title: In vivo muscarinic binding selectivity of (R,S)- and (R,R)-[18F]-fluoromethyl QNB.
abstract: We have developed a multistep radiochemical synthesis of two diastereomers of quinuclidinyl-4-[18F]-fluoromethyl-benzilate ([18F]-FMeQNB), a high-affinity ligand for muscarinic acetylcholine receptors. Previously, we have shown that the nonradioactive (R,R)-diastereomer displays an eightfold selectivity for M1 over M2 while the nonradioactive (R,S)-diastereomer displays a sevenfold selectivity for M2 over M1 in vitro. This paper reports the results of in vivo comparison studies. In the rat, uptake of (R,S)-[18F]-FMeQNB was nearly uniform in all brain regions following the concentration of M2 subtype. The uptake was reduced by 36-54% in all brain regions on coinjection with 50 nmol of unlabeled ligand. An injection of (R,S)-[18F]-FMeQNB followed at 60 min by injection of unlabeled ligand and subsequent sacrifice at 120 min displaced 30-50% of radioactivity in the pons, medulla, and cerebellum, which contain a high proportion of M2 subtype. The most dramatic displacement and inhibition of uptake on coinjection of (R,S)-[18F]-FMeQNB was observed in the heart. In rhesus monkey, the compound showed prolonged uptake and retention in the brain. In the blood, the parent compound degraded rapidly to a single radiolabeled polar metabolite believed to be fluoride. Within 30 min the parent compound represented less than 5% of the plasma activity. Displacement with (R)-QNB was generally slow, but was more rapid from those tissues which contain a higher proportion of M2 subtype. The results are consistent with the hypothesis that (R,S)-[18F]-FMeQNB is M2 selective in vivo. On the other hand, (R,R)-[18F]-FMeQNB showed higher uptake in those brain regions containing a higher concentration of M1 subtype. Uptake in the heart at 60 min was much lower than that observed with the (R,S)-diastereomer. Inhibition of uptake on coinjection with unlabeled (R,S)-FMeQNB is only significant in the heart, thalamus, and pons. Inhibition of uptake on coinjection with unlabeled (R,R)-FMeQNB is quite uniform in all brain regions. Displacement with (R)-QNB shows a more varying amount displaced. These results are consistent with (R,R)-[18F]-FMeQNB being M1 selective in vivo.
authors.affiliation: National Institutes of Health, Positron Emission Tomography Department, Warren G. Magnusen Clinical Center, Bethesda, MD 20892-1180, USA. dk7k@nih.gov
authors.forename: D O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: R E
authors.initials: RE
authors.lastname: Carson
authors.forename: E M
authors.initials: EM
authors.lastname: Jagoda
authors.forename: C J
authors.initials: CJ
authors.lastname: Endres
authors.forename: M G
authors.initials: MG
authors.lastname: Der
authors.forename: P
authors.initials: P
authors.lastname: Herscovitch
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
mesh_terms: D000778:Anesthetics, Dissociative / Q000494:pharmacology; D000818:Animals; D001561:Benzilates / Q000737:chemistry / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism*; D007649:Ketamine / Q000494:pharmacology; D008253:Macaca mulatta; D011812:Quinuclidines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D014055:Tomography, Emission-Computed
chemical_list: D000778:Anesthetics, Dissociative; D001561:Benzilates; D001798:Blood Proteins; D005462:Fluorine Radioisotopes; D011812:Quinuclidines; D011976:Receptors, Muscarinic; C105029:3-quinuclidinyl 4-fluoromethylbenzilate; D007649:Ketamine