Synthesis and biological evaluation of [11C]MK-912 as an α2- adrenergic receptor radioligand for PET studies

Chyng Yann Shiue, Richard C. Pleus, Grace G. Shiue, Joseph A. Rysavy, John J. Sunderland, Kurtis G Cornish, Steven D. Young, David B. Bylund

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

In vitro studies showed that MK-912 ((2S, 12bS)1',3'- dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2H-benzo[b]furo[2,3- a]quinolizine) 2,4'-pyrimidin-2'-one) is a potent α2-adrenergic receptor antagonist with high affinity (K(i) = 0.42, 0.26 and 0.03 nM to α(2A), α(2B) and α(2C), respectively) and high selectivity (α(2A)/α(1A) = 240; α(2A)/D-1 = 3600; α(2A)/D-2 = 3500; α(2A)/5-HT1 = 700; α(2A)/5-HT2 = 4100). The compound was labeled with 11C and evaluated in rodents and monkey as a specific radioligand for studying α2-adrenergic receptors using PET. [11C]MK-912 (2) was synthesized by methylation of its desmethyl precursor, L-668,929 (1), with [11C]CH3I in (Bu3O)P=O at 85°C for 8 min followed by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB). The specific activity was 0.83-0.93 Ci/μmol and the radiochemical purity was 97%. The initial uptake of [11C]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinjection) and the activities were then slowly cleared from these organs. The uptake of [11C]MK-912 in rat olfactory tubercle, a brain region with high density of α2-adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was reduced from 2:1 to 1:1 by coinjection of [11C]MK- 912 with a potent α2-adrenergic receptor antagonist, atipamezole (3 mg/kg), indicating that compound 2 binds to α2-adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [11C]MK-912 into various brain regions (cerebellum, cortex, olfactory tubercle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the high-density α2- adrenergic receptor brain regions exceeds a few millimeters in diameter, suggests that [11C]MK-912 is probably not an ideal radioligand for studying α2-adrenergic receptors in humans using commercially available PET.

Original languageEnglish (US)
Pages (from-to)127-133
Number of pages7
JournalNuclear Medicine and Biology
Volume25
Issue number2
DOIs
StatePublished - Feb 1 1998

Fingerprint

L 657743
Adrenergic Receptors
Brain
Adrenergic Antagonists
Cerebellum
Radioactivity
Macaca mulatta
Methylation
Haplorhini
Rodentia

Keywords

  • PET
  • [C]MK-912
  • α-Adrenergic receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Shiue, C. Y., Pleus, R. C., Shiue, G. G., Rysavy, J. A., Sunderland, J. J., Cornish, K. G., ... Bylund, D. B. (1998). Synthesis and biological evaluation of [11C]MK-912 as an α2- adrenergic receptor radioligand for PET studies. Nuclear Medicine and Biology, 25(2), 127-133. https://doi.org/10.1016/S0969-8051(97)00167-4

Synthesis and biological evaluation of [11C]MK-912 as an α2- adrenergic receptor radioligand for PET studies. / Shiue, Chyng Yann; Pleus, Richard C.; Shiue, Grace G.; Rysavy, Joseph A.; Sunderland, John J.; Cornish, Kurtis G; Young, Steven D.; Bylund, David B.

In: Nuclear Medicine and Biology, Vol. 25, No. 2, 01.02.1998, p. 127-133.

Research output: Contribution to journalArticle

Shiue, CY, Pleus, RC, Shiue, GG, Rysavy, JA, Sunderland, JJ, Cornish, KG, Young, SD & Bylund, DB 1998, 'Synthesis and biological evaluation of [11C]MK-912 as an α2- adrenergic receptor radioligand for PET studies', Nuclear Medicine and Biology, vol. 25, no. 2, pp. 127-133. https://doi.org/10.1016/S0969-8051(97)00167-4
Shiue, Chyng Yann ; Pleus, Richard C. ; Shiue, Grace G. ; Rysavy, Joseph A. ; Sunderland, John J. ; Cornish, Kurtis G ; Young, Steven D. ; Bylund, David B. / Synthesis and biological evaluation of [11C]MK-912 as an α2- adrenergic receptor radioligand for PET studies. In: Nuclear Medicine and Biology. 1998 ; Vol. 25, No. 2. pp. 127-133.
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T1 - Synthesis and biological evaluation of [11C]MK-912 as an α2- adrenergic receptor radioligand for PET studies

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AU - Pleus, Richard C.

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AU - Rysavy, Joseph A.

AU - Sunderland, John J.

AU - Cornish, Kurtis G

AU - Young, Steven D.

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AB - In vitro studies showed that MK-912 ((2S, 12bS)1',3'- dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2H-benzo[b]furo[2,3- a]quinolizine) 2,4'-pyrimidin-2'-one) is a potent α2-adrenergic receptor antagonist with high affinity (K(i) = 0.42, 0.26 and 0.03 nM to α(2A), α(2B) and α(2C), respectively) and high selectivity (α(2A)/α(1A) = 240; α(2A)/D-1 = 3600; α(2A)/D-2 = 3500; α(2A)/5-HT1 = 700; α(2A)/5-HT2 = 4100). The compound was labeled with 11C and evaluated in rodents and monkey as a specific radioligand for studying α2-adrenergic receptors using PET. [11C]MK-912 (2) was synthesized by methylation of its desmethyl precursor, L-668,929 (1), with [11C]CH3I in (Bu3O)P=O at 85°C for 8 min followed by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB). The specific activity was 0.83-0.93 Ci/μmol and the radiochemical purity was 97%. The initial uptake of [11C]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinjection) and the activities were then slowly cleared from these organs. The uptake of [11C]MK-912 in rat olfactory tubercle, a brain region with high density of α2-adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was reduced from 2:1 to 1:1 by coinjection of [11C]MK- 912 with a potent α2-adrenergic receptor antagonist, atipamezole (3 mg/kg), indicating that compound 2 binds to α2-adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [11C]MK-912 into various brain regions (cerebellum, cortex, olfactory tubercle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the high-density α2- adrenergic receptor brain regions exceeds a few millimeters in diameter, suggests that [11C]MK-912 is probably not an ideal radioligand for studying α2-adrenergic receptors in humans using commercially available PET.

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