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Synthesis and biological evaluation of carbon‐11‐labeled acyclic and furo[2,3‐d]pyrimidine derivatives of bicyclic nucleoside analogues (BCNAs) for structure–brain uptake relationship study of BCNA tracers
Author(s) -
Chitneni Satish K.,
Balzarini Jan,
Celen Sofie,
Dyubankova Natalia,
Verbruggen Alfons M.,
Bormans Guy M.
Publication year - 2008
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1494
Subject(s) - chemistry , bicyclic molecule , stereochemistry , nucleoside , pyrimidine , moiety , deoxyribose , methyl group , nucleic acid , biochemistry , organic chemistry , alkyl
We reported earlier on radiolabeled alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as potential positron emission tomography (PET) reporter probes for imaging of varicella zoster virus thymidine kinase (VZV‐tk) gene in vivo . Despite their favorable physicochemical properties, these tracers are not taken up in the brain in mice. In order to probe the role of the deoxyribose sugar moiety in blood‐brain barrier (BBB) penetration of these molecules, we have synthesized and evaluated a carbon‐11‐labeled acyclic bicyclic nucleoside derivative ([ 11 C]‐10) where the 2′‐deoxyribose sugar is replaced with a (2‐hydroxyethoxy)methyl group and [ 11 C]‐12, which has no sugar moiety but a [ 11 C]methyl group on the N‐3 position of the pyrimidine ring. Methylation was achieved on the phenol ([ 11 C]‐10) or the N‐3 position ([ 11 C]‐12) using [ 11 C]methyl triflate (radiosynthesis). The (non‐radioactive) acyclic O ‐methyl derivative 10 has rather poor affinity for the enzyme VZV‐TK in vitro (IC 50 : 430 µM), compared with the moderate affinity of the BCNA‐base N ‐methyl derivative 12 (IC 50 : 79 µM). In normal mice, none of the two tracers ([ 11 C]‐10 or [ 11 C]‐12) showed significant uptake in the brain, suggesting that compounds containing a furo[2,3‐ d ]pyrimidine system do not cross the BBB. Copyright © 2008 John Wiley & Sons, Ltd.