title: Radiosynthesis of N-(4-chloro-3-[(11)C]methoxyphenyl)-2-picolinamide ([(11)C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4).
abstract: N-(Chloro-3-methoxyphenyl)-2-picolinamide (3, ML128, VU0361737) is an mGlu4 positive allosteric modulator (PAM), which is potent and centrally penetrating. 3 is also the first mGlu4 PAM to show efficacy in a preclinical Parkinson disease model upon systemic dosing. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers a possibility to investigate mGlu4 expression in vivo under physiologic and pathological conditions. We synthesized a carbon-11 labeled ML128 ([(11)C]3) as a PET radiotracer for mGlu4, and characterized its biological properties in Sprague Dawley rats. [(11)C]3 was synthesized from N-(4-chloro-3-hydroxyphenyl)-2-picolinamide (2) using [(11)C]CH3I. Total synthesis time was 38±2.2min (n=7) from the end of bombardment to the formulation. The radioligand [(11)C]3 was obtained in 27.7±5.3% (n=5) decay corrected radiochemical yield based on the radioactivity of [(11)C]CO2. The radiochemical purity of [(11)C]3 was >99%. Specific activity was 188.7±88.8GBq/mol (n=4) at the end of synthesis (EOS). PET images were conducted in 20 normal male Sprague Dawley rats including 11 control studies, 6 studies blocking with an mGlu4 modulator (4) to investigate specificity and 3 studies blocking with an mGlu5 modulator (MTEP) to investigate selectivity. These studies showed fast accumulation of [(11)C]3 (peak activity between 1-3min) in several brain areas including striatum, thalamus, hippocampus, cerebellum, and olfactory bulb following with fast washout. Blocking studies with the mGlu4 modulator 4 showed 22-28% decrease of [(11)C]3 accumulation while studies of selectivity showed only minor decrease supporting good selectivity over mGlu5. Biodistribution studies and blood analyses support fast metabolism. Altogether this is the first PET imaging ligand for mGlu4, in which the labeled ML128 was used for imaging its in vivo distribution and pharmacokinetics in brain.
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, United States.
authors: Kun-Eek
authors: KE
authors: Kil
authors: Zhaoda
authors: Z
authors: Zhang
authors: Kimmo
authors: K
authors: Jokivarsi
authors: Chunyu
authors: C
authors: Gong
authors: Ji-Kyung
authors: JK
authors: Choi
authors: Sreekanth
authors: S
authors: Kura
authors: Anna-Liisa
authors: AL
authors: Brownell
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry*; D008297:Male; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry*
chemical_list: D000814:Aniline Compounds; D002250:Carbon Radioisotopes; C587536:N-(4-chloro-3-methoxyphenyl)-2-picolinamide; D010848:Picolinic Acids; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; C108823:metabotropic glutamate receptor 4
keywords: Metabotropic glutamate receptor subtype 4 (mGlu(4)); PET; Positive allosteric modulator; [(11)C]ML128
references: J Med Chem. 2003 Jan 16;46(2):204-6
references: 12519057
references: Annu Rev Pharmacol Toxicol. 1997;37:205-37
references: 9131252
references: Cell Signal. 2002 May;14(5):397-405
references: 11882384
references: J Med Chem. 2009 Jul 23;52(14):4115-8
references: 19469556
references: Future Med Chem. 2009 Jun;1(3):501-13
references: 20161443
references: Neuropharmacology. 2003 Dec;45(7):895-906
references: 14573382
references: NeuroRx. 2005 Oct;2(4):541-53
references: 16489364
references: Drugs Aging. 2003;20(5):377-97
references: 12696997
references: Nucl Med Biol. 2009 Feb;36(2):215-23
references: 19217534
references: Neurosci Lett. 1996 Apr 5;207(3):199-202
references: 8728484
references: J Nucl Med. 2006 Apr;47(4):698-705
references: 16595505
references: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3759-64
references: 17360426
references: Neuroscience. 2002;110(3):403-20
references: 11906782
references: Synapse. 2011 Feb;65(2):125-35
references: 20524178
references: Curr Drug Targets CNS Neurol Disord. 2002 Jun;1(3):297-317
references: 12769621
references: Synapse. 2007 Dec;61(12):951-61
references: 17787003
references: Neuropharmacology. 1999 Oct;38(10):1431-76
references: 10530808
references: ACS Chem Neurosci. 2012 Jan 18;3(1):50-68
references: 22267984
references: Nucl Med Biol. 2010 Jul;37(5):615-24
references: 20610166
references: ACS Chem Neurosci. 2011 Aug 17;2(8):433-49
references: 22860170
references: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13668-73
references: 14593202
references: J Comp Neurol. 1999 Apr 28;407(1):33-46
references: 10213186
references: Prog Neurobiol. 2000 Sep;62(1):63-88
references: 10821982