A Bone-Seeking trans-Cyclooctene for Pretargeting and Bioorthogonal Chemistry: A Proof of Concept Study Using99mTc- and177Lu-Labeled Tetrazines.
A high yield synthesis of a novel, small molecule, bisphosphonate-modified trans-cyclooctene (TCO-BP, 2) that binds to regions of active bone metabolism and captures functionalized tetrazines in vivo, via the bioorthogonal inverse electron demand Diels-Alder (IEDDA) cycloaddition, was developed. A99mTc-labeled derivative of 2 demonstrated selective localization to shoulder and knee joints in a biodistribution study in normal mice. Compound 2 reacted rapidly with a177Lu-labeled tetrazine in vitro, and pretargeting experiments in mice, using 2 and the177Lu-labeled tetrazine, yielded high activity concentrations in shoulder and knee joints, with minimal uptake in other tissues. Pretargeting experiments with 2 and a novel99mTc-labeled tetrazine also produced high activity concentrations in the knees and shoulders. Critically, both radiolabeled tetrazines showed negligible uptake in the skeleton and joints when administered in the absence of 2. Compound 2 can be utilized to target functionalized tetrazines to bone and represents a convenient reagent to test novel tetrazines for use with in vivo bioorthogonal pretargeting strategies.
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Abdolreza
A
Yazdani
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Holly
H
Bilton
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Alyssa
A
Vito
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Afaf R
AR
Genady
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Stephanie M
SM
Rathmann
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Zainab
Z
Ahmad
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Nancy
N
Janzen
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
Shannon
S
Czorny
Department of Chemistry, Hunter College , 695 Park Avenue New York, New York 10065, United States.|Ph.D. Program in Chemistry, The Graduate Center of the City University of New York , 365 Fifth Avenue, New York, New York 10016, United States.
Brian M
BM
Zeglis
Department of Chemistry, Hunter College , 695 Park Avenue New York, New York 10065, United States.|Ph.D. Program in Chemistry, The Graduate Center of the City University of New York , 365 Fifth Avenue, New York, New York 10016, United States.
Lynn C
LC
Francesconi
Department of Chemistry and Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
John F
JF
Valliant
D000818:Animals; D001842:Bone and Bones / Q000737:chemistry / Q000378:metabolism*; D034242:Cyclooctanes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008187:Lutetium / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011868:Radioisotopes; D013329:Structure-Activity Relationship; D017556:Technetium Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D034242:Cyclooctanes; D011868:Radioisotopes; D017556:Technetium Compounds; D013777:Tetrazoles; D008187:Lutetium
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