Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine.
Substituting a pyridine ring for a benzene ring in the acylation agent N-succinimidyl 3-iodobenzoate has resulted in a useful approach for the radiohalogenation of monoclonal antibodies, peptides, and labeled biotin conjugates. It was hypothesized that such a substitution in m-iodobenzylguanidine (MIBG), a radiotracer used in the detection and treatment of neuroendocrine tumors, might result in an analogue with more rapid normal tissue clearance, thereby facilitating its use for tumor therapy. For the preparation of this analogue, 3-guanidinomethyl-5-iodopyridine (GMIP; 9b), the silicon precursor 4 was synthesized starting from 5-bromonicotinic acid. Attempts to convert 4 to 9b under various conditions were not successful. Radioiodinated 9b could be prepared by the iododestannylation of the tin precursor 8 in 65-70% radiochemical yield. A number of in vitro, in vivo, and ex vivo studies showed that pyridine-for-benzene substitution in MIBG yielded a compound that no longer was taken up by the uptake-1 pathway.
Vaidyanathan
G
G
Department of Radiology, Duke University Medical Center, P.O. Box 3808, Durham, North Carolina 27710, USA. ganesan.v@duke.edu
Zalutsky
M R
MR
DeGrado
T R
TR
D019797:3-Iodobenzylguanidine / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007462:Iodobenzenes / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009206:Myocardium / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility; D027981:Symporters; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D007462:Iodobenzenes; D008055:Lipids; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; D027981:Symporters; D019797:3-Iodobenzylguanidine