Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

EJNMMI Radiopharmacy and Chemistry

Table 1 PSMA-binding affinities (IC₅₀), internalization (%) and lipophilicity (log D) of the investigated compounds^a

PSMA inhibitor	IC₅₀	%Internalization compared to the reference^b	log D
^natLu/[¹⁷⁷Lu]Lu-1	2.8 ± 0.5 nM	1 h: 177 ± 15	−3.78 ± 0.01
^natGa-2	> 3 μM (n = 2)	n.d.	n.d.
^natGa-3	21.3 ± 1.7 nM	n.d.	n.d.
^natLu/[¹⁷⁷Lu]Lu-3	7.1 ± 0.7 nM	1 h: 67.8 ± 0.5	− 3.40 ± 0.45
^natGa-4	> 1 μM (n = 2)	n.d.	n.d.
^natLu/[¹⁷⁷Lu]Lu-5	26 ± 16 μM	0.5 h: 0.00 ± 0.00 1 h: 0.00 ± 0.00 2 h: 0.17 ± 0.32 4 h: 0.01 ± 0.05	−2.89 ± 0.18
^natLu/[¹⁷⁷Lu]Lu-6	2.5 ± 1.2 μM	0.5 h: 0.00 ± 0.00 1 h: 0.00 ± 0.10 2 h: 0.03 ± 0.03 4 h: 0.01 ± 0.06	−2.52 ± 0.22
^natLu/[¹⁷⁷Lu]Lu-7	6.3 ± 3.6 μM	0.5 h: 0.00 ± 0.00 1 h: 0.00 ± 0.00 2 h: 0.00 ± 0.00 4 h: 0.00 ± 0.00	−2.37 ± 0.22
^natLu-8	> 2 μM (n = 2)	n.d.	n.d.
^natLu-9	> 440 nM (n = 2)	n.d.	n.d.
^natLu/[¹⁷⁷Lu]Lu-10	138 ± 53 nM	1 h: 1.2 ± 0.4	− 2.83 ± 0.08
^natLu/[¹⁷⁷Lu]Lu-11	16.4 ± 3.8 nM	1 h: 9.9 ± 3.2	− 2.91 ± 0.05

^aBinding assays (IC₅₀) were performed using LNCaP cells (150,000 cells/well) and ([¹²⁵I]I-BA)KuE (c = 0.2 nM) as radioligand. Cells were incubated in HBSS (1% BSA) at 4 °C for 1 h. ^bInternalization values were corrected for unspecific binding and normalized to the external reference ([¹²⁵I]I-BA)KuE (13.0 ± 2.5% internalization at 1 h (n = 21), c = 0.2 nM; 1.0 nM for ¹⁷⁷Lu-compounds; 37 °C, 1 h, 125,000 cells/well, PLL-coated plates). Data for binding (IC₅₀) and internalization are expressed as mean ± SD (n = 3) unless otherwise stated. Data are expressed as mean ± SD (n = 6) for log D