In Vivo Evaluation of the Uptake of [123I]FIAU, [123I]IVFRU and [123I]IVFAU by Normal Mouse Brain: Potential For Noninvasive Assessment of HSV-1 Thymidine Kinase Gene Expression in Gliomas

Abstract

Radioiodinated 5-iodo-1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)uracil (F *IAU) is most commonly used for noninvasive assessment of herpes simplex virus type 1 thymidine kinase (HSV-1-tk) gene expression. However, it does not permeate the intact blood-brain barrier (BBB) because of its moderate lipophilicity. In this work, three iodo-nucleosides, FIAU, IVFRU, and IVFAU, were radiolabeled with iodine-123 and tested for permeation of the BBB in mice and for potential measurement of HSV-1-tk gene expression in gliomas. The results demonstrate that brain uptake and retention of these nucleosides is not directly related to their lipophilicity. The low brain uptake of IVFAU, in conjunction with its higher and constant brain/blood ratio, may reflect greater stability against hydrolysis of the N-glycosidic bond. In vivo PET evaluations of [(124)I]IVFRU and [(124)I]IVFAU in tumor-bearing mice are warranted.

Synthesis and in Vitro Evaluation of 5-[18F]Fluoroalkyl Pyrimidine Nucleosides for Molecular Imaging of Herpes Simplex Virus Type 1 Thymidine Kinase Reporter Gene Expression

“…29 These results demonstrate that the usual relationship between the BBB permeability and the drug lipophilicity does not apply to these compounds. 29 In addition to log P ) 1-4, the optimal requirements for crossing the BBB include a molecular weight of <400 and a polar surface area (which highly correlates with hydrogen bonding ability) of <90 Å 2 . 31 The higher polar surface area of pyrimidine nucleosides (∼100 Å 2 ) 32 suggests that their capacity for passive BBB diffusion is inherently low.…”

“…By reason of log P values alone, [ 18 F]FFPeAU ( [ 18 F]1f ) would be expected to cross the BBB by passive diffusion more readily than FIAU or our other synthesized nucleosides. However, very recent studies with the fairly lipophilic 5-iodovinyl pyrimidine nucleosides [ 123 I]IVFRU (log P = 1.22) and [ 123 I]IVFAU (log P = 1.24) demonstrated a very low brain uptake in normal mice . These results demonstrate that the usual relationship between the BBB permeability and the drug lipophilicity does not apply to these compounds .…”

“…As alluded to in recent studies, a driving force, such as a glioma with HSV1- tk gene expression, may be required to increase the brain uptake of the radiolabeled pyrimidine nucleosides. 29 However, further in vivo studies are required to illustrate this point.…”

“…As alluded to in recent studies, a driving force, such as a glioma with HSV1-tk gene expression, may be required to increase the brain uptake of the radiolabeled pyrimidine nucleosides. 29 F]FFPeAU was studied in two glioma cell lines of murine origin. The first cell line is stably transduced with HSV1-tk (RG2TK+) and thus features cytosolic HSV1-TK enzyme activity.…”

“…The log P values can often indicate the ability of compounds to diffuse passively across intact cell membranes, including the blood−brain barrier (BBB). In recent years, there has been a drive to find reporter probes that are selectively phosphorylated by HSV1-TK while being able to permeate the BBB to allow for potential imaging of HSV1- tk gene expression in gliomas. , The moderately lipophilic FIAU does not diffuse across the intact BBB . By reason of log P values alone, [ 18 F]FFPeAU ( [ 18 F]1f ) would be expected to cross the BBB by passive diffusion more readily than FIAU or our other synthesized nucleosides.…”