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  NOVEL METHODS OF ALTERING PHARMACOKINETICS IN RADIOPHARMACEUTICAL DESIGN
Guest Editor: Hnatowich D.
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The Quarterly Journal of Nuclear Medicine 2002 September;46(3):233-43

Copyright © 2009 EDIZIONI MINERVA MEDICA

language: English

The influence of chain length and base se-quence on the pharmacokinetic behavior of 99mTc-morpholinos in mice

Liu G., Zhang S., He J., Liu N., Gupta S., Rusckowski M., Hnatowich D. J.

Division of Nuclear Medicine Department of Radiology University of Massachusetts Medical School, Worcester, MA, USA


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Back­ground. ­Despite in ­vivo use now ­over sev­eral ­years, in par­tic­ular for ­nuclear med­i­cine ­imaging, the influ­ences on phar­ma­cok­i­netics of ­chain ­length and ­base ­sequence of radio­lab­eled oli­gomers has not ­been inves­ti­gated.
­Methods. As ­test oli­gomer, mor­pho­linos (­MORFs), a DNA ana­logue, ­were radio­lab­eled ­with 99mTc via MAG3 and the phar­ma­cok­i­netics in ­normal ­mice deter­mined for 3 ­chain ­lengths (15, 18 and 25 mer) and 2 ­base ­sequences (­MORF and its com­ple­ment ­cMORF). In addi­tion, LS174T-­tumor ­bearing ­nude ­mice ­received the ­anti-CEA anti­body MN14 (Immu­no­medics) con­ju­gated ­either ­with ­MORF15 or ­MORF18 and sub­se­quently ­received 99mTc-­labeled ­cMORF15 or ­cMORF18 respec­tively in a pre­tar­geting ­strategy.
­Results. In ­normal ­mice, ­after 1 hr, regard­less of ­chain ­length or ­sequence, all ­labeled ­MORFs and ­cMORFs accu­mu­lated ­only ­slightly in all tis­sues (e.g. at 3 hr <0.15 ID%/g) ­except in kid­neys. ­Besides ­being exces­sive, the kid­neys ­were the ­only ­tissue ­with ­levels depen­dent ­upon ­chain ­length (e.g. at 1 hr, 5, 7 and 22 ID%/g for ­MORF15, 18 and 25, respec­tively) and ­sequence (e.g. at 3 hrs 9 ID%/g for ­MORF25 and 21 ID%/g for ­cMORF25). Iden­tical bio­dis­trib­u­tion ­trends ­were ­observed in ­tumored ­mice ­with all tis­sues ­including ­tumor ­showing ­levels inde­pen­dent of ­chain ­length or ­base ­sequence ­except for kid­neys. Fur­ther­more, ­while all ­other tis­sues ­cleared in the ­interval ­from 1-3 hrs, ­kidney ­levels ­remained con­stant in ­both ­normal and ­tumored ani­mals. ­Largely ­because of ­these dif­fer­ences in kid­neys, ­images ­obtained by pre­tar­geting ­with 99mTc-­cMORF15 ­were ­superior com­pared to 99mTc-­cMORF18 (­images of con­trol ani­mals not ­receiving the anti­body ­showed no ­tumor at all).
Con­clu­sions. ­Judged by radio­label accu­mu­la­tions in ­tissue, the phar­ma­cok­i­netics of 99mTc ­labeled mor­pho­linos ­were inde­pen­dent of ­chain ­length and ­base ­sequence. The ­only ­obvious excep­tion was kid­neys in ­which accu­mu­la­tions ­were sig­nif­i­cantly ­higher for the ­longer ­chain ­lengths and sig­nif­i­cantly dif­ferent for ­cMORF vs ­MORF. ­These ­results ­show ­that ­chain ­length and ­base ­sequences may be ­varied to ­alter the phar­ma­cok­i­netics of radio­lab­eled oli­gomers in ­nuclear med­i­cine ­imaging ­studies.

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