Table 2.

Structural scaffolds, calculated physicochemical properties (TPSA, clogD₇.₄), and blocking efficiencies of all investigated tetrazine derivatives. Compound 45 displayed a suitable profile to be translated into preclinical studies.

Tetrazine	clogD7.4 b	TPSA c	Blocking Effect f	% Tumor Uptake of [111In]47 after Blocking
1 a	−6.93	129	90 ± 5 g	10 ± 5 g
2 a	−6.83	138	98 ± 0.3 h	2 ± 0.3 h
41 *	3.65	35	22 ± 21	78 ± 21
45 a	−6.36	164	99 ± 0.7	1 ± 0.7
47 d	−4.13 e	358	99 ± 0.5	1 ± 0.5

^a The compounds were obtained as trifluoroacetate salt. ^b Calculated distribution coefficient at physiological pH (7.4) using Chemicalize software. ^c Calculated using Chemicalize software. ^d The compound was employed as a reference. ^e Calculated as chelated to a trivalent cation. ^f The blocking effect of nonradiolabeled Tz was determined as the change in tumor uptake of [¹¹¹In]47 22 h p.i. Each Tz was administered 1 h prior to [¹¹¹In]47, and the uptake was normalized to a group of animals in which no blocking was performed (control). Data represent mean from n = 3 mice/group; detailed information can be found in the Materials and Methods section. ^g Blocking data from [26]. ^h Blocking data from [27]. * Tz 41 was tested to demonstrate that the blocking effect was related to clogD₇.₄ and not the bispyridyl scaffold. TPSA = topological polar surface area.