Investigations Using Albumin Binders to Modify the Tissue Distribution Profile of Radiopharmaceuticals Exemplified with Folate Radioconjugates.

Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-( p -iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-( p -iodophenyl)pentanoate entities (DOTA-ALB-24 and DOTA-ALB-25) without and with a hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker unit, respectively, were synthesized and labeled with lutetium-177 for in vitro and in vivo comparison. Overall, [ 177 Lu]Lu-DOTA-ALB-1 demonstrated ~3-fold stronger in vitro albumin-binding affinity and a longer blood residence time (T 50%IA ~8 h) than [ 177 Lu]Lu-DOTA-ALB-24 (T 50%IA ~0.8 h). Introducing an AMBA linker enhanced the albumin-binding affinity, resulting in a T 50%IA of ~24 h for [ 177 Lu]Lu-DOTA-ALB-3 and ~2 h for [ 177 Lu]Lu-DOTA-ALB-25. The same albumin binders without or with the AMBA linker were incorporated into 6 R - and 6 S -5-methyltetrahydrofolate-based DOTA-conjugates ( 177 Lu-RedFols). Biodistribution studies in mice performed with both diastereoisomers of [ 177 Lu]Lu-RedFol-1 and [ 177 Lu]Lu-RedFol-3, which comprised the 4-( p -iodophenyl)butanoate moiety, demonstrated a slower accumulation in KB tumors than those of [ 177 Lu]Lu-RedFol-24 and [ 177 Lu]Lu-RedFol-25 with the 5-( p -iodophenyl)pentanoate entity. In all cases, the tumor uptake was high (30-45% IA/g) 24 h after injection. Both diastereoisomers of [ 177 Lu]Lu-RedFol-1 and [ 177 Lu]Lu-RedFol-3 demonstrated high blood retention (3.8-8.7% IA/g, 24 h p.i.) and a 2- to 4-fold lower kidney uptake than the corresponding diastereoisomers of [ 177 Lu]Lu-RedFol-24 and [ 177 Lu]Lu-RedFol-25, which were more rapidly cleared from the blood (<0.2% IA/g, 24 h after injection). Kidney retention of the 6 S -diastereoisomers of all 177 Lu-RedFols was consistently higher than that of the respective 6 R -diastereoisomers, irrespective of the albumin binder and linker unit used. It was demonstrated that the blood clearance data obtained with 177 Lu-DOTA-ALBs had predictive value for the blood retention times of the respective folate radioconjugates. The use of these albumin-binding entities without or with an AMBA linker may serve for fine-tuning the blood retention of folate radioconjugates and also other radiopharmaceuticals and, hence, optimize their tissue distribution profiles. Dosimetry estimations based on patient data obtained with one of the most promising folate radioconjugates will be crucial to identify the dose-limiting organ, which will allow for selecting the most suitable folate radioconjugate for therapeutic purposes.