摘要
碳11標誌1-Aminocyclobutane carboxylic acid (ACBC) 據文獻報導對再復發性腦腫瘤造影的精確度較18F-FDG高出許多。此碳11標誌之胺基酸在腦腫瘤對正常細胞或組織的吸收比值可高達10：1頗令人矚目。本研究擬提出一具有高親脂性的含硼之ACBC衍生物胺基酸以發展為治療肝癌之BNCT藥物1-Amino-3-[7-(4-boronphenyl)heptyl]cyclobutane carboxylic acid為本研究所選擇之化合物。

此化合物經由七個步驟之合成程序已經成功的製備出來，由第一步驟至最終產物的各個實驗條件被有系統地探討。起始步驟的產物9-(4-bromophenyl)-1-none在嚴謹的條件下(-70℃，一大氣壓，氬氣)經由4-bromobenzyl bromide和7-octenyl magnesium bromide進行SN2反應而得。而整個合成程序的關鍵性步驟在於前驅物p-boronophenyl-heptyl-cyclobutanone ethylene ketal之製備，此前驅物再經Bucherer-Strecker反應即可得最終產物。以上合成程序中所得各階段之化合物及最後產物利用1H-NMR及13C-NMR予以鑑定確認。

最終產物經進一步純化，以進行肝癌細胞攝取、動物體的生物分佈等試驗，探討此高親脂性含硼氨基酸化合物未來作為BNCT肝癌治療藥物之潛力。

Abstract
The 11C labeled 1-aminocyclobutanecarboxylic acid (ACBC) has been previously reported to be more accurate than 18F-FDG for diagnosing recurrent brain tumors. The tumor uptake of the 11C labeled ACBC was very impressive, with the tumor/normal tissue ratio as high as 10:1. In this study, the boronated derivative of the amino acid selected with high lipophilicity was proposed to develop as the BNCT (boron neutron capture therapy) drug for hepatoma, instead of brain tumor. 1-Amino-3-[7-(4-boronophenyl)heptyl]cyclobutane-carboxylic acid was chosen and studied for the purpose.

The compound has been synthesized via seven steps. The conditions proceeding from the first step to the final product have been systematically investigated. Initially, 9-(4-bromophenyl)-1-nonene was prepared under a crucial condition at -70℃and under argon atmosphere by the reaction of 4-bromobenzyl bromide with 7-octenyl magnesium bromide. The key step was the preparation of the precursor p-boronophenyl-heptyl-cyclobutane ethylene ketal, which was subsequently converted to the desired boronated amino acid via the Bucherer-Strecker reaction. 1H-NMR and 13C-NMR were used to identify all the compounds synthesized in the process. The final product was furthermore purified for a preliminary study as a BNCT agent including cell uptake, animal biodistribution etc.

1. Locher, G. L. Am. J. Roentgenol. Radiat. Ther. 1936, 36, 1.
2. Sweet, W. H. N.; Javid, M. J. Neurosurgery 1952, 9, 200.
3. Sweet, W. H. N.; Javid, M. J. Med. 1951, 245, 875.
4. Hatanaka, H.; Nakagawa, Y. Int. J. Radiat. Oncol. Biol.Phys.
1994, 28, No.5, 1061.
5. Haritz, D.; Gabel, D.; Huiskamp. R. Int. J. Radiat. Oncol.
Niol. Phys. 1994, 28,No. 5, 1061.
6. Edward, K. H.; Robert, M. H. J. Am. Chem. Soc. 1943, 21.
7. Stephen, B. K.; Ramesh, A. K. J. Am. Chem. Soc. 1996, 118,
1223-1224.
8. Rajiv, R. S.; George, W. K. J. Org. Chem. 1997, 62, 8730-
8734.
9. Rajiv, R. S.; Robert, R. S.; George, W. K. J. Org. Chem.
1999, 64, 8495-8500.
10. Hubner, K. F.; Thie, J. A.; Smith, G. T.; Kabalka, G. W.;
Keller, I. B.; Kliefoth, A. B.; Campbell, S. K.; Buonocore,
E. Clin. Positron Imag. 1998, 1, 165.
11. Raymond, K. M.; David, M. S.; Aitken, R. K. Guidebook to
organic synthesis 1990:39-45.
12. Larry, R. K.; Alfred, H. J. Org. Chem. 1978, 43, 2879-2882.
13. Brian, S. F.; Antony, J. H.; Peter, W. G. S.; Austin, R. T.
Textbook of practical organic chemistry 1989:467-468
14. Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.
15. Michael, T. C.; Joe, A. D. J. Am. Chem. Soc. 1986, 108, 800-
806.
16. Henry, R. H.; Robert, J. S. J. Am. Chem. Soc. 1942, 64, 522.
17. Edward, J. T.; Jitrangsri, C. Can. J. Chem. 1975, 53, 3339.
18. David, C. H.; Mary, J. M.; Simon, O. Tetrahedron Letters
1998, 39, 8729-8732.
19. Serkos, A. H.; Minas, P. G.; Moschos, G. P. J. Heter. Chem.
1989, 26, 1283.