title: Enantiopure bifunctional chelators for copper radiopharmaceuticals--does chirality matter in radiotracer design?
abstract: It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Basic Science, Appalachian College of Pharmacy, Oakwood, VA, USA.
authors.forename: Ajay N
authors.initials: AN
authors.lastname: Singh
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Dakanali
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Guiyang
authors.initials: G
authors.lastname: Hao
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Saleh
authors.initials: S
authors.lastname: Ramezani
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Xiankai.Sun@UTSouthwestern.edu.
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D003301:Copper Radioisotopes; D015195:Drug Design; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D002614:Chelating Agents; D003301:Copper Radioisotopes; D039302:Integrin alphaVbeta3; D047028:Macrocyclic Compounds; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals
keywords: Bifunctional chelator (BFC); Copper-64; Diagnosis; Imaging; Integrin α(v)β(3); Molecular imaging; Positron emission tomography; Prognosis