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THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING

Rivista di Medicina Nucleare e Imaging Molecolare


A Journal on Nuclear Medicine and Molecular Imaging
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  NOVEL METHODS OF ALTERING PHARMACOKINETICS IN RADIOPHARMACEUTICAL DESIGN
Guest Editor: Hnatowich D.


The Quarterly Journal of Nuclear Medicine 2002 September;46(3):233-43

lingua: Inglese

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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