Abstract

p-Boronophenylalanine (BPA) conjugated Gd–DTPA complex (3) was synthesized from the active methyne compound 6, the allylic carbonate 7, and BPA by the palladium-catalyzed allylation reaction followed by the DCC coupling reaction. The in vivo biodistribution of complex 3 was evaluated by prompt gamma-ray analysis and α-autoradiography using the tumor-bearing rats. High accumulation of gadolinium was observed in the kidney and the %ID values were 0.17 and 0.088 at 20 and 60 min after injection of 3, respectively. The accumulation was also observed in the tumor and the %ID values were 0.010 and 0.0025 at 20 and 60 min after injection, respectively. The visualization experiment of boron distribution in the tumor-bearing rat by α-autoradiography indicates that boron was accumulated in the tumor and the intestines at 20 min after injection.

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Keywords: MRI; Neutron capture therapy; p-Boronophenylalanine; Gadolinium complex; Gd–DTPA complex; Biodistribution

Article Outline

1. Introduction

2. Result and discussion

2.1. Chemistry

2.1.1. Design of BPA-conjugated Gd–DTPA complex (3)

2.1.2. Synthesis of the allylic carbonate 7

2.1.3. Synthesis of the precursor 4

2.1.4. Optimization of protective groups for a boronic acid of BPA

2.1.5. Synthesis of BPA–Gd–DTPA complex

2.2. Biodistribution study in vivo

2.2.1. Gadolinium concentrations in various tissues of tumor-bearing rats using prompt gamma-ray analysis (PGA)

2.2.2. Boron distribution of tumor-bearing rats visualized by α-autoradiography (α-ARG)

3. Discussion

4. Conclusion

5. Experimental

5.1. Chemistry

5.1.1. 5-(tert-Butyldimethylsilyloxy)pentanol 8

5.1.2. 5-(tert-Butyldimethylsilyloxy)pentanal 9

5.1.3. The allylic carbonate 7

5.1.4. Allylation of the diethylenetriaminehexaacetic acid hexaethyl ester 6 with the allylic carbonate 7

5.1.5. Desilylation of 10

5.1.6. The aldehyde 12

5.1.7. Synthesis of the precursor 4

5.1.8. BPA ethyl ester 13

5.1.9. Protection of BPA ethyl ester by pinanediol

5.1.10. DCC coupling of 4 with 15

5.1.11. Deprotection of the ethyl esters 16

5.1.12. Deprotection of the pinanediol ester 17

5.1.13. BPA–Gd–DTPA complex 3

5.2. In vivo biodistribution

5.2.1. Biodistribution of gadolinium using prompt gamma-ray analysis (PGA)

5.2.2. Biodistribution of boron using α-autoradiography (α-ARG)

Acknowledgements

References