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Synthesis, Rodent Biodistribution, Dosimetry, Metabolism, and Monkey Images of Carbon-11-Labeled (+)-2-Tropanyl Benzilate: A Central Muscarinic Receptor Imaging Agent

G. Keith Mulholland^*, Charlotte A. Otto, Douglas M. Jewett^*, Michael R. Kilbourn^*, Robert A. Koeppe^*, Phillip S. Sherman^*, Neil A. Petry^*, James E. Carey^*, Edward R. Atkinson, Sydney Archer, Kirk A. Frey^* and David E. Kuhl^*

^* Division of Nuclear Medicine, University of Michigan, Ann Arbor, Michigan
University of Michigan-Dearborn, Dearborn, Michigan
Amherst, Massachusetts
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York

Correspondence: For reprints contact: G. Keith Mulholland, PhD, University of Michigan, Division of Nuclear Medicine, Cyclotron/PET Facility, 3480 Kresge III, Ann Arbor, MI 48109.

ABSTRACT

Muscarinic cholinergic receptors (mAChR) are abundant in the brain, and the mAChR system mediates many aspects of brain function. There is evidence of alterations in muscarinic binding in degenerative brain disorders. A muscarinic receptor radiolig and, carbon-11-(+)-2-tropanyl benzilate ([¹¹C]TRB), has been prepared through N-[¹¹C]methylation of N-desmethyl TRB, and evaluated in rodents and primates. Full body biodistribution in rats has been determined and the expected human dosimetry calculated. Comparisons with [¹¹C]scopolamine in rats showed 2–6 times greater brain uptake of [¹¹C]TRB. Highly specific and saturable binding of [¹¹C]TRB in the striatum and cortex was demonstrated by greater than 85% blockade of uptake following QNB or scopolamine pretreatment. Striatum/cerebellum ratios in mice at 60 min exceeded 12.6. TLC analysis of rat tissues showed the absence of ¹¹C-metabolites in brain and heart, and a rapid solid phase C-18 Sep-Pak method found that unmetabolized plasma [¹¹C]TRB in monkeys fell from 81% at 5 min to 48% at 80 min. Finally, brains of living primates have been imaged using PET and [¹¹C]TRB; regional localization was consistent with muscarinic receptor distribution. These results represent intermediate steps in the development of [¹¹C]TRB for quantification of central muscarinic receptors in man.