33(3):292-300. DOI: 10.1007/s00259-005-1966-x. View

Aubert I, Araujo D, Cecyre D, Robitaille Y, Gauthier S, Quirion R . Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases. J Neurochem. 1992; 58(2):529-41. DOI: 10.1111/j.1471-4159.1992.tb09752.x. View

Podruchny T, Connolly C, Bokde A, Herscovitch P, Eckelman W, Kiesewetter D . In vivo muscarinic 2 receptor imaging in cognitively normal young and older volunteers. Synapse. 2003; 48(1):39-44. DOI: 10.1002/syn.10165. View

10.

Baskin D, Browning J, Pirozzolo F, Korporaal S, Baskin J, Appel S . Brain choline acetyltransferase and mental function in Alzheimer disease. Arch Neurol. 1999; 56(9):1121-3. DOI: 10.1001/archneur.56.9.1121. View

11.

Ross S, Seibyl J . Research applications of selected 123I-labeled neuroreceptor SPECT imaging ligands. J Nucl Med Technol. 2004; 32(4):209-14. View

12.

Sauerberg P, Olesen P, Nielsen S, Treppendahl S, Sheardown M, Honore T . Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines . J Med Chem. 1992; 35(12):2274-83. DOI: 10.1021/jm00090a019. View

13.

Kiesewetter D, Lee J, Lang L, Park S, Paik C, Eckelman W . Preparation of 18F-labeled muscarinic agonist with M2 selectivity. J Med Chem. 1995; 38(1):5-8. DOI: 10.1021/jm00001a002. View

14.

Mash D, Flynn D, Potter L . Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer's disease and experimental cholinergic denervation. Science. 1985; 228(4703):1115-7. DOI: 10.1126/science.3992249. View

15.

Candy J, Perry R, Perry E, Irving D, Blessed G, Fairbairn A . Pathological changes in the nucleus of Meynert in Alzheimer's and Parkinson's diseases. J Neurol Sci. 1983; 59(2):277-89. DOI: 10.1016/0022-510x(83)90045-x. View

16.

Tiraboschi P, Hansen L, Alford M, Sabbagh M, Schoos B, Masliah E . Cholinergic dysfunction in diseases with Lewy bodies. Neurology. 2000; 54(2):407-11. DOI: 10.1212/wnl.54.2.407. View

17.

McPherson D, Dehaven-Hudkins D, Callahan A, Knapp Jr F . Synthesis and biodistribution of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate. A new ligand for the potential imaging of muscarinic receptors by single photon emission computed.... J Med Chem. 1993; 36(7):848-54. DOI: 10.1021/jm00059a009. View

18.

Maziere M . Cholinergic neurotransmission studied in vivo using positron emission tomography or single photon emission computerized tomography. Pharmacol Ther. 1995; 66(1):83-101. DOI: 10.1016/0163-7258(95)00003-y. View

19.

Nobuhara K, Halldin C, Hall H, Karlsson P, Farde L, Hiltunen J . Z-IQNP: a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease. Psychopharmacology (Berl). 2000; 149(1):45-55. DOI: 10.1007/s002139900356. View

20.

Pei X, Gupta T, Badio B, Padgett W, Daly J . 6beta-Acetoxynortropane: a potent muscarinic agonist with apparent selectivity toward M2-receptors. J Med Chem. 1998; 41(12):2047-55. DOI: 10.1021/jm9705115. View