Radiolabeled neuronal nitric oxide synthase inhibitors: Synthesis, in vivo evaluation, and primate PET studies

M. G. Pomper, J. L. Musachio, U. Scheffel, J. E. Macdonald, D. J. McCarthy, D. W. Reif, V. L. Villemagne, F. Yokoi, R. F. Dannals, D. F. Wong

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The objectives of this study were to synthesize neuronal nitric oxide synthase (NOS-I)-selective imaging agents based on the 2 potent, selective inhibitors AR-R 17443 [N-(4-((2-((phenylmethyl) (methyl)amino)ethyl)phenyl)-2-thiophenecarboximidamide)] and AR-R 18512 [(N-(2-methyl-1,2,3,4-tetrahydroisoquinoline-7-yl)-2-thiophenecar boximidamide)] in positron-emitting form and to evaluate regional brain uptake in rodents and primates. Methods: [11C]AR-R 17443 and [11C]AR-R 18512 were produced by N-alkylation of the corresponding desmethyl precursors using [11C]iodomethane. Regional brain uptake of [11C]AR-R 17443 and [11C]AR-R 18512 was assayed in rats and NOS-I knockout mice, and PET was performed in baboons. Tracer kinetic modeling used a 2-compartment plasma and brain tissue model. Results: Yields of [11C]AR-R 17443 and [11C]AR-R 18512 ranged from 8% to 16% at the end of synthesis, with specific activities of 50-178 GBq/μmol (1350-4800 Ci/mmol) at the end of synthesis. In rat cerebellum and cortex at 30 min after injection, [11C]AR-R 17443 showed 1.01 ± 0.01 and 1.63 ± 0.12 percentage injected dose per gram (%lD/g) uptake, respectively, whereas [11C]AR-R 18512 showed 0.88 ± 0.01 and 1.30 ± 0.07 %ID/g uptake, respectively. Attempts to block tracer uptake by pretreatment with the NOS-I-selective inhibitor 7-nitroindazole or the corresponding unlabeled inhibitor (or desmethyl precursor to AR-R 17443 of similar potency) were unsuccessful. A small but significant (20%) decrease in cerebellar uptake of [11C]AR-R 18512 was present in NOS-I knockout mice compared with control mice. PET of [11C]AR-R 18512 in baboons with concurrent regional cerebral blood flow (rCBF) determination before and after administration of blocker showed dose-related decreases in cerebellar uptake that were greater than or equal to decreases in rCBF. Plasma metabolites accounted for 27% of total activity at 30 min after injection. Kinetic modeling of binding potentials revealed a distribution volume of 334 in cerebral blood that dropped 51% after blocker administration. Conclusion: Rodent studies for [11C]AR-R 17443 and [11C]AR-R 18512 showed little evidence of specific NOS-I binding. In baboons, we detected a higher uptake of [11C]AR-R 18512 in the cerebellum than in the cortex (approximately 5%, accounting for decreased rCBF because of blockade), indicating minimal specific binding. Analogs of higher affinity are likely required if this class of agents is to prove viable for PET.

Original languageEnglish
Pages (from-to)1417-1425
Number of pages9
JournalJournal of Nuclear Medicine
Issue number8
StatePublished - 2000


  • Baboon
  • Knockout mice
  • Nitric oxide synthase
  • PET
  • Thiopheneamidine


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