RT Journal Article
SR Electronic
T1 <sup>111</sup>In-LLP2A-DOTA Polyethylene Glycol–Targeting α4β1 Integrin: Comparative Pharmacokinetics for Imaging and Therapy of Lymphoid Malignancies
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 625
OP 634
DO 10.2967/jnumed.108.056903
VO 50
IS 4
A1 DeNardo, Sally J.
A1 Liu, Ruiwu
A1 Albrecht, Huguette
A1 Natarajan, Arutselvan
A1 Sutcliffe, Julie L.
A1 Anderson, Carolyn
A1 Peng, Li
A1 Ferdani, Riccardo
A1 Cherry, Simon R.
A1 Lam, Kit S.
YR 2009
UL http://jnm.snmjournals.org/content/50/4/625.abstract
AB N-[[4-[[[(2-ethylphenyl)amino]carbonyl]amino]phenyl]acetyl]-Nε-6-[(2E)-1-oxo-3-(3-pyridinyl-2-propenyl)]-l-lysyl-l-2-aminohexanedioyl-(1-amino-1-cyclohexane)carboxamide (LLP2A) is a high-affinity, high-specificity peptidomimetic ligand (inhibitory concentration of 50% = 2 pM) that binds the activated α4β1 integrin found on a variety of malignant lymphoid cell lines. To better determine whether this ligand holds promise for imaging and therapy in lymphoid malignancies, 6 LLP2A derivatives, as LLP2A-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (LLP2A-DOTA) and LLP2A-DOTA-polyethylene glycol (LLP2A-DOTA-PEG), were designed, synthesized, and radiolabeled with 111In. Comparative pharmacokinetic studies in mice with Raji B-cell lymphoma xenografts were then complemented by small-animal PET of the lead molecular LLP2A format using 64Cu-LLP2A-11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (64Cu-LLP2A-CB-TE2A). Methods: LLP2A-DOTA and LLP2A-CB-TE2A were prepared using solid-phase synthesis; LLP2A-DOTA-PEG2,000, LLP2A-DOTA-PEG5,000, LLP2A-DOTA-PEG10,000, (LLP2A-DOTA)2PEG10,000, and (LLP2A-DOTA)4PEG10,000 were prepared by PEGylation. 111In radiolabeling of DOTA and 64Cu radiolabeling of CB-TE2A conjugates yielded 370–1,850 and 3,700–7,400 kBq/μg (10–50 and 100–200 μCi/μg), respectively. The pharmacokinetics of the six 111In radioconjugates were studied in vivo using biodistribution data (4 and 24 h) and whole-body autoradiography (24 h) in mice with Raji tumor xenografts. 64Cu-LLP2A-CB-TE2A was imaged (4 and 24 h) on a small-animal PET scanner in the same mouse model. Results: The highest tumor uptake in pharmacokinetic studies was obtained with LLP2A-DOTA and (LLP2A-DOTA)4-PEG10,000. For 111In-LLP2A-DOTA (1 nM) at 4 and 24 h after injection, ratios of tumor to blood and tumor to nontumor (normal) organ (T/NT) were 8 to 35:1 for all organs or tissue except the spleen, marrow, and kidney, which were between 2:1 and 1:1. Tetravalent (LLP2A-DOTA)4-PEG10,000 (1.1 nM) had tumor uptake similar to the univalent LLP2A-DOTA but higher liver, marrow, and kidney uptake. The excellent T/NT of LLP2A was also demonstrated by small-animal PET with 64Cu-LLP2A-CB-TE2A at both 4 and 24 h after injection; obvious spleen targeting was apparent, but little kidney or liver activity was observed. Conclusion: Of the conjugates investigated, the univalent, non-PEGylated ligand 111In-LLP2A-DOTA exhibited the best T/NT ratios and showed the greatest potential for imaging of α4β1 in human lymphoma. Furthermore, this univalent non-PEGylated LLP2A format, as 64Cu-LLP2A-CB-TE2A, demonstrated excellent tumor targeting by small-animal PET and warrants further investigation as an agent for the study of α4β1 expression in human lymphoid malignancies.