A 99Tcm-labelled leukotriene B4 receptor antagonist for scintigraphic detection of infection in rabbits

Abstract

In a search for a rapid and accurate imaging agent for scintigraphic detection of infection and inflammation, an LTB4 receptor antagonist, 99Tcm-RP517, which contains the hydrazino nicotinamide moiety, has been developed recently. To study the in vivo behaviour of 99Tcm-RP517, rabbits with Escherichia coli infection were injected intravenously with 99Tcm-RP517. Gamma camera images were obtained and ex vivo bio-distribution was determined at several hours post-injection (p.i.). In a separate set of rabbits the choledochal duct was cannulated to quantitatively monitor the hepatobiliary clearance of the radiopharmaceutical. The receptor binding fraction of the radiolabelled RP517 exceeded 70%. Accumulation of 99Tcm-RP517 in the abscess was visualized as early as 1 h p.i. Due to rapid blood clearance (t1/2 alpha=18+/-0.6 min, t1/2 beta=6.5+/-0.4 h) and high abscess uptake, the abscess-to-muscle ratios increased with time from 7.0+/-2.3 at 1 h p.i. to 44.3+/-4.6 at 20 h p.i. The agent mainly cleared via the hepatobiliary route: 50% of the radiolabel was recovered in the small bowel at 1 h p.i., whereas 85% was found in cecum and sigmoid at 20 h p.i. In conclusion, 99Tcm-RP517 rapidly visualized E. coli abscesses in rabbits. The agent rapidly cleared from the blood, mainly via the hepatobiliary route. High abscess-to-background ratios were achieved. The accumulation in the intestines could limit the applicability of this agent for detecting infectious processes in the abdominal area. The development of a more hydrophilic analogue of 99Tcm-RP517 could improve the clinical applicability of this agent.

6-Hydrazinonicotinamide Derivatives as Bifunctional Coupling Agents for 99mTc-Labeling of Small Biomolecules

“…Therefore, future research should be focused on receptor antagonists as targeting BMs for imaging infection or inflammation. LTB 4 is a product derived from the action of 5-lipoxygenase on arachidonic acid, and is known to stimulate degranulation, aggregation, chemotaxis, and chemokinesis of polymorphonuclear leukocytes, as well as to promote superoxide generation [36][37][38][39]. LTB 4 receptors are highly expressed on a number of inflammatory cells such as neutrophils and lymphocytes.…”

“…Since then, the HYNIC technology has successfully been used for the 99m Tc-labeling of antibodies [3][4][5][6][7][8] and small biomolecules (BMs), including chemotactic peptides [9][10][11][12][13][14][15][16][17][18], somatostatin analogs [19][20][21][22][23][24][25],"stealth" liposomes [26,27], antisense oligonucleotides [28][29][30][31], a folate receptor ligand [32], and polypeptides [32][33][34]. A ternary ligand system (HYNIC, tricine, and trisodium triphenylphosphine-3,3¢,3≤-trisulfonate, TPPTS) has been used for the 99m Tc-labeling of chemotactic peptides [35] and leukotriene B 4 (LTB 4 ) receptor antagonists [36][37][38][39] for imaging infection and inflammation, integrin a v b 3 receptor antagonists for tumor imaging [40], and a glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist for imaging thrombosis [41][42][43][44][45][46]…”

“…A ternary ligand system (HYNIC, tricine, and trisodium triphenylphosphine-3,3¢,3≤-trisulfonate, TPPTS) has been used for the 99m Tc-labeling of chemotactic peptides [35] and leukotriene B 4 (LTB 4 ) receptor antagonists [36][37][38][39] for imaging infection and inflammation, integrin a v b 3 receptor antagonists for tumor imaging [40], and a glycoprotein IIb/IIIa (GPIIb/IIIa) receptor antagonist for imaging thrombosis [41][42][43][44][45][46][47][48]. The advantage of HYNIC is its high labeling efficiency (rapid and high yield radiolabeling) and the high in vivo stability of the resulting complexes [35][36][37][38][39][40][41][42][43][44][45][46][49][50][51][52]. Since HYNIC can only occupy one or two coordination sites, a coligand such as tricine is needed to complete the coordination sphere of technetium.…”

“…Since HYNIC can only occupy one or two coordination sites, a coligand such as tricine is needed to complete the coordination sphere of technetium. The choice of coligands allows easy modification of hydrophilicity and pharmacokinetics of 99m Tc-labeled small BMs [35][36][37][38][39][40][41][42][43][44][45][46][49][50][51][52]]. …”

Assessment of Myocardial Inflammation Produced by Experimental Coronary Occlusion and Reperfusion With 99m Tc-RP517, a New Leukotriene B4 Receptor Antagonist That Preferentially Labels Neutrophils In Vivo

“…After intravenous injection, 99m Tc-RP517 has been shown to localize at sites of inflammation in rabbit models of Escherichia coli-induced and Staphylococcus aureus-induced infection or phorbol ester-induced inflammatory bowel, making this tracer a potential candidate for imaging inflammation. 8 A tracer such as 99m Tc-RP517 might be an important tool for noninvasively assessing the degree of inflammation in several cardiac conditions, such as myocarditis or transplant rejection or in conjunction with reperfusion therapy after myocardial infarction to monitor the extent of myocardial inflammation and potentially assess the effect of antiinflammatory treatments.…”